Burnett, Terrilea

3567 Background: The ability to genotype large numbers of people rapidly and inexpensively for research purposes highlights the need to develop guidelines for providing medically-relevant research results - including unanticipated findings - to study participants. The Colon Cancer Family Registry (C-CFR) is the oldest and largest international colon cancer population-based registry; its experience managing genetic research findings can offer guidance to clinicians and researchers. The C-CFR has enrolled 10,019 cases with colon cancer and 24,708 family members in six registries in the US, Canada, Australia, and New Zealand. Deleterious (“high risk”) germline mutations have been identified in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) and the MutYH gene. The aims of this presentation are to: (1) report the uptake of genetic test results by C-CFR participants; (2) systematically compare disclosure protocols and barriers to uptake by registry; (3) make recommendations to guide clinicians and researchers. Methods: Uptake of genetic test results was calculated from data collected by the C-CFR; key investigators (KIs) from each registry completed a survey about disclosure decision-making; KIs also took part in discussions to generate recommendations. Results: Registry-wide molecular testing has identified deleterious MMR germline mutations for at least one member of 424 families (4%) and 48 biallelic MutYH gene carriers. Uptake of test results ranged from 56-86% (n= 1542) across registries. Barriers to disclosure include: (1) lack of pre-existing notification protocols; (2) logistics of re-consent; (3) limited involvement of genetic counselors at some registries; (4) in the US, the requirement that genetic testing be performed in a CLIA approved laboratory; (5) IRBs declining approval; and (6) budget constraints. Conclusions: Based on our international registry’s findings we recommend that researchers generating genetic information establish plans for disclosure at the outset; obtain subject consent a priori; consider subject knowledge and disclosure preferences; provide guidance and budget for clinical follow-up; and involve genetic counselors.

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first‐ and 3,255 second‐degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7–97) and ovarian cancer 17 (2.4–115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7–13); hepatobiliary cancer 4.5 (2.7–7.5); endometrial cancer 2.1 (1.1–3.9) and breast cancer 1.4 (1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5–77%) for males and 8% (2–33%) for females and ovarian cancer 14% (2–65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4–7%) for males and 2.3% (1.7–3.3%) for females; hepatobiliary cancer 3% (2–5%) for males and 1.4% (0.8–2.3%) for females; endometrial cancer 3% (2%–6%) and breast cancer 11% (8–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

Abstract To identify genetic variants that contribute to colorectal cancer (CRC) susceptibility, we performed a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, followed by a replication of genome-wide statistically significant associations (P < 5E-8) in 16,823 cases and 18,211 controls of European ancestry. This study revealed a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.5E-9), providing additional insight into the etiology of CRC and highlighting the value of association mapping in diverse populations. Citation Format: Hansong Wang, Terrilea Burnett, Suminori Kono, Christopher Haiman, Motoki Iwasaki, Lynne Wilkens, Lenora Loo, David Van Den Berg, Laurence Kolonel, Brian Henderson, Temitope Keku, Robert Sandler, Lisa Signorello, William Blot, Polly Newcomb, Mala Pande, Christopher Amos, Dee West, Stéphane Bézieau, Sonja Berndt, Brent Zanke, Li Hsu, Noralane Lindor, Robert Haile, John Hopper, Mark Jenkins, Steven Gallinger, Graham Casey, Stephanie Stenzel, Fredrick Schumacher, Ulrike Peters, Stephen Gruber, Shoichiro Tsugane, Dan Stram, Loic Le Marchand. Transethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-282. doi:10.1158/1538-7445.AM2014-LB-282

AbstractBackground: It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways.Methods: In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for more than 600 tagSNPs and 99 single-nucleotide polymorphisms (SNP) were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls).Results: The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (OR per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the “effective” number of markers in stage II (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency < 0.03) in whites, Japanese Americans, Latinos, and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, body mass index (BMI) levels, regular aspirin use, or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822.Conclusions: Our results provide new evidence of association between PPARG variants and colorectal cancer risk.Impact: Further replication in independent samples is warranted. Cancer Epidemiol Biomarkers Prev; 22(11); 2094–101. ©2013 AACR.

Abstract Introduction: Colorectal adenomas and other types of polyps are commonly used as end points or risk factors in epidemiologic studies. However, it is not known how accurately patients are able to self-report the presence or absence of adenomas following colonoscopy. Methods: Participants in the Colon Cancer Family Registry provided self-reports of recent colorectal cancer (CRC) screening activity, and whether or not they had ever been told they had a polyp. Positive and negative predictive values for polyp self-report were calculated by comparing medical records with self-reports from 488 participants. Results: The positive predictive value for self-reported polyp was 80.9%, and the negative predictive value was 85.8%. The predictive values did not differ by age group or sex, but participants with a previous diagnosis of CRC had a lower negative predictive value (76.2%) than participants with no personal history of CRC (89.0%; P = 0.04). Conclusions: Predictive values for self-reports of polyps are fairly high, but researchers needing accurate polyp data should obtain medical record confirmation. Pursuing medical records on only those participants self-reporting a polyp could result in an underestimation of the polyp prevalence in a study population. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1898–901)