Lindor, Noralane M.

Abstract It is widely appreciated that early detection is the key to making inroads in the fight against cancers. Despite the availability of endoscopic screening, compliance is poor. The diagnosis of CRC is often made in advanced stages, and the consequence is a dismal 50% five year survival across all CRC. There is urgent need for biomarkers with performance that can meet the need of early diagnosis. Like most cancers, colorectal cancers (CRCs) express tumor antigens that can induce humoral immune response. The identification of the autoantibodies against tumor antigens may facilitate early diagnosis of CRC. The goal for this pilot project was to demonstrate the feasibility of discovering autoantibody biomarkers for colorectal cancer using Nucleic Acid Programmable Protein Arrays (NAPPA). Autoantibodies in serum samples collected from 40 patients with DNA mismatch repair proficient colorectal cancer who had died of their cancer within 18 months of their blood draw and from 40 age-gender matched healthy controls were profiled on NAPPA arrays with randomly selected 2000 human protein. The fact that p53, a tumor antigen that has been previously reported to be related to various cancers including CRC, was one of the top candidates based on the statistical analysis demonstrates the validity of our discovery platform. Besides p53, thirty-one candidate antigens were identified to have sensitivity greater than or equal to 25% at 95% specificity and fifty-one candidate antigens had an area under the ROC curve (AUC) equal to or greater than 0.6. Validation of the combined 83 unique genes selected based on these two different data analysis methods in an independent sample set in a blind fashion is on-going. This pilot study using late stage cancer samples demonstrates the feasibility and power of an immunoproteomics study using protein arrays. This approach may rapidly lead to identification of markers that could have relevance in monitoring disease progression as well as in early cancer detection. Citation Format: Gokhan Demirkan, Leah Soderberg, Garrick Wallstrom, Emily Szeto, Kristi Barker, Jie Wang, Joshua LaBaer, Noralane M. Lindor, Ji Qiu. Proteome scale identification of autoantibody biomarkers in colorectal cancer. [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 887. doi:10.1158/1538-7445.AM2014-887

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

Abstract Background: Tumor features such as stage, grade, and microsatellite instability (MSI) status have relevance for colorectal cancer survival whereas the prognostic role of body mass index (BMI) is unclear. We assessed the association of BMI and adult weight gain on colorectal cancer survival, overall and by strata of sex and MSI. Methods: Participants were identified from a multi-center cohort that includes 6,763 colorectal cancer patients with invasive colorectal cancer who were enrolled into the Colon Cancer Family Registry from 1997 to 2008. Vital status was updated through direct contact with patients/next-of-kin and/or linkage with mortality records. BMI 2 years before diagnosis, BMI at age 20 years, and adult weight gain were derived from self-reports of height and weight (i.e., weight 2 years before diagnosis and weight at age 20 years). Tumor MSI status was available for 4,987 patients. Multivariable, two-sided hazard ratios (HR) and 95% confidence intervals (CIs) were estimated from delayed-entry Cox proportional hazards models, controlling for age at diagnosis, TNM summary stage (i.e., I, II, III, IV or missing), smoking (current, former, never), and study center. Results: After a maximum of 13.7 years of follow-up from enrollment to end-of-study (median: 5.3 years), 2,335 patients had died. Higher BMI 2 years before cancer diagnosis (per 5-kg/m2) was associated with higher risk of all-cause mortality overall (HR, 1.10; 95% CI, 1.05 to 1.14), with similar associations when stratified by sex (men: HR, 1.07; 95% CI, 1.02 to 1.14; women: HR, 1.11: 95% CI, 1.05 to 1.17; p-interaction: 0.18) and MSI status (MS-stable/MSI-low: HR, 1.08; 95% CI, 1.03 to 1.14; MSI-high, HR: 1.19; 95% CI, 1.02 to 1.40; p-interaction: 0.88). In joint models, with MS-stable/MSI-low and normal BMI as the referent group, risk of death was lower for those with MSI-high and normal BMI (HR: 0.77; 95% CI: 0.59 to 1.00), higher for MS-stable/MSI-low and high (≥30) BMI (HR: 1.23; 95% CI: 1.07 to 1.42), and essentially the same for MSI-high and high BMI (HR: 0.97; 95% CI: 0.72 to 1.30). Similar patterns of association were observed for BMI at age 20 years and when the outcome was colorectal cancer-specific mortality, although not all associations remained statistically significant for some of the smaller sub-group analyses. After controlling for BMI at age 20 years, adult weight gain was only modestly associated with all-cause mortality (per 5 kg HR: 1.01; 95% CI: 1.00 to 1.02; p-trend: 0.07). Conclusion: High pre-diagnosis BMI was associated with increased mortality after colorectal cancer diagnosis; this association was consistent for men and women and by tumor MSI status. These results also suggest that obesity attenuates the survival advantage observed with MSI-high tumors. Citation Format: Peter T. Campbell, Christina Newton, Polly A. Newcomb, Dennis Ahnen, John Baron, Sean Cleary, Michelle Cotterchio, A. Brad Farris, Jane Figueiredo, Roger C. Green, Loic Le Marchand, John McLaughlin, Amanda Phipps, John D. Potter, Andrew Renehan, Aung Ko Win, Noralane Lindor, Paul Limburg. Prospective study of body mass index and adult weight change with colorectal cancer survival, overall and by tumor microsatellite instability status. [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-276. doi:10.1158/1538-7445.AM2014-LB-276

Studies indicate variant of uncertain significance (VUS) results are challenging for genetic counselors and patients, often resulting in negative patient outcomes. Genetic counselors' current practices regarding VUS are unknown. This study utilized a national survey of genetic counselors (n = 932) to examine current practices and confidence related to disclosing BRCA VUS results and reclassification information. For participants (n = 398), descriptive statistics were calculated regarding patient demographic characteristics, practices and confidence, and cross tabulation was used to identify participant's actions when receiving a reclassified VUS. Upon receiving a BRCA VUS report, the majority reported providing patients with information about the frequency with which their VUS was seen and patient ancestry, but a minority discussed DNA banking. Most were confident in their understanding of, and ability to explain, VUS results to patients, but felt less confident about achieving high levels of patient understanding. Upon reclassification, the majority reported calling the patient and mailing the results, but when the reclassification was deleterious, the majority also met with the patient face‐to‐face. Given the lack of standard professional guidelines about informing patients of initial and reclassified VUS results, this overview provides important insight into genetic counselors' current practices and confidence.

Abstract Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case–case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case–case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P < 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5–2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0–5.5), and family history of CRC (ccOR = 0.6; 95% CI, 0.5–0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend < 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation–based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 512–9. ©2015 AACR.

Abstract Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.