Peter Hulick, MD

The past year has seen tremendous media coverage surrounding genetic testing, sparking conversations regarding who should consider genetic testing – and with which genetic test – to determine if they have an increased risk for a particular condition such as cancer ("The Jolie effect on BRCA risks," Internal Medicine News, July 2013, p. 13).

Added to this is the recent Supreme Court ruling that overturned some of Myriad Genetics’ patents on BRCA1 and BRCA2 testing, arguably the best known hereditary cancer genes by patients and physicians ("Keep your patents off my genes!" Internal Medicine News, Oct. 1, 2013, p. 18). Many laboratories have jumped into the cancer testing arena, offering their version of genetic testing panels that examine a variety of genes based on cancer type. Some of these panels test for more than 50 genes related to hereditary cancers – and they go well beyond BRCA1 and BRCA2 testing, using next-generation sequencing (NGS) technology.

The emergence, promise, and application of NSG in cancer genetics have been discussed from numerous angles in this column, but it’s important not to forget chromosomal disorders.

Approximately 1 in 300 live births will carry chromosome abnormalities, and as medical care improves for these conditions, primary care physicians will see more children, such as those with Down syndrome, "graduate" from their pediatricians and require care from primary care physicians. New insight into adult-onset health issues (e.g., early-onset Alzheimer’s disease in Down syndrome) is emerging, but our understanding of the pathology and mechanism of disease remains a challenge. Although animal models exist, it has been a major challenge to recapitulate the effects of having an "extra copy" of an entire chromosome in order to study the biological effects, let alone develop a strategy to silence an entire extra chromosome in order to provide a potential therapy.

Exciting research by Jeanne Lawrence, Ph.D., and her colleagues was presented at the recent American Society of Human Genetics meeting in Boston regarding trisomy 21 (Down syndrome), and it caught my attention despite the onslaught of NSG data presented related to single-gene disorders. By using genome editing, they were able to silence the extra copy of chromosome 21 in Down syndrome pluripotent stem cells by taking advantage of the known genetic processes that silence X chromosomes.

In a normal female cell, there are two copies of the X chromosome; however, only one copy is active, because the other copy is "silenced" through a process called X-inactivation or Lyonization. This is driven by the X-inactivation gene (XIST), which produces a noncoding RNA that covers the entire X chromosome and essentially silences it – making it inactive and condensing it into what is termed a Barr body.

The investigators set out to determine if they could insert a copy of the XIST gene into the extra chromosome 21 – at a very specific location so as not to disrupt any known functional genes – and thereby silence the extra chromosome without affecting other chromosomes. After preliminary success in other cell lines, they attempted this in pluripotent stem cells from a Down syndrome patient, so that differentiation and different tissue subtypes could be studied.

Remarkably, Dr. Lawrence and her colleagues were able to accomplish this integration and overcome two major obstacles: the challenge of working with pluripotent stem cells, and inserting such a large amount of DNA (the XIST gene) via genomic editing. They demonstrated their successful silencing of the extra chromosome 21 through a variety of molecular, cellular, cytological, and genomic assays. Added to the elegance of their work, the strategy they used to insert the XIST gene created an inducible system – meaning they could turn on or off the chromosome 21 silencing based on whether the cells were exposed to doxycycline.

In essence, the investigators created a model to study human chromosome inactivation, which opens the doors to understanding the pathology and molecular pathways involved in chromosome abnormalities such as Down syndrome. This is the potential first step toward developing targeted "chromosomal therapies," something that was not thought to be feasible given the difficulty surrounding gene therapy for single-gene disorders.

While there have been many exciting advances in single-gene disorders and NGS technology, it is refreshing to see exciting research advance in other areas of genetics. I encourage readers to explore this groundbreaking research further.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinician educator at the University of Chicago. He reported having no conflicts of interest.

The past year has seen tremendous media coverage surrounding genetic testing, sparking conversations regarding who should consider genetic testing – and with which genetic test – to determine if they have an increased risk for a particular condition such as cancer ("The Jolie effect on BRCA risks," Internal Medicine News, July 2013, p. 13).

Added to this is the recent Supreme Court ruling that overturned some of Myriad Genetics’ patents on BRCA1 and BRCA2 testing, arguably the best known hereditary cancer genes by patients and physicians ("Keep your patents off my genes!" Internal Medicine News, Oct. 1, 2013, p. 18). Many laboratories have jumped into the cancer testing arena, offering their version of genetic testing panels that examine a variety of genes based on cancer type. Some of these panels test for more than 50 genes related to hereditary cancers – and they go well beyond BRCA1 and BRCA2 testing, using next-generation sequencing (NGS) technology.

The emergence, promise, and application of NSG in cancer genetics have been discussed from numerous angles in this column, but it’s important not to forget chromosomal disorders.

Approximately 1 in 300 live births will carry chromosome abnormalities, and as medical care improves for these conditions, primary care physicians will see more children, such as those with Down syndrome, "graduate" from their pediatricians and require care from primary care physicians. New insight into adult-onset health issues (e.g., early-onset Alzheimer’s disease in Down syndrome) is emerging, but our understanding of the pathology and mechanism of disease remains a challenge. Although animal models exist, it has been a major challenge to recapitulate the effects of having an "extra copy" of an entire chromosome in order to study the biological effects, let alone develop a strategy to silence an entire extra chromosome in order to provide a potential therapy.

Exciting research by Jeanne Lawrence, Ph.D., and her colleagues was presented at the recent American Society of Human Genetics meeting in Boston regarding trisomy 21 (Down syndrome), and it caught my attention despite the onslaught of NSG data presented related to single-gene disorders. By using genome editing, they were able to silence the extra copy of chromosome 21 in Down syndrome pluripotent stem cells by taking advantage of the known genetic processes that silence X chromosomes.

In a normal female cell, there are two copies of the X chromosome; however, only one copy is active, because the other copy is "silenced" through a process called X-inactivation or Lyonization. This is driven by the X-inactivation gene (XIST), which produces a noncoding RNA that covers the entire X chromosome and essentially silences it – making it inactive and condensing it into what is termed a Barr body.

The investigators set out to determine if they could insert a copy of the XIST gene into the extra chromosome 21 – at a very specific location so as not to disrupt any known functional genes – and thereby silence the extra chromosome without affecting other chromosomes. After preliminary success in other cell lines, they attempted this in pluripotent stem cells from a Down syndrome patient, so that differentiation and different tissue subtypes could be studied.

Remarkably, Dr. Lawrence and her colleagues were able to accomplish this integration and overcome two major obstacles: the challenge of working with pluripotent stem cells, and inserting such a large amount of DNA (the XIST gene) via genomic editing. They demonstrated their successful silencing of the extra chromosome 21 through a variety of molecular, cellular, cytological, and genomic assays. Added to the elegance of their work, the strategy they used to insert the XIST gene created an inducible system – meaning they could turn on or off the chromosome 21 silencing based on whether the cells were exposed to doxycycline.

In essence, the investigators created a model to study human chromosome inactivation, which opens the doors to understanding the pathology and molecular pathways involved in chromosome abnormalities such as Down syndrome. This is the potential first step toward developing targeted "chromosomal therapies," something that was not thought to be feasible given the difficulty surrounding gene therapy for single-gene disorders.

While there have been many exciting advances in single-gene disorders and NGS technology, it is refreshing to see exciting research advance in other areas of genetics. I encourage readers to explore this groundbreaking research further.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinician educator at the University of Chicago. He reported having no conflicts of interest.

The past year has seen tremendous media coverage surrounding genetic testing, sparking conversations regarding who should consider genetic testing – and with which genetic test – to determine if they have an increased risk for a particular condition such as cancer ("The Jolie effect on BRCA risks," Internal Medicine News, July 2013, p. 13).

Added to this is the recent Supreme Court ruling that overturned some of Myriad Genetics’ patents on BRCA1 and BRCA2 testing, arguably the best known hereditary cancer genes by patients and physicians ("Keep your patents off my genes!" Internal Medicine News, Oct. 1, 2013, p. 18). Many laboratories have jumped into the cancer testing arena, offering their version of genetic testing panels that examine a variety of genes based on cancer type. Some of these panels test for more than 50 genes related to hereditary cancers – and they go well beyond BRCA1 and BRCA2 testing, using next-generation sequencing (NGS) technology.

The emergence, promise, and application of NSG in cancer genetics have been discussed from numerous angles in this column, but it’s important not to forget chromosomal disorders.

Approximately 1 in 300 live births will carry chromosome abnormalities, and as medical care improves for these conditions, primary care physicians will see more children, such as those with Down syndrome, "graduate" from their pediatricians and require care from primary care physicians. New insight into adult-onset health issues (e.g., early-onset Alzheimer’s disease in Down syndrome) is emerging, but our understanding of the pathology and mechanism of disease remains a challenge. Although animal models exist, it has been a major challenge to recapitulate the effects of having an "extra copy" of an entire chromosome in order to study the biological effects, let alone develop a strategy to silence an entire extra chromosome in order to provide a potential therapy.

Exciting research by Jeanne Lawrence, Ph.D., and her colleagues was presented at the recent American Society of Human Genetics meeting in Boston regarding trisomy 21 (Down syndrome), and it caught my attention despite the onslaught of NSG data presented related to single-gene disorders. By using genome editing, they were able to silence the extra copy of chromosome 21 in Down syndrome pluripotent stem cells by taking advantage of the known genetic processes that silence X chromosomes.

In a normal female cell, there are two copies of the X chromosome; however, only one copy is active, because the other copy is "silenced" through a process called X-inactivation or Lyonization. This is driven by the X-inactivation gene (XIST), which produces a noncoding RNA that covers the entire X chromosome and essentially silences it – making it inactive and condensing it into what is termed a Barr body.

The investigators set out to determine if they could insert a copy of the XIST gene into the extra chromosome 21 – at a very specific location so as not to disrupt any known functional genes – and thereby silence the extra chromosome without affecting other chromosomes. After preliminary success in other cell lines, they attempted this in pluripotent stem cells from a Down syndrome patient, so that differentiation and different tissue subtypes could be studied.

Remarkably, Dr. Lawrence and her colleagues were able to accomplish this integration and overcome two major obstacles: the challenge of working with pluripotent stem cells, and inserting such a large amount of DNA (the XIST gene) via genomic editing. They demonstrated their successful silencing of the extra chromosome 21 through a variety of molecular, cellular, cytological, and genomic assays. Added to the elegance of their work, the strategy they used to insert the XIST gene created an inducible system – meaning they could turn on or off the chromosome 21 silencing based on whether the cells were exposed to doxycycline.

In essence, the investigators created a model to study human chromosome inactivation, which opens the doors to understanding the pathology and molecular pathways involved in chromosome abnormalities such as Down syndrome. This is the potential first step toward developing targeted "chromosomal therapies," something that was not thought to be feasible given the difficulty surrounding gene therapy for single-gene disorders.

While there have been many exciting advances in single-gene disorders and NGS technology, it is refreshing to see exciting research advance in other areas of genetics. I encourage readers to explore this groundbreaking research further.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinician educator at the University of Chicago. He reported having no conflicts of interest.

Angelina Jolie caused a social and public media storm recently when she revealed that she carries a mutation in the BRCA1 gene, thus putting her at heightened risk for developing breast cancer and ovarian cancer. She also disclosed her very personal decision to have preventative bilateral mastectomy, at the age of 37, to reduce her risk of breast cancer, which she was informed was 87%.

Jolie was courageous in sharing this personal decision and bringing the conversation of genetics and one’s health to the forefront. It did spark discussion and debate on genetic testing and how to manage the risk associated with having a BRCA mutation. When a star of Jolie’s status makes such an announcement, it provides an opportunity to help educate patients and discuss their management options. It gives them the chance to decide on a risk reduction strategy that is medically sound and their own personal choice.

My clinic did see an influx of patients calling about having BRCA testing. But what was more interesting were the calls from former patients who had tested positive for a BRCA mutation – they were concerned about the actual level of risk (87%) being quoted by the media’s medical correspondents, many of whom were physicians. They were worried about whether "they are doing enough" to manage their risk, given that they had decided on a different strategy involving high-risk breast cancer screening, which consists of an annual breast MRI, an annual mammogram, a clinical breast exam every 6 months (one with a breast specialist), and a self-exam monthly.

These patients’ reactions raise an important point: Physicians need to have an ongoing conversation about the different options for managing risk – specifically, about screening vs. prevention.

While mastectomy is certainly a medically sound option, high-risk screening is, too, if the protocol is followed. There are additional ways to reduce risk, and the conversation cannot be one-sided in favor of surgery.

Many women who choose the option of high-risk breast cancer screening will opt to take tamoxifen preventively. This can reduce breast cancer risk up to 50% and, when combined with high-risk screening, is a medically sound plan. A similar reduction in breast cancer risk is achieved with prophylactic salpingo-oophorectomy, if performed premenopausally, which is necessary to manage the ovarian cancer risk associated with the BRCA genes.

Finally, making a decision on the right risk-reduction strategy to pursue relies on having an appropriate understanding of risk – so one can understand what "reducing risk by 50%" really means. The 87% breast cancer risk that made the media reports is a very high estimate based on early studies in BRCA families. Most genetics professionals would quote lower lifetime estimates (60%-70%) and use age-adjusted data that are more recent.

For example, Dr. Sining Chen and Dr. Giovanni Parmigiani have provided a nice meta-analysis to estimate BRCA1 and BRCA2 mutation carriers’ risks of developing breast cancer or ovarian cancer, broken down by decade, all the way to age 70 years (J. Clin. Oncol. 2007;25:1329-33).

In Angelina Jolie’s case, her BRCA1-associated risk from age 40 to age 70 is approximately 49%. For comparison, the risk for a BRCA2 carrier from age 40 to age 70 is approximately 38%. Granted, the risk remains elevated (average breast cancer risk is 12% lifetime), and there is risk beyond age 70. But the data provide a more informed perspective on actual risk.

This is key to having patients understand their own risk and the timing of that risk. That understanding can help them make an informed decision regarding their strategy to manage BRCA-related cancer risks.

While Jolie’s decision is sound medically, there are sound alternatives. Choosing the right plan requires an in-depth conversation with our patients to make sure they understand their risk and devise a medically sound plan that is personalized to them.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinician educator at the University of Chicago. He reported having no conflicts of interest.

Angelina Jolie caused a social and public media storm recently when she revealed that she carries a mutation in the BRCA1 gene, thus putting her at heightened risk for developing breast cancer and ovarian cancer. She also disclosed her very personal decision to have preventative bilateral mastectomy, at the age of 37, to reduce her risk of breast cancer, which she was informed was 87%.

Jolie was courageous in sharing this personal decision and bringing the conversation of genetics and one’s health to the forefront. It did spark discussion and debate on genetic testing and how to manage the risk associated with having a BRCA mutation. When a star of Jolie’s status makes such an announcement, it provides an opportunity to help educate patients and discuss their management options. It gives them the chance to decide on a risk reduction strategy that is medically sound and their own personal choice.

My clinic did see an influx of patients calling about having BRCA testing. But what was more interesting were the calls from former patients who had tested positive for a BRCA mutation – they were concerned about the actual level of risk (87%) being quoted by the media’s medical correspondents, many of whom were physicians. They were worried about whether "they are doing enough" to manage their risk, given that they had decided on a different strategy involving high-risk breast cancer screening, which consists of an annual breast MRI, an annual mammogram, a clinical breast exam every 6 months (one with a breast specialist), and a self-exam monthly.

These patients’ reactions raise an important point: Physicians need to have an ongoing conversation about the different options for managing risk – specifically, about screening vs. prevention.

While mastectomy is certainly a medically sound option, high-risk screening is, too, if the protocol is followed. There are additional ways to reduce risk, and the conversation cannot be one-sided in favor of surgery.

Many women who choose the option of high-risk breast cancer screening will opt to take tamoxifen preventively. This can reduce breast cancer risk up to 50% and, when combined with high-risk screening, is a medically sound plan. A similar reduction in breast cancer risk is achieved with prophylactic salpingo-oophorectomy, if performed premenopausally, which is necessary to manage the ovarian cancer risk associated with the BRCA genes.

Finally, making a decision on the right risk-reduction strategy to pursue relies on having an appropriate understanding of risk – so one can understand what "reducing risk by 50%" really means. The 87% breast cancer risk that made the media reports is a very high estimate based on early studies in BRCA families. Most genetics professionals would quote lower lifetime estimates (60%-70%) and use age-adjusted data that are more recent.

For example, Dr. Sining Chen and Dr. Giovanni Parmigiani have provided a nice meta-analysis to estimate BRCA1 and BRCA2 mutation carriers’ risks of developing breast cancer or ovarian cancer, broken down by decade, all the way to age 70 years (J. Clin. Oncol. 2007;25:1329-33).

In Angelina Jolie’s case, her BRCA1-associated risk from age 40 to age 70 is approximately 49%. For comparison, the risk for a BRCA2 carrier from age 40 to age 70 is approximately 38%. Granted, the risk remains elevated (average breast cancer risk is 12% lifetime), and there is risk beyond age 70. But the data provide a more informed perspective on actual risk.

This is key to having patients understand their own risk and the timing of that risk. That understanding can help them make an informed decision regarding their strategy to manage BRCA-related cancer risks.

While Jolie’s decision is sound medically, there are sound alternatives. Choosing the right plan requires an in-depth conversation with our patients to make sure they understand their risk and devise a medically sound plan that is personalized to them.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinician educator at the University of Chicago. He reported having no conflicts of interest.

Angelina Jolie caused a social and public media storm recently when she revealed that she carries a mutation in the BRCA1 gene, thus putting her at heightened risk for developing breast cancer and ovarian cancer. She also disclosed her very personal decision to have preventative bilateral mastectomy, at the age of 37, to reduce her risk of breast cancer, which she was informed was 87%.

Jolie was courageous in sharing this personal decision and bringing the conversation of genetics and one’s health to the forefront. It did spark discussion and debate on genetic testing and how to manage the risk associated with having a BRCA mutation. When a star of Jolie’s status makes such an announcement, it provides an opportunity to help educate patients and discuss their management options. It gives them the chance to decide on a risk reduction strategy that is medically sound and their own personal choice.

My clinic did see an influx of patients calling about having BRCA testing. But what was more interesting were the calls from former patients who had tested positive for a BRCA mutation – they were concerned about the actual level of risk (87%) being quoted by the media’s medical correspondents, many of whom were physicians. They were worried about whether "they are doing enough" to manage their risk, given that they had decided on a different strategy involving high-risk breast cancer screening, which consists of an annual breast MRI, an annual mammogram, a clinical breast exam every 6 months (one with a breast specialist), and a self-exam monthly.

These patients’ reactions raise an important point: Physicians need to have an ongoing conversation about the different options for managing risk – specifically, about screening vs. prevention.

While mastectomy is certainly a medically sound option, high-risk screening is, too, if the protocol is followed. There are additional ways to reduce risk, and the conversation cannot be one-sided in favor of surgery.

Many women who choose the option of high-risk breast cancer screening will opt to take tamoxifen preventively. This can reduce breast cancer risk up to 50% and, when combined with high-risk screening, is a medically sound plan. A similar reduction in breast cancer risk is achieved with prophylactic salpingo-oophorectomy, if performed premenopausally, which is necessary to manage the ovarian cancer risk associated with the BRCA genes.

Finally, making a decision on the right risk-reduction strategy to pursue relies on having an appropriate understanding of risk – so one can understand what "reducing risk by 50%" really means. The 87% breast cancer risk that made the media reports is a very high estimate based on early studies in BRCA families. Most genetics professionals would quote lower lifetime estimates (60%-70%) and use age-adjusted data that are more recent.

For example, Dr. Sining Chen and Dr. Giovanni Parmigiani have provided a nice meta-analysis to estimate BRCA1 and BRCA2 mutation carriers’ risks of developing breast cancer or ovarian cancer, broken down by decade, all the way to age 70 years (J. Clin. Oncol. 2007;25:1329-33).

In Angelina Jolie’s case, her BRCA1-associated risk from age 40 to age 70 is approximately 49%. For comparison, the risk for a BRCA2 carrier from age 40 to age 70 is approximately 38%. Granted, the risk remains elevated (average breast cancer risk is 12% lifetime), and there is risk beyond age 70. But the data provide a more informed perspective on actual risk.

This is key to having patients understand their own risk and the timing of that risk. That understanding can help them make an informed decision regarding their strategy to manage BRCA-related cancer risks.

While Jolie’s decision is sound medically, there are sound alternatives. Choosing the right plan requires an in-depth conversation with our patients to make sure they understand their risk and devise a medically sound plan that is personalized to them.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinician educator at the University of Chicago. He reported having no conflicts of interest.

Prostate cancer screening has been the subject of much debate, given the recent recommendation by the U.S. Preventive Services Task Force against utilizing prostate-specific antigen for screening asymptomatic healthy males. Other organizations, including the American Cancer Society, recommend that men be offered PSA screening after an informed decision of the pros and cons of its use as a screening test.

About one in six men will be diagnosed with prostate cancer during their lifetime. For many, the disease will remain indolent. Identifying men who are at high risk for an aggressive form of the cancer or those who will develop it at an earlier age remains a challenge.

Clearly, we need to improve screening options and our ability to accurately identify patients whose risk for aggressive prostate cancer is high. This seems like an ideal situation for genetics and genomics to help stratify risk and to guide treatment or screening interventions based on an individual’s risk for developing an aggressive tumor.

The identification of high-risk genes for prostate cancer has proved difficult. We do not have highly penetrant and relatively common genes for prostate cancer, similar to, for instance, the BRCA1/2 genes among families at high risk for breast and ovarian cancers. Some discoveries have been achieved, including the identification of a rare mutation in HOXB13. But such discoveries have so far provided answers for only a minority of families and patients (N. Engl. J. Med. 2012;366:141-9).

Given the challenge of identifying single genes that confer a high risk for developing disease, prostate cancer research has focused on detecting weaker genetic markers that in aggregate could potentially help explain why certain men face a higher risk for developing prostate cancer, or a more aggressive subtype of cancer.

Genomewide association studies (GWAS) have been conducted and single nucleotide polymorphisms (SNPs) "panels" have been designed to help predict the risk of prostate cancer. These panels have led to commercial testing that is either physician directed or geared directly to the consumer. Most of the SNPs on these panels have low odds ratios (less than 2.0), so individually, they are not helpful for predicting significant disease risk or the likelihood of having aggressive disease. However, if multiple SNPs are aggregated on a panel and tested, a clinically useful picture could – in theory – be created.

In July, as part of the EGAPP (Evaluation of Genomic Applications in Practice and Prevention) project, the Agency for Healthcare Research and Quality issued a final report on the current evidence of the "validity and utility of using SNP panels in the detection, diagnosis, and clinical management of prostate cancer." The extensive review identified 15 distinct SNP-based prostate cancer risk panels, including those marketed by Proactive Genomics LLC and deCode Genetics.

How well did these SNP panels perform in stratifying future risk or screening for current disease? Screening performance is often reported by generating an ROC (receiver operating characteristic) curve and measuring the AUC (area under the curve). Typically an AUC of at least 75% is necessary for the test to be considered clinically useful. AUCs for a 5-SNP panel ranged from 58% to 73%. The conclusion: There was little incremental gain over non-SNP–based models of prediction, and therefore there was little evidence that they improved risk stratification.

Could the SNP panels discriminate between clinically significant and indolent prostate cancer? Four panels ranging in size from 5 to 35 SNPs were evaluated, and none of the panels was able to reliably distinguish between more- or less-aggressive tumors.

As for prognosis prediction, a 5-SNP panel (with and without inclusion of family history), a 6-SNP panel, and a 16-SNP panel were used to predict mortality in men who had prostate cancer. Follow-up periods ranged from 3.7 to 10 years, depending on the study. Again, there was no evidence that the SNP panels improved the prediction of mortality – and thus prognosis – even when the information gained from the panel was added to models that included conventional prognostic factors (age, PSA, Gleason score, and tumor stage).

Given the limitations of PSA screening for detecting and determining the aggressiveness of prostate cancer, physicians hoping for a better screening tool may be tempted to utilize a genomics-based risk profile test such as an SNP panel. To date, unfortunately, the SNP-based risk models for prostate cancer risk assessment have not helped us to reliably distinguish between aggressive and nonaggressive disease, nor have they identified high-risk patients. Thus, such testing should not be utilized in clinical settings outside of research protocols.

The concept of applying SNP-based panels to assess disease risk is not novel, but we remain in the early stages of understanding how genomics plays a role in risk assessment and disease prognosis. A better understanding of both gene-gene interactions and how these interactions affect risk assessment for patients are paramount in moving such technology forward. Until then, it is premature to use these panels in the clinic.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinical assistant professor at the University of Chicago. He reported having no conflicts of interest.

Prostate cancer screening has been the subject of much debate, given the recent recommendation by the U.S. Preventive Services Task Force against utilizing prostate-specific antigen for screening asymptomatic healthy males. Other organizations, including the American Cancer Society, recommend that men be offered PSA screening after an informed decision of the pros and cons of its use as a screening test.

About one in six men will be diagnosed with prostate cancer during their lifetime. For many, the disease will remain indolent. Identifying men who are at high risk for an aggressive form of the cancer or those who will develop it at an earlier age remains a challenge.

Clearly, we need to improve screening options and our ability to accurately identify patients whose risk for aggressive prostate cancer is high. This seems like an ideal situation for genetics and genomics to help stratify risk and to guide treatment or screening interventions based on an individual’s risk for developing an aggressive tumor.

The identification of high-risk genes for prostate cancer has proved difficult. We do not have highly penetrant and relatively common genes for prostate cancer, similar to, for instance, the BRCA1/2 genes among families at high risk for breast and ovarian cancers. Some discoveries have been achieved, including the identification of a rare mutation in HOXB13. But such discoveries have so far provided answers for only a minority of families and patients (N. Engl. J. Med. 2012;366:141-9).

Given the challenge of identifying single genes that confer a high risk for developing disease, prostate cancer research has focused on detecting weaker genetic markers that in aggregate could potentially help explain why certain men face a higher risk for developing prostate cancer, or a more aggressive subtype of cancer.

Genomewide association studies (GWAS) have been conducted and single nucleotide polymorphisms (SNPs) "panels" have been designed to help predict the risk of prostate cancer. These panels have led to commercial testing that is either physician directed or geared directly to the consumer. Most of the SNPs on these panels have low odds ratios (less than 2.0), so individually, they are not helpful for predicting significant disease risk or the likelihood of having aggressive disease. However, if multiple SNPs are aggregated on a panel and tested, a clinically useful picture could – in theory – be created.

In July, as part of the EGAPP (Evaluation of Genomic Applications in Practice and Prevention) project, the Agency for Healthcare Research and Quality issued a final report on the current evidence of the "validity and utility of using SNP panels in the detection, diagnosis, and clinical management of prostate cancer." The extensive review identified 15 distinct SNP-based prostate cancer risk panels, including those marketed by Proactive Genomics LLC and deCode Genetics.

How well did these SNP panels perform in stratifying future risk or screening for current disease? Screening performance is often reported by generating an ROC (receiver operating characteristic) curve and measuring the AUC (area under the curve). Typically an AUC of at least 75% is necessary for the test to be considered clinically useful. AUCs for a 5-SNP panel ranged from 58% to 73%. The conclusion: There was little incremental gain over non-SNP–based models of prediction, and therefore there was little evidence that they improved risk stratification.

Could the SNP panels discriminate between clinically significant and indolent prostate cancer? Four panels ranging in size from 5 to 35 SNPs were evaluated, and none of the panels was able to reliably distinguish between more- or less-aggressive tumors.

As for prognosis prediction, a 5-SNP panel (with and without inclusion of family history), a 6-SNP panel, and a 16-SNP panel were used to predict mortality in men who had prostate cancer. Follow-up periods ranged from 3.7 to 10 years, depending on the study. Again, there was no evidence that the SNP panels improved the prediction of mortality – and thus prognosis – even when the information gained from the panel was added to models that included conventional prognostic factors (age, PSA, Gleason score, and tumor stage).

Given the limitations of PSA screening for detecting and determining the aggressiveness of prostate cancer, physicians hoping for a better screening tool may be tempted to utilize a genomics-based risk profile test such as an SNP panel. To date, unfortunately, the SNP-based risk models for prostate cancer risk assessment have not helped us to reliably distinguish between aggressive and nonaggressive disease, nor have they identified high-risk patients. Thus, such testing should not be utilized in clinical settings outside of research protocols.

The concept of applying SNP-based panels to assess disease risk is not novel, but we remain in the early stages of understanding how genomics plays a role in risk assessment and disease prognosis. A better understanding of both gene-gene interactions and how these interactions affect risk assessment for patients are paramount in moving such technology forward. Until then, it is premature to use these panels in the clinic.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinical assistant professor at the University of Chicago. He reported having no conflicts of interest.

Prostate cancer screening has been the subject of much debate, given the recent recommendation by the U.S. Preventive Services Task Force against utilizing prostate-specific antigen for screening asymptomatic healthy males. Other organizations, including the American Cancer Society, recommend that men be offered PSA screening after an informed decision of the pros and cons of its use as a screening test.

About one in six men will be diagnosed with prostate cancer during their lifetime. For many, the disease will remain indolent. Identifying men who are at high risk for an aggressive form of the cancer or those who will develop it at an earlier age remains a challenge.

Clearly, we need to improve screening options and our ability to accurately identify patients whose risk for aggressive prostate cancer is high. This seems like an ideal situation for genetics and genomics to help stratify risk and to guide treatment or screening interventions based on an individual’s risk for developing an aggressive tumor.

The identification of high-risk genes for prostate cancer has proved difficult. We do not have highly penetrant and relatively common genes for prostate cancer, similar to, for instance, the BRCA1/2 genes among families at high risk for breast and ovarian cancers. Some discoveries have been achieved, including the identification of a rare mutation in HOXB13. But such discoveries have so far provided answers for only a minority of families and patients (N. Engl. J. Med. 2012;366:141-9).

Given the challenge of identifying single genes that confer a high risk for developing disease, prostate cancer research has focused on detecting weaker genetic markers that in aggregate could potentially help explain why certain men face a higher risk for developing prostate cancer, or a more aggressive subtype of cancer.

Genomewide association studies (GWAS) have been conducted and single nucleotide polymorphisms (SNPs) "panels" have been designed to help predict the risk of prostate cancer. These panels have led to commercial testing that is either physician directed or geared directly to the consumer. Most of the SNPs on these panels have low odds ratios (less than 2.0), so individually, they are not helpful for predicting significant disease risk or the likelihood of having aggressive disease. However, if multiple SNPs are aggregated on a panel and tested, a clinically useful picture could – in theory – be created.

In July, as part of the EGAPP (Evaluation of Genomic Applications in Practice and Prevention) project, the Agency for Healthcare Research and Quality issued a final report on the current evidence of the "validity and utility of using SNP panels in the detection, diagnosis, and clinical management of prostate cancer." The extensive review identified 15 distinct SNP-based prostate cancer risk panels, including those marketed by Proactive Genomics LLC and deCode Genetics.

How well did these SNP panels perform in stratifying future risk or screening for current disease? Screening performance is often reported by generating an ROC (receiver operating characteristic) curve and measuring the AUC (area under the curve). Typically an AUC of at least 75% is necessary for the test to be considered clinically useful. AUCs for a 5-SNP panel ranged from 58% to 73%. The conclusion: There was little incremental gain over non-SNP–based models of prediction, and therefore there was little evidence that they improved risk stratification.

Could the SNP panels discriminate between clinically significant and indolent prostate cancer? Four panels ranging in size from 5 to 35 SNPs were evaluated, and none of the panels was able to reliably distinguish between more- or less-aggressive tumors.

As for prognosis prediction, a 5-SNP panel (with and without inclusion of family history), a 6-SNP panel, and a 16-SNP panel were used to predict mortality in men who had prostate cancer. Follow-up periods ranged from 3.7 to 10 years, depending on the study. Again, there was no evidence that the SNP panels improved the prediction of mortality – and thus prognosis – even when the information gained from the panel was added to models that included conventional prognostic factors (age, PSA, Gleason score, and tumor stage).

Given the limitations of PSA screening for detecting and determining the aggressiveness of prostate cancer, physicians hoping for a better screening tool may be tempted to utilize a genomics-based risk profile test such as an SNP panel. To date, unfortunately, the SNP-based risk models for prostate cancer risk assessment have not helped us to reliably distinguish between aggressive and nonaggressive disease, nor have they identified high-risk patients. Thus, such testing should not be utilized in clinical settings outside of research protocols.

The concept of applying SNP-based panels to assess disease risk is not novel, but we remain in the early stages of understanding how genomics plays a role in risk assessment and disease prognosis. A better understanding of both gene-gene interactions and how these interactions affect risk assessment for patients are paramount in moving such technology forward. Until then, it is premature to use these panels in the clinic.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinical assistant professor at the University of Chicago. He reported having no conflicts of interest.

Approximately 12% of women will develop breast cancer over the course of their lifetimes with more than 200,000 expected to be newly diagnosed in 2010. Given the prevalence of breast cancer in the general population, identifying those patients who likely represent a sporadic occurrence vs. those with a significant inherited or genetic component poses a significant challenge for the busy primary care physician.

Many aspects in medicine require the recognition of patterns, whether they relate to symptoms and physical exam findings, or in the setting of genetics, patterns of disease within the family history and then following through on one’s differential diagnosis by ordering confirmatory testing. The specialty of medical genetics is rooted in recognizing patterns and only recently has there been an explosion in molecular data available to assist in establishing a diagnosis and better categorizing a patient’s genetic risk for disease.

Individually, highly penetrant Mendelian inherited single genes that increase risk for breast cancer (for example, BRCA1, BRCA2, PTEN and TP53) might seem rare, but collectively they are involved in 5%-10% of breast cancers. Identifying the hereditary factors can affect the patient’s management and naturally has implications for family members. The lifetime risk for developing breast cancer is 25%-80% depending on the affected gene. This is substantially higher than the general population’s risk.

Identifying patients who should be counseled on potential genetic risk is critical and relies on recognizing “warning signs” and specific patterns. One’s suspicion should increase if breast cancer is diagnosed in two or more close relatives at an early age, if there are multiple or bilateral primary tumors, and if there is evidence of autosomal dominant transmission (multiple generations affected).

Certain patient populations might have a higher baseline risk for harboring a mutation – so called “founder mutations.” For example on average, a woman diagnosed with breast cancer has a 5% chance of harboring a BRCA1 or BRCA2. This chance is modified based on the age of the patient at the time of diagnosis. For a woman diagnosed by 45 years of age, the risk increases to 10%. If she is older than 45 years, the risk decreases to 2%. If the woman is of Ashkenazi Jewish ancestry (which has a carrier rate for a BRCA1/2 mutations of 1:40) and is diagnosed with breast cancer, her baseline risk for detecting a mutation is 10%. If the breast cancer occurred by age 45 years, her risk of having a mutation increases to 25%. These numbers can be further modified based on family structure and history and provide a quick benchmark for assessing risk during a primary care visit.

The combination of cancers in a family also contributes to the risk assessment. Proper assessment requires a three-generation family history, which is time intensive in a busy medical practice. Fortunately, there are online tools such as My Family Health Portrait that patients can utilize prior to their visit.

Combinations of cancers in a family history can serve as warning sign that further investigation into the family history is warranted. For example, breast cancer is the most common cancer in females with Li-Fraumeni syndrome, which is caused by a mutation in TP53. Early diagnosis of breast cancer in the setting of a family or personal history of childhood leukemia, sarcoma, or brain tumor should raise suspicion.

Our “recognized” patterns continue to evolve. Most physicians recognize the association of BRCA1 and BRCA2 mutations with breast and ovarian cancer, but there is more to the pattern. For example, males with BRCA1/2 mutations have a higher risk for prostate cancer (30-40% lifetime risk), which can occur at an earlier age and is often more aggressive. Pancreatic cancer also is included in the spectrum of BRCA1/2–associated tumors. In fact, BRCA2 mutations have been identified in 5%-7% of unselected pancreatic cancer patients. Recognizing these associations is not only paramount to identifying future cancer risk, it may also open the door to novel therapeutics (PARP inhibitors) that impair the ability of BRCA-related tumors to repair DNA damage.

The reality is that we often are confronted with a family history in which several members are affected with breast cancer, but a specific genetic cause cannot be identified. Intuitively, we think there must be a “genetic component,” however assessing the magnitude of risk represents a challenge. An estimated 20% of breast cancer occurs in such familial clusters and it is important to recognize these families, as there are implications for breast cancer screening recommendations.

In families that exhibit a clustering of breast cancer, women who are unaffected may meet recently established criteria by the American Cancer Society (ACS) to have breast MRI as an adjunct to routine mammography as part of their annual screening regimen. If a woman’s lifetime risk for developing breast cancer surpasses 20%-25%, the addition of MRI screening should be considered as per the ACS guideline. This risk estimate is calculated using models that are dependent on family history in addition to personal risk factors. Common examples include BRCAPRO and the Tyrer-Cuzick models that are used by many high-risk cancer assessment/genetics clinics. The Gail model is another popular model. While it is limited in assessing the family history, it has a prominent role in predicting a woman’s 5-year risk of developing breast cancer and in determining whether she may benefit taking tamoxifen for the prevention of breast cancer.

Time constraints on primary care physicians can be a significant barrier to obtaining an adequate family history for assessing risk. By having a patient complete the family history via online tools and remembering some key associations, we can better assess for genetic risk and, ultimately, improve the care we provide to our patients.

Following are the combination of cancers that might suggest recommending a risk assessment:

BRCA1/2

Breast, ovarian, pancreatic, stomach, and prostate cancer

CDH1

Lobular breast and diffuse gastric cancer

PTEN

Thyroid and endometrial cancer

TP53

Sarcoma, childhood leukemia/lymphoma, brain cancer

STK11

Colorectal (Peutz-Jeghers–type hamartomatous polyps), gastric, pancreatic, breast, and ovarian cancers

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinical assistant professor at the University of Chicago Pritzker School of Medicine.

Approximately 12% of women will develop breast cancer over the course of their lifetimes with more than 200,000 expected to be newly diagnosed in 2010. Given the prevalence of breast cancer in the general population, identifying those patients who likely represent a sporadic occurrence vs. those with a significant inherited or genetic component poses a significant challenge for the busy primary care physician.

Many aspects in medicine require the recognition of patterns, whether they relate to symptoms and physical exam findings, or in the setting of genetics, patterns of disease within the family history and then following through on one’s differential diagnosis by ordering confirmatory testing. The specialty of medical genetics is rooted in recognizing patterns and only recently has there been an explosion in molecular data available to assist in establishing a diagnosis and better categorizing a patient’s genetic risk for disease.

Individually, highly penetrant Mendelian inherited single genes that increase risk for breast cancer (for example, BRCA1, BRCA2, PTEN and TP53) might seem rare, but collectively they are involved in 5%-10% of breast cancers. Identifying the hereditary factors can affect the patient’s management and naturally has implications for family members. The lifetime risk for developing breast cancer is 25%-80% depending on the affected gene. This is substantially higher than the general population’s risk.

Identifying patients who should be counseled on potential genetic risk is critical and relies on recognizing “warning signs” and specific patterns. One’s suspicion should increase if breast cancer is diagnosed in two or more close relatives at an early age, if there are multiple or bilateral primary tumors, and if there is evidence of autosomal dominant transmission (multiple generations affected).

Certain patient populations might have a higher baseline risk for harboring a mutation – so called “founder mutations.” For example on average, a woman diagnosed with breast cancer has a 5% chance of harboring a BRCA1 or BRCA2. This chance is modified based on the age of the patient at the time of diagnosis. For a woman diagnosed by 45 years of age, the risk increases to 10%. If she is older than 45 years, the risk decreases to 2%. If the woman is of Ashkenazi Jewish ancestry (which has a carrier rate for a BRCA1/2 mutations of 1:40) and is diagnosed with breast cancer, her baseline risk for detecting a mutation is 10%. If the breast cancer occurred by age 45 years, her risk of having a mutation increases to 25%. These numbers can be further modified based on family structure and history and provide a quick benchmark for assessing risk during a primary care visit.

The combination of cancers in a family also contributes to the risk assessment. Proper assessment requires a three-generation family history, which is time intensive in a busy medical practice. Fortunately, there are online tools such as My Family Health Portrait that patients can utilize prior to their visit.

Combinations of cancers in a family history can serve as warning sign that further investigation into the family history is warranted. For example, breast cancer is the most common cancer in females with Li-Fraumeni syndrome, which is caused by a mutation in TP53. Early diagnosis of breast cancer in the setting of a family or personal history of childhood leukemia, sarcoma, or brain tumor should raise suspicion.

Our “recognized” patterns continue to evolve. Most physicians recognize the association of BRCA1 and BRCA2 mutations with breast and ovarian cancer, but there is more to the pattern. For example, males with BRCA1/2 mutations have a higher risk for prostate cancer (30-40% lifetime risk), which can occur at an earlier age and is often more aggressive. Pancreatic cancer also is included in the spectrum of BRCA1/2–associated tumors. In fact, BRCA2 mutations have been identified in 5%-7% of unselected pancreatic cancer patients. Recognizing these associations is not only paramount to identifying future cancer risk, it may also open the door to novel therapeutics (PARP inhibitors) that impair the ability of BRCA-related tumors to repair DNA damage.

The reality is that we often are confronted with a family history in which several members are affected with breast cancer, but a specific genetic cause cannot be identified. Intuitively, we think there must be a “genetic component,” however assessing the magnitude of risk represents a challenge. An estimated 20% of breast cancer occurs in such familial clusters and it is important to recognize these families, as there are implications for breast cancer screening recommendations.

In families that exhibit a clustering of breast cancer, women who are unaffected may meet recently established criteria by the American Cancer Society (ACS) to have breast MRI as an adjunct to routine mammography as part of their annual screening regimen. If a woman’s lifetime risk for developing breast cancer surpasses 20%-25%, the addition of MRI screening should be considered as per the ACS guideline. This risk estimate is calculated using models that are dependent on family history in addition to personal risk factors. Common examples include BRCAPRO and the Tyrer-Cuzick models that are used by many high-risk cancer assessment/genetics clinics. The Gail model is another popular model. While it is limited in assessing the family history, it has a prominent role in predicting a woman’s 5-year risk of developing breast cancer and in determining whether she may benefit taking tamoxifen for the prevention of breast cancer.

Time constraints on primary care physicians can be a significant barrier to obtaining an adequate family history for assessing risk. By having a patient complete the family history via online tools and remembering some key associations, we can better assess for genetic risk and, ultimately, improve the care we provide to our patients.

Following are the combination of cancers that might suggest recommending a risk assessment:

BRCA1/2

Breast, ovarian, pancreatic, stomach, and prostate cancer

CDH1

Lobular breast and diffuse gastric cancer

PTEN

Thyroid and endometrial cancer

TP53

Sarcoma, childhood leukemia/lymphoma, brain cancer

STK11

Colorectal (Peutz-Jeghers–type hamartomatous polyps), gastric, pancreatic, breast, and ovarian cancers

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinical assistant professor at the University of Chicago Pritzker School of Medicine.

Approximately 12% of women will develop breast cancer over the course of their lifetimes with more than 200,000 expected to be newly diagnosed in 2010. Given the prevalence of breast cancer in the general population, identifying those patients who likely represent a sporadic occurrence vs. those with a significant inherited or genetic component poses a significant challenge for the busy primary care physician.

Many aspects in medicine require the recognition of patterns, whether they relate to symptoms and physical exam findings, or in the setting of genetics, patterns of disease within the family history and then following through on one’s differential diagnosis by ordering confirmatory testing. The specialty of medical genetics is rooted in recognizing patterns and only recently has there been an explosion in molecular data available to assist in establishing a diagnosis and better categorizing a patient’s genetic risk for disease.

Individually, highly penetrant Mendelian inherited single genes that increase risk for breast cancer (for example, BRCA1, BRCA2, PTEN and TP53) might seem rare, but collectively they are involved in 5%-10% of breast cancers. Identifying the hereditary factors can affect the patient’s management and naturally has implications for family members. The lifetime risk for developing breast cancer is 25%-80% depending on the affected gene. This is substantially higher than the general population’s risk.

Identifying patients who should be counseled on potential genetic risk is critical and relies on recognizing “warning signs” and specific patterns. One’s suspicion should increase if breast cancer is diagnosed in two or more close relatives at an early age, if there are multiple or bilateral primary tumors, and if there is evidence of autosomal dominant transmission (multiple generations affected).

Certain patient populations might have a higher baseline risk for harboring a mutation – so called “founder mutations.” For example on average, a woman diagnosed with breast cancer has a 5% chance of harboring a BRCA1 or BRCA2. This chance is modified based on the age of the patient at the time of diagnosis. For a woman diagnosed by 45 years of age, the risk increases to 10%. If she is older than 45 years, the risk decreases to 2%. If the woman is of Ashkenazi Jewish ancestry (which has a carrier rate for a BRCA1/2 mutations of 1:40) and is diagnosed with breast cancer, her baseline risk for detecting a mutation is 10%. If the breast cancer occurred by age 45 years, her risk of having a mutation increases to 25%. These numbers can be further modified based on family structure and history and provide a quick benchmark for assessing risk during a primary care visit.

The combination of cancers in a family also contributes to the risk assessment. Proper assessment requires a three-generation family history, which is time intensive in a busy medical practice. Fortunately, there are online tools such as My Family Health Portrait that patients can utilize prior to their visit.

Combinations of cancers in a family history can serve as warning sign that further investigation into the family history is warranted. For example, breast cancer is the most common cancer in females with Li-Fraumeni syndrome, which is caused by a mutation in TP53. Early diagnosis of breast cancer in the setting of a family or personal history of childhood leukemia, sarcoma, or brain tumor should raise suspicion.

Our “recognized” patterns continue to evolve. Most physicians recognize the association of BRCA1 and BRCA2 mutations with breast and ovarian cancer, but there is more to the pattern. For example, males with BRCA1/2 mutations have a higher risk for prostate cancer (30-40% lifetime risk), which can occur at an earlier age and is often more aggressive. Pancreatic cancer also is included in the spectrum of BRCA1/2–associated tumors. In fact, BRCA2 mutations have been identified in 5%-7% of unselected pancreatic cancer patients. Recognizing these associations is not only paramount to identifying future cancer risk, it may also open the door to novel therapeutics (PARP inhibitors) that impair the ability of BRCA-related tumors to repair DNA damage.

The reality is that we often are confronted with a family history in which several members are affected with breast cancer, but a specific genetic cause cannot be identified. Intuitively, we think there must be a “genetic component,” however assessing the magnitude of risk represents a challenge. An estimated 20% of breast cancer occurs in such familial clusters and it is important to recognize these families, as there are implications for breast cancer screening recommendations.

In families that exhibit a clustering of breast cancer, women who are unaffected may meet recently established criteria by the American Cancer Society (ACS) to have breast MRI as an adjunct to routine mammography as part of their annual screening regimen. If a woman’s lifetime risk for developing breast cancer surpasses 20%-25%, the addition of MRI screening should be considered as per the ACS guideline. This risk estimate is calculated using models that are dependent on family history in addition to personal risk factors. Common examples include BRCAPRO and the Tyrer-Cuzick models that are used by many high-risk cancer assessment/genetics clinics. The Gail model is another popular model. While it is limited in assessing the family history, it has a prominent role in predicting a woman’s 5-year risk of developing breast cancer and in determining whether she may benefit taking tamoxifen for the prevention of breast cancer.

Time constraints on primary care physicians can be a significant barrier to obtaining an adequate family history for assessing risk. By having a patient complete the family history via online tools and remembering some key associations, we can better assess for genetic risk and, ultimately, improve the care we provide to our patients.

Following are the combination of cancers that might suggest recommending a risk assessment:

BRCA1/2

Breast, ovarian, pancreatic, stomach, and prostate cancer

CDH1

Lobular breast and diffuse gastric cancer

PTEN

Thyroid and endometrial cancer

TP53

Sarcoma, childhood leukemia/lymphoma, brain cancer

STK11

Colorectal (Peutz-Jeghers–type hamartomatous polyps), gastric, pancreatic, breast, and ovarian cancers

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinical assistant professor at the University of Chicago Pritzker School of Medicine.