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Background & Aims: Direct germline analysis could be used to screen high-risk patients for mutations in DNA mismatch repair genes associated with Lynch Syndrome. We examined the prevalence of mutations in MLH1, MSH2, and MSH6 in a population-based sample of patients with young-onset (age <50 years) colorectal cancer (CRC). Methods: Young-onset CRC cases were randomly selected from 3 Colon Cancer Family Registry sites. DNA was extracted from peripheral blood leukocytes; MLH1, MSH2, and MSH6 were sequenced, and duplication and deletion analyses was performed for MLH1 and MSH2. Results were reported as deleterious or suspected deleterious, likely neutral, variant of uncertain significance, or no alteration detected. Germline data were compared to Amsterdam II criteria (ACII) and immunohistochemistry results in secondary analyses. Results: Among 195 subjects, 11 had deleterious/suspected deleterious mutations (5.6%; 95% confidence interval [CI], 2.8%–9.9%), 12 had likely neutral alterations (6.2%; 95% CI, 3.2%–10.5%), 14 had variants of uncertain significance (7.2%; 95% CI, 4.0%–11.8%), 2 had a likely neutral alteration and a variant of uncertain significance (1.0%; 95% CI, 0.1%–3.7%), and 156 had no alteration detected (80.0%; 95% CI, 73.7%–85.4%). Sensitivity, specificity, and positive and negative predictive values for detecting deleterious/suspected deleterious mutations, based on ACII, were 36.4% (4/11), 96.7% (178/184), 40.0% (4/10), and 96.2% (178/185), respectively; based on immunohistochemistry these values were 85.7% (6/7), 91.9% (136/148), 33.3% (6/18), and 99.3% (136/137), respectively. Conclusions: In a population-based sample of young-onset CRC cases, germline mutations in MLH1, MSH, and/or MSH6 were more prevalent than reported for CRC patients overall. Because only about 5% of young-onset CRC cases had confirmed deleterious or suspected deleterious mutations, further comparative effectiveness research is needed to determine the most appropriate screening strategy for Lynch Syndrome in this high-risk group. [Copyright &y& Elsevier]

Background & Aims: Type 2 diabetes mellitus (DM) is associated with an increased risk of colorectal cancer (CRC); it is not clear if this association varies by sex or other factors. Insulin use might also be associated with CRC risk. We investigated associations of type 2 DM and insulin use with CRC risk. Methods: The Cancer Prevention Study II Nutrition Cohort is a prospective study of cancer incidence. In 1992 or 1993, adult participants (n = 184,194) completed a detailed, self-administered questionnaire. Follow-up questionnaires were sent in 1997 and every 2 years thereafter. Cox proportional hazards regression analysis was used to calculate relative risks (RR) and 95% confidence intervals (CI), adjusting for covariates. Results: After exclusions, 73,312 men and 81,663 women remained in the final analytic cohort; 1567 men (227 with type 2 DM) and 1242 women (108 with type 2 DM) were diagnosed with colon or rectal cancer by 2007. Among men, type 2 DM was associated with increased risk of incident CRC compared to not having type 2 DM (RR: 1.24; 95% CI: 1.08−1.44); risk was higher for participants with type 2 DM using insulin (RR: 1.36; 95% CI: 1.05−1.78), and participants with type 2 DM not using insulin (RR: 1.22, 95% CI: 1.04−1.45). Among women, type 2 DM and insulin use were not associated with risk of incident CRC (RR: 1.01; 95% CI: 0.82−1.23 and RR: 0.95; 95% CI: 0.64−1.41, respectively). Conclusions: There is a modest association between type 2 DM and CRC among men, but not women. Insulin use is not associated with a substantially increased risk of CRC. [ABSTRACT FROM AUTHOR]

Background & Aims: Hyperinsulinemia is a putative colorectal cancer (CRC) risk factor. Insulin resistance (IR) commonly precedes hyperinsulinemia and can be quantitatively measured by using the homeostasis model assessment–insulin resistance (HOMA-IR) index. To date, few studies have directly examined serum insulin as an indicator of CRC risk, and none have reported associations on the basis of HOMA-IR. Methods: We performed a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (n = 29,133). Baseline exposure and fasting serum biomarker data were available for 134 incident CRC case and 399 non-case subjects. HOMA-IR was derived as fasting insulin × fasting glucose/22.5. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by using age-adjusted and multivariable-adjusted Cox proportional hazards regression models. Results: Median (interquartile range) values for serum insulin, glucose, and HOMA-IR were 4.1 (2.9–7.2) mIU/L, 101 (94–108) mg/dL, and 0.99 (0.69–1.98) for case subjects and 4.1 (2.7–6.1) mIU/L, 99 (93–107) mg/dL, and 1.02 (0.69–1.53) for non-case subjects, respectively. On the basis of comparison of the highest versus lowest quartiles for each biomarker, insulin (HR, 1.84; 95% CI, 1.03–3.30) and HOMA-IR (HR, 1.85; 95% CI, 1.06–3.24) were significantly associated with incident CRC, whereas glucose was marginally associated with incident CRC (HR, 1.70; 95% CI, 0.92–3.13) in age-adjusted risk models. However, trends across biomarker quartiles were somewhat inconsistent (P trend = .12, .04, and .12, respectively), and multivariable adjustment generally attenuated the observed risk estimates. Conclusions: Data from this prospective study of male smokers provide limited support for hyperinsulinemia, hyperglycemia, and/or insulin resistance as CRC risk factors. [Copyright &y& Elsevier]

Background & Aims: Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women’s Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times. Methods: We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest. Results: Patients’ mean age (P = .03) and tumors’ anatomic subsite (P = .0001) and grade (P = .0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07−2.89, compared with the traditional pathway). Conclusions: We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis. [Copyright &y& Elsevier]

Background & Aims: Colorectal cancer (CRC) is the third most common cancer worldwide. Several preclinical and observational studies have shown that bisphosphonates may have chemopreventive effects against CRC. We performed a systematic review and meta-analysis of all studies evaluating the effect of bisphosphonates on the risk of CRC. Methods: We conducted a systematic search of Medline, Embase, and Web of Science through August 2012 and manually reviewed the literature. Studies were included if they met the following criteria: (1) evaluated and clearly defined exposure to bisphosphonates, (2) reported CRC outcomes, and (3) reported relative risks or odds ratio (OR) or provided sufficient data for their estimation. Summary OR estimates with 95% confidence intervals (CIs) were estimated using the random-effects model. Statistical heterogeneity was assessed with the Cochran''s Q and I2 statistic. Results: We analyzed data from 6 population-based observational studies reporting 20,001 cases of CRC in 392,106 patients. A meta-analysis of these studies showed a statistically significant 17% reduction in CRC incidence with bisphosphonate use (unadjusted OR, 0.83; 95% CI, 0.76–0.90), with borderline heterogeneity across studies (Cochran''s Q, P = .16; I2 = 37%). This effect persisted after correcting for multiple covariates in individual studies (adjusted OR, 0.85; 95% CI, 0.74–0.98). When the analysis was restricted to women only, use of bisphosphonates was associated with a 16% reduction in CRC incidence, which bordered on statistical significance (n = 5 studies; adjusted OR, 0.84; 95% CI, 0.70–1.01). This chemopreventive effect of bisphosphonates was observed for proximal and distal colon cancers, as well as rectal cancer, independently. Conclusions: Based on meta-analysis, bisphosphonate use is associated with a modest, but statistically significant, reduction in CRC risk. [Copyright &y& Elsevier]