Genetic Colorectal Cancer Risk Variants are Associated with Increasing Adenoma Counts

Article Type
Changed
Fri, 09/06/2019 - 10:22

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.

Author and Disclosure Information

Correspondence: Thomas Redding, IV (thomas.redding28@va.gov)

Publications
Topics
Sections
Author and Disclosure Information

Correspondence: Thomas Redding, IV (thomas.redding28@va.gov)

Author and Disclosure Information

Correspondence: Thomas Redding, IV (thomas.redding28@va.gov)

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.

Publications
Publications
Topics
Article Type
Sections
Citation Override
Abstract Presented at the 2019 Association of VA Hematology/Oncology Annual Meeting
Disallow All Ads
Content Gating
No Gating (article Unlocked/Free)
Alternative CME
Disqus Comments
Default
Gate On Date
Fri, 09/06/2019 - 10:15
Un-Gate On Date
Fri, 09/06/2019 - 10:15
Use ProPublica
CFC Schedule Remove Status
Fri, 09/06/2019 - 10:15
Hide sidebar & use full width
render the right sidebar.