Colon Cancer Family Registry Research Articles

Childhood cancers in families with and without Lynch syndrome

Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes or the EPCAM gene is associated with an increased risk of colorectal cancer, endometrial cancer, and other adult malignancies (Lynch syndrome). The risk of childhood cancers in Lynch syndrome families, however, is not well studied. Using data from the Colon Cancer Family Registry, we compared the proportion of childhood cancers (diagnosed before 18 years of age) in the first-, second-, and third-degree relatives of 781 probands with a pathogenic mutation in one of the MMR genes; MLH1 (n = 275), MSH2 (n = 342), MSH6 (n = 99), or PMS2 (n = 55) or in EPCAM (n = 10) (Lynch syndrome families), with that of 5073 probands with MMR-deficient colorectal cancer (non-Lynch syndrome families). There was no evidence of a difference in the proportion of relatives with a childhood cancer between Lynch syndrome families (41/17,230; 0.24%) and non-Lynch syndrome families (179/94,302; 0.19%; p = 0.19). Incidence rate of all childhood cancers was estimated to be 147 (95% CI 107-206) per million population per year in Lynch syndrome families and 115 (95% CI 99.1-134) per million population per year in non-Lynch syndrome families. There was no evidence for a significant increase in the risk of all childhood cancers, hematologic cancers, brain and central nervous system cancers, Lynch syndrome-associated cancers, or other cancers in Lynch syndrome families compared with non-Lynch syndrome families. Larger studies, however, are required to more accurately define the risk of specific individual childhood cancers in Lynch syndrome families.

Highlights of This Issue

The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread DNA hypermethylation at select CpG islands, but risk factors for CIMP tumors are not known. Weisenberger and colleagues measured the CIMP status of 3,119 primary population–based colorectal cancer tumors from the multinational Colon Cancer Family Registry and found associations between tumor CIMP status and microsatellite instability, BRAF gene V600E mutation status, proximal tumor site, female sex, and age. NSAID use in males and females and BMI and smoking in females were also associated with CIMP status.To explore temporal DNA methylation changes within and between individuals, Shvetsov and colleagues analyzed DNA methylation at over 400,000 CpG-site–specific DNA methylation loci in leukocyte DNA from 24 healthy Chinese women over a nine-month period. The authors found that most CpG sites did not exhibit temporal trend that is sufficiently strong to be detected in a small time window of <1 year. This study supports that methylation levels can be reliably assessed with one blood sample.Germline mutations in the BRCA1 and BRCA2 genes confer a 58–80% lifetime risk of breast cancer. There are few data on the prevalence of BRCA1/2 mutations in Mexican women with breast cancer. Torres-Mejía and colleagues screened 810 unselected women with breast cancer from three cities in Mexico for mutations in BRCA1 and BRCA2. Thirty-five mutations were identified in 34 women, 20 BRCA1 mutations and 15 BRCA2 mutations. Only five of the 34 mutation carriers had a first-degree relative with breast cancer. These results support a strategy of screening all women with breast cancer in Mexico for BRCA1/2 mutations.Patient navigation can boost colorectal cancer screening in primary care. To explore this, Ritvo and colleagues tested the impact of a patient navigation intervention that included support for performance of the participants' preferred screening test (colonoscopy or stool blood testing). Primary care patients were randomly assigned to an intervention group or a usual care control group, and the intervention group participants were contacted by and met with a navigator who helped them identify and arrange for the preferred screening. Screening adherence was higher in the intervention group, compared to the control group.

Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history.

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. 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). 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). 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. 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.

Dual role of TGFBR1 as a modifier of colorectal cancer risk.

600 Background: Experimental and clinical evidence suggests that constitutively decreased Transforming Growth Factor Beta type I receptor (TGFBR1) signaling predisposes to colorectal cancer (CRC) development. However, associations between TGFBR1 variants and CRC risk in case-control studies have been inconsistent. Methods: We utilized 1,043 CRC cases and their 1,627 unaffected sibling controls obtained from the Colon Cancer Family Registry (C-CFR). Individuals were genotyped for twelve TGFBR1 haplotype tagging SNPs. SNPs associated with CRC risk were validated in 261 CRC cases and 531 controls of African American ancestry and 990 CRC cases and 3,427 controls of Han Chinese ancestry. Validated SNPs were functionally characterized with respect to TGFBR1 expression and TGF-β signaling. Results: The TGFBR1 rs7034462-TT genotype was associated with CRC risk in C-CFR participants (OR 3.80[1.46-9.85]) and African Americans (OR 8.16[2.07-32.08]) (see Table). The TT genotype was associated with stage III and stage IV at diagnosis in C-CFR participants (OR 2.99[1.15-7.81] and OR 9.38[1.54-57.28]) and African Americans (OR 5.89[1.15-30.02] and OR 12.75[1.88-86.33]), respectively. The rs7034462-CT genotype was associated with decreased risk for CRC in African Americans (OR 0.55[0.31-0.99]) and Han Chinese (OR 0.67[0.48-0.95]) (see table). Cells carrying the rs7034462-TT genotype exhibited decreased constitutive TGFBR1 expression, increased SMAD7 expression, and decreased TGF-β signaling. Conclusions: The TGFBR1 rs7034462-T allele has dual, opposite roles with respect to CRC risk. The rare rs7034462-TT genotype is a moderate penetrance genotype associated with risk for CRC and advanced stage disease at diagnosis. In contrast, the common rs7034462-CT genotype is associated with decreased CRC risk. [Table: see text]

Red meat intake, NAT2, and risk of colorectal cancer: a pooled analysis of 11 studies.

Red meat intake has been associated with risk of colorectal cancer, potentially mediated through heterocyclic amines. The metabolic efficiency of N-acetyltransferase 2 (NAT2) required for the metabolic activation of such amines is influenced by genetic variation. The interaction between red meat intake, NAT2 genotype, and colorectal cancer has been inconsistently reported. We used pooled individual-level data from the Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium. Red meat intake was collected by each study. We inferred NAT2 phenotype based on polymorphism at rs1495741, highly predictive of enzyme activity. Interaction was assessed using multiplicative interaction terms in multivariate-adjusted models. From 11 studies, 8,290 colorectal cancer cases and 9,115 controls were included. The highest quartile of red meat intake was associated with increased risk of colorectal cancer compared with the lowest quartile [OR, 1.41; 95% confidence interval (CI), 1.29-1.55]. However, a significant association was observed only for studies with retrospective diet data, not for studies with diet prospectively assessed before cancer diagnosis. Combining all studies, high red meat intake was similarly associated with colorectal cancer in those with a rapid/intermediate NAT2 genotype (OR, 1.38; 95% CI, 1.20-1.59) as with a slow genotype (OR, 1.43; 95% CI, 1.28-1.61; P interaction = 0.9). We found that high red meat intake was associated with increased risk of colorectal cancer only from retrospective case-control studies and not modified by NAT2 enzyme activity. Our results suggest no interaction between NAT2 genotype and red meat intake in mediating risk of colorectal cancer.

Abstract LB-276: Prospective study of body mass index and adult weight change with colorectal cancer survival, overall and by tumor microsatellite instability status

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

Abstract 2176: Obesity and risk of colorectal cancer: A Mendelian randomization study

Abstract Background: Obesity has been consistently linked to higher risk of colorectal cancer (CRC) in men, whereas the association is generally lower in women. Although these findings come from well conducted epidemiologic studies, it is difficult to exclude all other explanations for associations in observational studies, such as measurement error and other forms of bias, reverse causality and confounding. Mendelian randomization studies, using instrumental variables (IVs), can overcome some of the inherent limitations of observational studies and provide an unbiased and unconfounded estimate of the causal association between an exposure and outcome. Objective: We used genetic variants that are associated with body mass index (BMI) or waist-hip ratio (WHR) to examine the causal association between obesity and CRC. Methods: We used epidemiologic and genetic data from 10 226 CRC cases and 10 286 controls of European ancestry from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) or the Colon Cancer Family Registry (CCFR). The primary Mendelian randomization analysis was performed using a genetic risk score, derived from 77 established “BMI-increasing” genetic variants, as an instrumental variable for higher BMI. We additionally derived a risk score for WHR using 47 variants for WHR. We compared the IV odds ratio (OR) with the OR obtained using a traditional multivariable logistic regression model adjusted for age, sex, smoking status, family history, aspirin use, and HRT use (women). Results: For men and women combined, in traditional multivariable analysis, each 5 kg/m2 increase in BMI was associated with a 24% (95% confidence interval [CI]: 1.17-1.32) increase in risk of CRC. In the IV analysis, the OR was higher (IV-OR per 5 kg/m2=1.54, 95% CI: 1.15-2.06); however, the two estimates were not statistically significantly different (Pdifference=0.07). For men, there was a statistically significant association between BMI and CRC in traditional multivariable analysis (OR per 5kg/m2=1.33, 95% CI: 1.21-1.46), but no association in the IV analysis (IV-OR per 5 kg/m2=1.13, 95% CI: 0.70-1.83). The estimates however were not significantly different (Pdifference=0.56). In contrast, for women, the IV estimate (IV-OR per 5 kg/m2=1.94, 95% CI: 1.33-2.82) was significantly higher than the estimate from the traditional multivariable analysis (OR per 5 kg/m2=1.18, 95% CI: 1.11-1.25; Pdifference=0.01). In secondary analysis, we found a positive association between WHR and CRC in men (IV-OR per 0.1 unit increase=1.84, 95% CI: 1.02-3.31) but no statistically significant association in women (IV-OR per 0.1 unit increase=1.22, 95% CI: 0.75-1.98). Conclusions: Obesity is independently associated with risk of CRC and may confer greater risk of CRC in women than previously reported. The mechanisms remain largely unknown; however these results suggest that visceral abdominal fat may be particularly important for promoting CRC in men. Citation Format: Aaron P. Thrift, Sonja I. Berndt, Andrew T. Chan, Jenny Chang-Claude, Martha L. Slattery, Michelle Cotterchio, Graham Casey, John D. Potter, Polly A. Newcomb, Emily White, Hermann Brenner, Ulrike Peters, Peter T. Campbell. Obesity and risk of colorectal cancer: A Mendelian randomization study. [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 2176. doi:10.1158/1538-7445.AM2014-2176

Abstract 2190: Fine-mapping of common genetic variants associated with colorectal tumor risk identified potential functional variants

Abstract Background: Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci facilitates detection of functional candidates and additional independent risk variants. Methods: We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Results: Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. However, in most regions the SNP showing the smallest P-value was correlated (r2≥0.2) with the index SNP. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22,2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We observed evidence for an additional independent association signal in 8q24 located between POU5F1B and MYC (rs28629385; minor allele frequency=0.06; per-allele odds ratio=1.37; P=7.9E-06). Conclusions: Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates for laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). Citation Format: Mengmeng Du, Shuo Jiao, Stephanie A. Rosse, Manish Gala, Goncalo Abecasis, Stephane Bezieau, Hermann Brenner, Graham Casey, Jenny Chang-Claude, Steven Gallinger, Thomas J. Hudson, Sébastien Küry, Loic Le Marchand, Suzanne M. Leal, Polly A. Newcomb, Deborah A. Nickerson, John D. Potter, Martha L. Slattery, Li Hsu, Andrew T. Chan, Emily White, Sonja I. Berndt, Ulrike Peters. Fine-mapping of common genetic variants associated with colorectal tumor risk identified potential functional variants. [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 2190. doi:10.1158/1538-7445.AM2014-2190

Association Between Molecular Subtypes of Colorectal Cancer and Patient Survival

Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival. Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (N = 2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]-high, CpG island methylator phenotype [CIMP] -positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history. Compared with participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR = 2.20, 95% CI: 1.47-3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR = 1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR = 0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality. Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC.

Abstract 2172: Physical activity in relation to overall and colorectal cancer specific survival in the Seattle Colon Cancer Family Registry

Abstract Background Previous studies have suggested that physical activity is associated with a reduced risk of colon cancer. The association of physical activity with colorectal cancer (CRC) survival, however, is less clear. Studies evaluating the association between post-diagnostic physical activity and CRC survival suggest a favorable survival among those who engage in regular physical activity after diagnosis. However, such studies are limited by the possibility of reverse causality since individuals engaging in regular physical activity after diagnosis may have had a better prognosis to begin with. Methods We evaluated the association between pre-diagnostic physical activity and survival, both overall and CRC-specific, within the Seattle Colon Cancer Family Registry (SCCFR), a prospective cohort of persons diagnosed with CRC between 1997 and 2002. All cases completed a risk-factor questionnaire including information on medical history, demographic and lifestyle factors, such as obesity and decade-specific recreational physical activity. Vital status and cause of death was determined through linkage to a regional cancer registry and National Death Index. Tumor markers (BRAF and KRAS mutation status) were evaluated for a subset of cases. Physical activity was summarized as average weekly metabolic equivalent-task hours (MET-h/week). Adjusted hazard ratios (HR) and 95% confidence limits (95%CI) were estimated using Cox regression. Results Primary analyses included 1171 persons who self-reported their physical activity status, of whom 471 died (292 deaths attributable to CRC; median follow-up 6.3 years). After adjusting for age at diagnosis, sex, body mass index and smoking status, those who engaged in physical activity had a significantly lower risk of dying from any cause compared to those who did not engage in any physical activity (HR 0.72, 95%CI 0.51-0.99; HR 0.62, 95%CI 0.44-0.87; and HR 0.60, 95%CI 0.43-0.85 for &amp;gt;0-6.4, 6.4-19.2, and &amp;gt;19.2 MET-h/wk, respectively; P for trend=0.035). Results for CRC-specific survival were similar and suggested improved survival among physically active individuals compared to those that were inactive, although no trend was evident (HR 0.81, 95%CI 0.51-1.28; HR 0.72, 95%CI 0.45-1.15; and HR 0.72, 95% CI 0.44-1.14 for &amp;gt;0-6.4, 6.4-19.2, &amp;gt;19.2 MET-h/wk respectively; P for trend= 0.52). Further adjustment for stage at diagnosis or BRAF and KRAS mutation status did not alter the results. Conclusion Our results suggest that individuals who are physically active prior to CRC diagnosis experience more favorable survival than those who are inactive. Increased physical activity was also associated with better CRC-specific survival, but this trend was not statistically significant. Continued follow-up of this and other larger cohorts is needed to further clarify the role of physical activity in CRC prognosis. Citation Format: Sheetal S. Hardikar, Polly A. Newcomb, Michael N. Passarelli, Peter T. Campbell, Amanda I. Phipps. Physical activity in relation to overall and colorectal cancer specific survival in the Seattle Colon Cancer Family Registry. [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 2172. doi:10.1158/1538-7445.AM2014-2172

Gene-environment interaction involving recently identified colorectal cancer susceptibility Loci.

Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer. Prior research has evaluated the presence of gene-environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279. Data on 9,160 cases and 9,280 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR) were used to evaluate the presence of interaction involving the above-listed SNPs and sex, body mass index (BMI), alcohol consumption, smoking, aspirin use, postmenopausal hormone (PMH) use, as well as intake of dietary calcium, dietary fiber, dietary folate, red meat, processed meat, fruit, and vegetables. Interaction was evaluated using a fixed effects meta-analysis of an efficient Empirical Bayes estimator, and permutation was used to account for multiple comparisons. None of the permutation-adjusted P values reached statistical significance. The associations between recently identified genetic susceptibility loci and colorectal cancer are not strongly modified by sex, BMI, alcohol, smoking, aspirin, PMH use, and various dietary factors. Results suggest no evidence of strong gene-environment interactions involving the recently identified 16 susceptibility loci for colorectal cancer taken one at a time.

High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry.

The question of whether prostate cancer is part of the Lynch syndrome spectrum of tumors is unresolved. We investigated the mismatch repair (MMR) status and pathologic features of prostate cancers diagnosed in MMR gene mutation carriers. Prostate cancers (mean age at diagnosis = 62 ± SD = 8 years) from 32 MMR mutation carriers (23 MSH2, 5 MLH1 and 4 MSH6) enrolled in the Australasian, Mayo Clinic and Ontario sites of the Colon Cancer Family Registry were examined for clinico-pathologic features and MMR-deficiency (immunohistochemical loss of MMR protein expression and high levels of microsatellite instability; MSI-H). Tumor MMR-deficiency was observed for 22 cases [69 %; 95 % confidence interval (CI) 50-83 %], with the highest prevalence of MMR-deficiency in tumors from MSH2 mutation carriers (19/23, 83 %) compared with MLH1 and MSH6 carriers combined (3/9, 33 %; p = 0.01). MMR-deficient tumors had increased levels of tumor infiltrating lymphocytes compared with tumors without MMR-deficiency (p = 0.04). Under the assumption that tumour MMR-deficiency occurred only because the cancer was caused by the germline mutation, mutation carriers are at 3.2-fold (95 % CI 2.0-6.3) increased risk of prostate cancer, and when assessed by gene, the relative risk was greatest for MSH2 carriers (5.8, 95 % CI 2.6-20.9). Prostate cancer was the first or only diagnosed tumor in 37 % of carriers. MMR gene mutation carriers have at least a twofold or greater increased risk of developing MMR-deficient prostate cancer where the risk is highest for MSH2 mutation carriers. MMR IHC screening of prostate cancers will aid in identifying MMR gene mutation carriers.

Family history of colorectal cancer is not associated with colorectal cancer survival regardless of microsatellite instability status.

Individuals with a family history of colorectal cancer in first-degree relatives have an elevated risk of developing colorectal cancer themselves, particularly colorectal cancer exhibiting high microsatellite instability (MSI-high). Given that MSI-high colorectal cancer is associated with a favorable prognosis, it is plausible that having a family history of colorectal cancer could, in turn, be favorably associated with colorectal cancer survival. This study comprised N = 4,284 incident colorectal cancer cases enrolled in the Colon Cancer Family Registry via population-based cancer registries. Using Cox proportional hazards regression, we evaluated the association between family history and both overall and disease-specific survival, accounting for MSI status and tumor site via stratified analyses and statistical adjustment. There was no evidence of association between family history and overall [hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.79-1.08] or disease-specific survival (HR, 1.03; 95% CI, 0.85-1.24) for all cases combined, after adjustment for MSI status or tumor site. Only for rectal cancer cases was colorectal cancer family history modestly associated with more favorable overall survival (HR, 0.75; 95% CI, 0.56-0.99). Although individuals with a family history of colorectal cancer were more likely to have MSI-high tumors than those with nonfamilial disease, this did not translate to a survival benefit. Overall, there is no evidence that family history of colorectal cancer is associated with colorectal cancer survival; however, specific mechanisms underlying family history may have prognostic impact and merit further study.

A novel colorectal cancer risk locus at 4q32.2 identified from an international genome-wide association study.

Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genome-wide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10(-9); nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.

Characterisation of Familial Colorectal Cancer Type X, Lynch syndrome, and non-familial colorectal cancer

Background:Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and ‘non-familial' (non-AC1) CRC cases.Methods:From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression.Results:Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage.Conclusions:FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.

Genetic variation in prostaglandin synthesis and related pathways, NSAID use and colorectal cancer risk in the Colon Cancer Family Registry.

Although use of non-steroidal anti-inflammatory drugs (NSAIDs) generally decreases colorectal cancer (CRC) risk, inherited genetic variation in inflammatory pathways may alter their potential as preventive agents. We investigated whether variation in prostaglandin synthesis and related pathways influences CRC risk in the Colon Cancer Family Registry by examining associations between 192 single nucleotide polymorphisms (SNPs) and two variable nucleotide tandem repeats (VNTRs) within 17 candidate genes and CRC risk. We further assessed interactions between these polymorphisms and NSAID use on CRC risk. Using a case-unaffected-sibling-control design, this study included 1621 primary invasive CRC cases and 2592 sibling controls among Caucasian men and women aged 18-90. After adjustment for multiple comparisons, two intronic SNPs were associated with rectal cancer risk: rs11571364 in ALOX12 [OR(het/hzv) = 1.87, 95% confidence interval (CI) = 1.19-2.95, P = 0.03] and rs45525634 in PTGER2 (OR(het/hzv) = 0.49, 95% CI = 0.29-0.82, P = 0.03). Additionally, there was an interaction between NSAID use and the intronic SNP rs2920421 in ALOX12 on risk of CRC (P = 0.03); among those with heterozygous genotypes, risk was reduced for current NSAID users compared with never or former users (OR(het) = 0.60, 95% CI = 0.45-0.80), though not among those with homozygous wild-type or variant genotypes. The results of this study suggest that genetic variation in ALOX12 and PTGER2 may affect the risk of rectal cancer. In addition, this study suggests plausible interactions between NSAID use and variants in ALOX12 on CRC risk. These results may aid in the development of genetically targeted cancer prevention strategies with NSAIDs.

No association between germline variation in catechol-O-methyltransferase and colorectal cancer survival in postmenopausal women

Sex steroid hormones play a role in colorectal cancer (CRC) development, but little is known about their influence on tumor progression and metastasis. Because catechol-O-methyltransferase (COMT; 22q11.21) activity is an important component of estrogen-mediated carcinogenesis, we hypothesized that germline variation in COMT may be associated with CRC survival. We identified 10 single nucleotide polymorphisms that tagged variation across two isoforms of COMT in 2,458 women with CRC from the Nurses' Health Study, Postmenopausal Hormones Supplementary Study to the Colon Cancer Family Registry, VITamins And Lifestyle Study, and Women's Health Initiative. All four studies participated in the Genetics and Epidemiology of Colorectal Cancer Consortium. During a median follow-up of 7 years across all studies, there were 799 deaths, including 566 deaths from CRC. Based on multiple comparisons, no associations between single nucleotide polymorphisms and CRC-specific or overall survival reached statistical significance, including the well-characterized Val108/158Met polymorphism (rs4680; CRC-specific survival: hazard ratio per minor allele, 1.04; 95% CI, 0.92-1.17; overall survival: hazard ratio per minor allele, 1.01; 95% CI, 0.90-1.14). In this large study of women with CRC, we find no evidence that common inherited variation in COMT is associated with survival time after diagnosis.

Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: Colon cancer family registry

The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal neoplasia. Previous studies have reported that polymorphisms in NSAID‐metabolizing enzymes central to NSAID metabolism including UDP‐glucuronosyltransferases (UGT) and cytochrome P450 (CYP) 2C9 may modify this protective effect. We investigated whether 35 functionally relevant polymorphisms within CYP2C9 and UGT genes were associated with colorectal cancer risk or modified the protective effect of NSAIDs on colorectal cancer susceptibility, using 1,584 colorectal cancer cases and 2,516 unaffected sibling controls from the Colon Cancer Family Registry. A three‐SNP genotype in UGT1A6 (G–A–A; Ala7–Thr181–Arg184) and the Asp85 variant in UGT2B15 increased the risk of colorectal cancer (OR 3.87; 95% CI 1.04–14.45 and OR 1.34; 95% CI 1.10–1.63, respectively). We observed interactions between UGT1A3 Thr78Thr (A&gt;G) and NSAID use (P‐interaction = 0.02), a three‐SNP genotype within UGT2B4 and ibuprofen use (P‐interaction = 0.0018), as well as UGT2B15 Tyr85Asp (T&gt;G) and aspirin use (P‐interaction = 0.01). The interaction with the UGT2B4 and the UGT2B15 polymorphisms were noteworthy at the 25% FDR level. This study highlights the need for further pharmacogenetic studies to identify individuals who might benefit from NSAID use as part of developing effective strategies for prevention of colorectal neoplasia. © 2014 Wiley Periodicals, Inc.

Does risk of endometrial cancer for women without a germline mutation in a DNA mismatch repair gene depend on family history of endometrial cancer or colorectal cancer?

ObjectiveTo determine whether risk of endometrial cancer for women without a germline mutation in a DNA mismatch repair (MMR) gene depends on family history of endometrial or colorectal cancer. MethodsWe retrospectively followed a cohort of 79,166 women who were recruited to the Colon Cancer Family Registry, after exclusion of women who were relatives of a carrier of a MMR gene mutation. The Kaplan–Meier failure method was used to estimate the cumulative risk of endometrial cancer. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for association between family history of endometrial or colorectal cancer and risk of endometrial cancer. ResultsA total of 628 endometrial cancer cases were observed, with mean age at diagnosis of 54.4 (standard deviation: 15.7) years. The cumulative risk of endometrial cancer to age 70years was estimated to be 0.94% (95% CI 0.83–1.05) for women with no family history of endometrial cancer, and 3.80% (95% CI 2.75–4.98) for women with at least one first- or second-degree relative with endometrial cancer. Compared with women without family history, we found an increased risk of endometrial cancer for women with at least one first- or second-degree relative with endometrial cancer (HR 3.66, 95% CI 2.63–5.08), and for women with one first-degree relative with colorectal cancer diagnosed at age <50years (HR 1.48, 95% CI 1.15–1.91). ConclusionAn increased risk of endometrial cancer is associated with a family history of endometrial cancer or early-onset colorectal cancer for women without a MMR gene mutation, indicating for potential underlying genetic and environmental factors shared by colorectal and endometrial cancers other than caused by MMR gene mutations.

Colorectal cancer and self-reported tooth agenesis

BackgroundGermline mutations in APC and AXIN2 are both associated with colon neoplasia as well as anomalous dental development. We tested the hypothesis that congenitally missing teeth may occur more commonly in individuals diagnosed with colorectal cancer than in individuals without this diagnosis.MethodsVia a survey conducted on 1636 individuals with colorectal cancer (CRC) and 2788 individuals with no colorectal cancer from the Colon Cancer Family Registry, self-reported information on congenitally missing teeth was collected. The frequency of missing teeth between cases and controls was compared using Pearson’s chi-squared test or Fisher’s exact test.Results4.8% of cases and 5.7% of controls reported having at least one missing tooth (p = 0.20). When we stratified by recruitment site, gender, and mutation status where available, frequency of missing teeth was not statistically significantly different between cases and controls.ConclusionsThis study did not provide support for there being a general predisposition to missing teeth among a large cohort of CRC patients. The study neither addresses nor excludes the possibility, however, that individuals presenting with notable hypodontia/oligodontia might still have an increased risk for colorectal neoplasia.