Novel genetic marker predicts pancreatic cancer risk

ORLANDO – Researchers have identified a novel genetic marker for increased pancreatic cancer risk.

The marker, a single nucleotide polymorphism (SNP) of the cholecystokinin-B (CCK-B) receptor, could serve as a screening test for high-risk subjects, Dr. Jill P. Smith reported at the annual Digestive Disease Week.

The CCK-B receptor is a G-protein coupled receptor through which the effects of the peptide gastrin – which regulates pancreatic cancer growth – are mediated. Both gastrin and the CCK-B receptor are overexpressed in pancreatic cancer.

Dr. Smith and her colleagues discovered a splice variant of the CCK-B receptor, known as the CCK-C receptor, which results from retention of the fourth intron on the CCK-B receptor and the insertion of 69 amino acids to the third intracellular loop, she explained.

This change increases the affinity to gastrin and is associated with a more aggressive pancreatic cancer phenotype.

"So we hypothesized that the missplicing of the fourth intron of the CCK-B receptor was the result of a genetic mutation. We also felt that the translation of the additional 69 amino acids in the third intracellular loop of the CCK-B receptor would then contribute to the aggressive phenotype that we know of as pancreatic cancer," said Dr. Smith of the National Institutes of Health.

The investigators analyzed DNA extracted from blood or surgical cancer tissue specimens of 962 pancreatic cancer patients with ductal adenocarcinoma who were treated at three major medical centers, as well as from samples of normal pancreas tissue. The analysis confirmed that the etiology of the misspliced receptor was due to a SNP (involving a transition from C to A) at position 32 of the fourth intron that corresponded to the known SNP rs1800843. The newly identified SNP was not previously identified in genomewide association studies due to its location within an intron, rather than an exon, she noted.

The frequency of the A allele was significantly greater among those with pancreatic cancer than among controls (odds ratio, 1.57).

In addition, survival was significantly reduced in subjects who had the A allele (either AA or AC), compared with subjects with the CC genotype: Survival was about 14 months for patients with AA and 17 months for those with AC, compared with nearly 20 months for CC, Dr. Smith said.

The reduced survival was not a result of more advanced disease state at diagnosis, as the mean stage of subjects with two A alleles (AA) was slightly lower than in those with the CC genotype, she noted.

The findings are notable given that survival from pancreatic cancer has not improved over the past several decades, and that no test exists to diagnose pancreatic cancer in the early stages; more than 90% of patients have advanced disease at the time of diagnosis. Also, no screening tests without radiation are available for high-risk patients, Dr. Smith said.

"The finding of a germline mutation linked to a phenotype that’s significantly increased in patients with pancreatic cancer makes the CCK-B receptor relevant for clinical screening in high-risk subjects or families. Use of this new genetic marker may lead to early detection or even prevention of pancreatic cancer," she concluded.

This study was supported by a National Institutes of Health grant. Dr. Smith disclosed that she is a TNI Biotech stock shareholder.

ORLANDO – Researchers have identified a novel genetic marker for increased pancreatic cancer risk.

The marker, a single nucleotide polymorphism (SNP) of the cholecystokinin-B (CCK-B) receptor, could serve as a screening test for high-risk subjects, Dr. Jill P. Smith reported at the annual Digestive Disease Week.

The CCK-B receptor is a G-protein coupled receptor through which the effects of the peptide gastrin – which regulates pancreatic cancer growth – are mediated. Both gastrin and the CCK-B receptor are overexpressed in pancreatic cancer.

Dr. Smith and her colleagues discovered a splice variant of the CCK-B receptor, known as the CCK-C receptor, which results from retention of the fourth intron on the CCK-B receptor and the insertion of 69 amino acids to the third intracellular loop, she explained.

This change increases the affinity to gastrin and is associated with a more aggressive pancreatic cancer phenotype.

"So we hypothesized that the missplicing of the fourth intron of the CCK-B receptor was the result of a genetic mutation. We also felt that the translation of the additional 69 amino acids in the third intracellular loop of the CCK-B receptor would then contribute to the aggressive phenotype that we know of as pancreatic cancer," said Dr. Smith of the National Institutes of Health.

The investigators analyzed DNA extracted from blood or surgical cancer tissue specimens of 962 pancreatic cancer patients with ductal adenocarcinoma who were treated at three major medical centers, as well as from samples of normal pancreas tissue. The analysis confirmed that the etiology of the misspliced receptor was due to a SNP (involving a transition from C to A) at position 32 of the fourth intron that corresponded to the known SNP rs1800843. The newly identified SNP was not previously identified in genomewide association studies due to its location within an intron, rather than an exon, she noted.

The frequency of the A allele was significantly greater among those with pancreatic cancer than among controls (odds ratio, 1.57).

In addition, survival was significantly reduced in subjects who had the A allele (either AA or AC), compared with subjects with the CC genotype: Survival was about 14 months for patients with AA and 17 months for those with AC, compared with nearly 20 months for CC, Dr. Smith said.

The reduced survival was not a result of more advanced disease state at diagnosis, as the mean stage of subjects with two A alleles (AA) was slightly lower than in those with the CC genotype, she noted.

The findings are notable given that survival from pancreatic cancer has not improved over the past several decades, and that no test exists to diagnose pancreatic cancer in the early stages; more than 90% of patients have advanced disease at the time of diagnosis. Also, no screening tests without radiation are available for high-risk patients, Dr. Smith said.

"The finding of a germline mutation linked to a phenotype that’s significantly increased in patients with pancreatic cancer makes the CCK-B receptor relevant for clinical screening in high-risk subjects or families. Use of this new genetic marker may lead to early detection or even prevention of pancreatic cancer," she concluded.

This study was supported by a National Institutes of Health grant. Dr. Smith disclosed that she is a TNI Biotech stock shareholder.

ORLANDO – Researchers have identified a novel genetic marker for increased pancreatic cancer risk.

The marker, a single nucleotide polymorphism (SNP) of the cholecystokinin-B (CCK-B) receptor, could serve as a screening test for high-risk subjects, Dr. Jill P. Smith reported at the annual Digestive Disease Week.

The CCK-B receptor is a G-protein coupled receptor through which the effects of the peptide gastrin – which regulates pancreatic cancer growth – are mediated. Both gastrin and the CCK-B receptor are overexpressed in pancreatic cancer.

Dr. Smith and her colleagues discovered a splice variant of the CCK-B receptor, known as the CCK-C receptor, which results from retention of the fourth intron on the CCK-B receptor and the insertion of 69 amino acids to the third intracellular loop, she explained.

This change increases the affinity to gastrin and is associated with a more aggressive pancreatic cancer phenotype.

"So we hypothesized that the missplicing of the fourth intron of the CCK-B receptor was the result of a genetic mutation. We also felt that the translation of the additional 69 amino acids in the third intracellular loop of the CCK-B receptor would then contribute to the aggressive phenotype that we know of as pancreatic cancer," said Dr. Smith of the National Institutes of Health.

The investigators analyzed DNA extracted from blood or surgical cancer tissue specimens of 962 pancreatic cancer patients with ductal adenocarcinoma who were treated at three major medical centers, as well as from samples of normal pancreas tissue. The analysis confirmed that the etiology of the misspliced receptor was due to a SNP (involving a transition from C to A) at position 32 of the fourth intron that corresponded to the known SNP rs1800843. The newly identified SNP was not previously identified in genomewide association studies due to its location within an intron, rather than an exon, she noted.

The frequency of the A allele was significantly greater among those with pancreatic cancer than among controls (odds ratio, 1.57).

In addition, survival was significantly reduced in subjects who had the A allele (either AA or AC), compared with subjects with the CC genotype: Survival was about 14 months for patients with AA and 17 months for those with AC, compared with nearly 20 months for CC, Dr. Smith said.

The reduced survival was not a result of more advanced disease state at diagnosis, as the mean stage of subjects with two A alleles (AA) was slightly lower than in those with the CC genotype, she noted.

The findings are notable given that survival from pancreatic cancer has not improved over the past several decades, and that no test exists to diagnose pancreatic cancer in the early stages; more than 90% of patients have advanced disease at the time of diagnosis. Also, no screening tests without radiation are available for high-risk patients, Dr. Smith said.

"The finding of a germline mutation linked to a phenotype that’s significantly increased in patients with pancreatic cancer makes the CCK-B receptor relevant for clinical screening in high-risk subjects or families. Use of this new genetic marker may lead to early detection or even prevention of pancreatic cancer," she concluded.

This study was supported by a National Institutes of Health grant. Dr. Smith disclosed that she is a TNI Biotech stock shareholder.