Gellad Z

Background: High lifetime counts of pre-cancerous polyps, termed “adenomas,” are associated with increased risk for colorectal cancer (CRC). Given that a genetic predisposition to adenomas may increase susceptibility to CRC, further studies are needed to characterize low-penetrance germline factors in those with increased cumulative adenoma counts.

Purpose: To investigate if known CRC or adenomarisk single nucleotide polymorphisms (SNPs) are associated with increasing cumulative adenoma counts in a prospective screening cohort of veterans.

Data Analysis: The CSP #380 screening colonoscopy cohort includes a biorepository of selected individuals with baseline advanced neoplasia and matched individuals without neoplasia (n=612). Blood samples were genotyped using the Illumina Infinium Omni2.5-8 GWAS chip and associated cumulative adenoma counts were summed over 10 years. A corrected Poisson regression (adjusted for age at last colonoscopy, gender, and race) was used to evaluate associations between higher cumulative adenoma counts and 43 pre-specified CRC-risk SNPs or a subset of these SNPs shown also to be associated with adenomas in published literature. SNPs were evaluated singly or combined in a Genetic Risk Score (GRS). The GRS was constructed from only the eight adenomarisk SNPs and calculated based on the total number of present risk alleles (0-2) summed across all SNPs per individual (both weighted for published effect size and unweighted).

Results: Four CRC-risk SNPs were associated with increasing mean adenoma counts (P<0.05): rs12241008 (gene: VTI1A), rs2423279 (BMP2/HAO1), rs3184504 (SH2B3), and rs961253 (FERMT1/BMP2), with risk allele risk ratios (RR) of 1.31, 1.29, 1.24, and 1.23, respectively. Only one known adenoma-risk SNP was significant in our dataset (rs961253; OR 1.23 per risk allele; P=0.01). An increasing weighted GRS was associated with increased cumulative adenoma counts (weighted RR 1.58, P=0.03; unweighted RR 1.03, P=0.39).

Implications: In this CRC screening cohort, four known CRC-risk SNPs were found to be associated with increasing cumulative adenoma counts. Additionally, an increasing burden of adenoma-risk SNPs, as measured by a weighted GRS, was associated with higher cumulative adenoma counts. Future work will evaluate predictive tools based on a precancerous, adenoma GRS to better risk stratify patients during CRC screening, and compare to current CRC genetic risk scores.

Background: High lifetime counts of pre-cancerous polyps, termed “adenomas,” are associated with increased risk for colorectal cancer (CRC). Given that a genetic predisposition to adenomas may increase susceptibility to CRC, further studies are needed to characterize low-penetrance germline factors in those with increased cumulative adenoma counts.

Purpose: To investigate if known CRC or adenomarisk single nucleotide polymorphisms (SNPs) are associated with increasing cumulative adenoma counts in a prospective screening cohort of veterans.

Data Analysis: The CSP #380 screening colonoscopy cohort includes a biorepository of selected individuals with baseline advanced neoplasia and matched individuals without neoplasia (n=612). Blood samples were genotyped using the Illumina Infinium Omni2.5-8 GWAS chip and associated cumulative adenoma counts were summed over 10 years. A corrected Poisson regression (adjusted for age at last colonoscopy, gender, and race) was used to evaluate associations between higher cumulative adenoma counts and 43 pre-specified CRC-risk SNPs or a subset of these SNPs shown also to be associated with adenomas in published literature. SNPs were evaluated singly or combined in a Genetic Risk Score (GRS). The GRS was constructed from only the eight adenomarisk SNPs and calculated based on the total number of present risk alleles (0-2) summed across all SNPs per individual (both weighted for published effect size and unweighted).

Results: Four CRC-risk SNPs were associated with increasing mean adenoma counts (P<0.05): rs12241008 (gene: VTI1A), rs2423279 (BMP2/HAO1), rs3184504 (SH2B3), and rs961253 (FERMT1/BMP2), with risk allele risk ratios (RR) of 1.31, 1.29, 1.24, and 1.23, respectively. Only one known adenoma-risk SNP was significant in our dataset (rs961253; OR 1.23 per risk allele; P=0.01). An increasing weighted GRS was associated with increased cumulative adenoma counts (weighted RR 1.58, P=0.03; unweighted RR 1.03, P=0.39).

Implications: In this CRC screening cohort, four known CRC-risk SNPs were found to be associated with increasing cumulative adenoma counts. Additionally, an increasing burden of adenoma-risk SNPs, as measured by a weighted GRS, was associated with higher cumulative adenoma counts. Future work will evaluate predictive tools based on a precancerous, adenoma GRS to better risk stratify patients during CRC screening, and compare to current CRC genetic risk scores.

Background: High lifetime counts of pre-cancerous polyps, termed “adenomas,” are associated with increased risk for colorectal cancer (CRC). Given that a genetic predisposition to adenomas may increase susceptibility to CRC, further studies are needed to characterize low-penetrance germline factors in those with increased cumulative adenoma counts.

Purpose: To investigate if known CRC or adenomarisk single nucleotide polymorphisms (SNPs) are associated with increasing cumulative adenoma counts in a prospective screening cohort of veterans.

Data Analysis: The CSP #380 screening colonoscopy cohort includes a biorepository of selected individuals with baseline advanced neoplasia and matched individuals without neoplasia (n=612). Blood samples were genotyped using the Illumina Infinium Omni2.5-8 GWAS chip and associated cumulative adenoma counts were summed over 10 years. A corrected Poisson regression (adjusted for age at last colonoscopy, gender, and race) was used to evaluate associations between higher cumulative adenoma counts and 43 pre-specified CRC-risk SNPs or a subset of these SNPs shown also to be associated with adenomas in published literature. SNPs were evaluated singly or combined in a Genetic Risk Score (GRS). The GRS was constructed from only the eight adenomarisk SNPs and calculated based on the total number of present risk alleles (0-2) summed across all SNPs per individual (both weighted for published effect size and unweighted).

Results: Four CRC-risk SNPs were associated with increasing mean adenoma counts (P<0.05): rs12241008 (gene: VTI1A), rs2423279 (BMP2/HAO1), rs3184504 (SH2B3), and rs961253 (FERMT1/BMP2), with risk allele risk ratios (RR) of 1.31, 1.29, 1.24, and 1.23, respectively. Only one known adenoma-risk SNP was significant in our dataset (rs961253; OR 1.23 per risk allele; P=0.01). An increasing weighted GRS was associated with increased cumulative adenoma counts (weighted RR 1.58, P=0.03; unweighted RR 1.03, P=0.39).

Implications: In this CRC screening cohort, four known CRC-risk SNPs were found to be associated with increasing cumulative adenoma counts. Additionally, an increasing burden of adenoma-risk SNPs, as measured by a weighted GRS, was associated with higher cumulative adenoma counts. Future work will evaluate predictive tools based on a precancerous, adenoma GRS to better risk stratify patients during CRC screening, and compare to current CRC genetic risk scores.

Background: Colorectal cancer (CRC) surveillance guidelines suggest that timing of a 3rd colonoscopy should be based on results of two prior exams. However, data are limited on whether baseline screening colonoscopy can inform the risk of advanced neoplasia (AN) at 3rd exam.

Methods: This study describes the risk of AN at 3rd colonoscopy stratified by findings on two previous exams in a prospective screening cohort and compares this risk over time from a negative 2nd exam between those with differing 1st exam findings.

The CSP #380 cohort included 3,121 Veterans aged 50-75 years who underwent screening colonoscopy from 1994-1997 and were followed for at least 10 years. Exclusion criteria included not having three colonoscopies more than one year apart, or having CRC at 1st or 2nd exam. The primary outcome was the proportion of AN at 3rd exam. Findings at 1st and 2nd exam were classified as high-risk adenoma (HRA), low-risk adenoma (LRA), or no adenoma. Chi-square tests compared proportions of AN on the 3rd exam between those with different baseline screening results but similar 2nd exam findings.

Results: This analysis included 891 participants: 58 (6.5%) had AN at 3rd exam. The proportion of AN at 3rd exam ranged from 3.2% to 21.4% when stratified by results of two previous exams. In participants with HRA or LRA on the 2nd exam, baseline screening colonoscopy was not associated with risk of AN at 3rd exam. However, for participants with no adenomas on the 2nd exam, baseline screening colonoscopy was associated with risk of AN at 3rd exam (P =.04). Furthermore, all AN was identified within about 5 years of the negative 2nd exam in those with HRA on the 1st exam.

Conclusions: Results of the 1st exam remain a risk factor for AN at 3rd exam in those with no adenomas at 2nd exam. This supports current guidelines which recommend a shortened surveillance interval in those with no adenomas at 2nd exam but HRA at 1st. Future work will combine CRC risk factors with genomic risk and colonoscopy outcomes over time to better identify individuals who might benefit from continued surveillance and to help inform appropriate surveillance intervals.

Background: Colorectal cancer (CRC) surveillance guidelines suggest that timing of a 3rd colonoscopy should be based on results of two prior exams. However, data are limited on whether baseline screening colonoscopy can inform the risk of advanced neoplasia (AN) at 3rd exam.

Methods: This study describes the risk of AN at 3rd colonoscopy stratified by findings on two previous exams in a prospective screening cohort and compares this risk over time from a negative 2nd exam between those with differing 1st exam findings.

The CSP #380 cohort included 3,121 Veterans aged 50-75 years who underwent screening colonoscopy from 1994-1997 and were followed for at least 10 years. Exclusion criteria included not having three colonoscopies more than one year apart, or having CRC at 1st or 2nd exam. The primary outcome was the proportion of AN at 3rd exam. Findings at 1st and 2nd exam were classified as high-risk adenoma (HRA), low-risk adenoma (LRA), or no adenoma. Chi-square tests compared proportions of AN on the 3rd exam between those with different baseline screening results but similar 2nd exam findings.

Results: This analysis included 891 participants: 58 (6.5%) had AN at 3rd exam. The proportion of AN at 3rd exam ranged from 3.2% to 21.4% when stratified by results of two previous exams. In participants with HRA or LRA on the 2nd exam, baseline screening colonoscopy was not associated with risk of AN at 3rd exam. However, for participants with no adenomas on the 2nd exam, baseline screening colonoscopy was associated with risk of AN at 3rd exam (P =.04). Furthermore, all AN was identified within about 5 years of the negative 2nd exam in those with HRA on the 1st exam.

Conclusions: Results of the 1st exam remain a risk factor for AN at 3rd exam in those with no adenomas at 2nd exam. This supports current guidelines which recommend a shortened surveillance interval in those with no adenomas at 2nd exam but HRA at 1st. Future work will combine CRC risk factors with genomic risk and colonoscopy outcomes over time to better identify individuals who might benefit from continued surveillance and to help inform appropriate surveillance intervals.

Background: Colorectal cancer (CRC) surveillance guidelines suggest that timing of a 3rd colonoscopy should be based on results of two prior exams. However, data are limited on whether baseline screening colonoscopy can inform the risk of advanced neoplasia (AN) at 3rd exam.

Methods: This study describes the risk of AN at 3rd colonoscopy stratified by findings on two previous exams in a prospective screening cohort and compares this risk over time from a negative 2nd exam between those with differing 1st exam findings.

The CSP #380 cohort included 3,121 Veterans aged 50-75 years who underwent screening colonoscopy from 1994-1997 and were followed for at least 10 years. Exclusion criteria included not having three colonoscopies more than one year apart, or having CRC at 1st or 2nd exam. The primary outcome was the proportion of AN at 3rd exam. Findings at 1st and 2nd exam were classified as high-risk adenoma (HRA), low-risk adenoma (LRA), or no adenoma. Chi-square tests compared proportions of AN on the 3rd exam between those with different baseline screening results but similar 2nd exam findings.

Results: This analysis included 891 participants: 58 (6.5%) had AN at 3rd exam. The proportion of AN at 3rd exam ranged from 3.2% to 21.4% when stratified by results of two previous exams. In participants with HRA or LRA on the 2nd exam, baseline screening colonoscopy was not associated with risk of AN at 3rd exam. However, for participants with no adenomas on the 2nd exam, baseline screening colonoscopy was associated with risk of AN at 3rd exam (P =.04). Furthermore, all AN was identified within about 5 years of the negative 2nd exam in those with HRA on the 1st exam.

Conclusions: Results of the 1st exam remain a risk factor for AN at 3rd exam in those with no adenomas at 2nd exam. This supports current guidelines which recommend a shortened surveillance interval in those with no adenomas at 2nd exam but HRA at 1st. Future work will combine CRC risk factors with genomic risk and colonoscopy outcomes over time to better identify individuals who might benefit from continued surveillance and to help inform appropriate surveillance intervals.