Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.

Importance: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.

Objective: To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.

Design, Setting, And Participants: Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011.

Oral bisphosphonate use and risk of postmenopausal endometrial cancer.

Purpose: Bisphosphonates are common medications used for the treatment of osteoporosis and are also used to reduce metastases to bone in patients with cancer. Several studies, including the Women's Health Initiative (WHI), have found that use of bisphosphonates is associated with reduced risk of developing breast cancer, but less is known about associations with other common malignancies. This study was aimed at examining the effects of bisphosphonates on the risk of endometrial cancer.

A model to determine colorectal cancer risk using common genetic susceptibility loci.

Background & Aims: Risk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci.

Methods: By using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations.

Blood lipids and colorectal polyps: testing an etiologic hypothesis using phenotypic measurements and Mendelian randomization.

Purpose: Studies linking cholesterol levels to the development of colorectal neoplasia are inconsistent, and Mendelian randomization has been suggested as a way to help avoid problems with confounding and reverse causation.

Methods: We genotyped individuals who received a colonoscopy at Group Health (1998-2007) for 96 of 102 single-nucleotide polymorphisms identified by the Global Lipids Genetics Consortium. Participants included 139 advanced adenoma cases, 518 non-advanced adenoma cases, 380 non-adenomatous polyp cases, and 754 polyp-free controls.

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

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.

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

Background: 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.

Rare circulating microRNAs as biomarkers of colorectal neoplasia.

Background: MicroRNAs (miRNAs) are regulatory RNAs, stable in circulation, and implicated in colorectal cancer (CRC) etiology and progression. Therefore they are promising as early detection biomarkers of colorectal neoplasia. However, many circulating miRNAs are highly expressed in blood cells, and therefore may not be specific to colorectal neoplasia.

Association between molecular subtypes of colorectal cancer and patient survival.

Background And Aims: 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.

No evidence of gene-calcium interactions from genome-wide analysis of colorectal cancer risk.

Background: Calcium intake may reduce risk of colorectal cancer, but the mechanisms remain unclear. Studies of interaction between calcium intake and SNPs in calcium-related pathways have yielded inconsistent results.

Methods: To identify gene-calcium interactions, we tested interactions between approximately 2.

Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A.

The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform 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, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P<5 × 10(-8)) in 16,823 cases and 18,211 controls of European ancestry.

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

Background: 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.

Methods: 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.

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.

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

Background: 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.

Methods: This study comprised N = 4,284 incident colorectal cancer cases enrolled in the Colon Cancer Family Registry via population-based cancer registries.

Variation in the association between colorectal cancer susceptibility loci and colorectal polyps by polyp type.

We conducted a case-control study of the association between subsets of colorectal polyps, including adenomas and serrated polyps, and single-nucleotide polymorphisms (SNPs) related to colorectal cancer through prior genome-wide association studies (GWAS). Participants were enrollees in the Group Health Cooperative (Seattle, Washington) aged 24-79 years who received a colonoscopy from 1998 to 2007, donated a buccal or blood sample, and completed a structured questionnaire. We performed genotyping of 13 colorectal cancer susceptibility SNPs.

Reproductive windows, genetic loci, and breast cancer risk.

Purpose: The reproductive windows between age at menarche and age at first birth (standardized age at first birth) and from menarche to menopause (reproductive lifespan) may interact with genetic variants in association with breast cancer risk.

Methods: We assessed this hypothesis in 6131 breast cancer cases and 7274 controls who participated in the population-based Collaborative Breast Cancer Study. Risk factor information was collected through telephone interviews, and DNA samples were collected on a subsample (N= 1484 cases, 1307 controls) to genotype for 13 genome-wide association study-identified loci.

Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis.

To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.

Cervical screening and cervical cancer death among older women: a population-based, case-control study.

Recent research suggests that cervical screening of older women is associated with a considerable decrease in cervical cancer incidence. We sought to quantify the efficacy of cervical cytology screening to reduce death from this disease. Among enrollees of 2 US health plans, we compared Papanicolaou smear screening histories of women aged 55-79 years who died of cervical cancer during 1980-2010 (cases) to those of women at risk of cervical cancer (controls).

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.

Fatal breast cancer risk in relation to use of unopposed estrogen and combined hormone therapy.

Use of combined hormone therapy (CHT) is associated with increased breast cancer incidence, but it is unclear whether this translates into increased breast cancer mortality. To address this question, we conducted a population-based nested case-control study in Saskatchewan, Canada, where a population-based prescription drug database has existed since 1975. We evaluated fatal breast cancer risk in relation to recency and duration of use of CHT and unopposed estrogen hormone therapy (EHT).

Modification of breast cancer risk according to age and menopausal status: a combined analysis of five population-based case-control studies.

While several risk factors for breast cancer have been identified, studies have not consistently shown whether these factors operate more strongly at certain ages or for just pre- or postmenopausal women. We evaluated whether risk factors for breast cancer differ according to age or menopausal status. Data from five population-based case-control studies conducted during 1988-2008 were combined and analyzed.

Dietary cadmium exposure and risk of breast, endometrial, and ovarian cancer in the Women's Health Initiative.

Background: In vitro and animal data suggest that cadmium, a heavy metal that contaminates some foods and tobacco plants, is an estrogenic endocrine disruptor. Elevated estrogen exposure is associated with breast, endometrial, and ovarian cancer risk.

Objectives: We examined the association between dietary cadmium intake and risk of these cancers in the large, well-characterized Women's Health Initiative (WHI).

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?

Objective: To 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.

Methods: We 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.

Role of tumour molecular and pathology features to estimate colorectal cancer risk for first-degree relatives.

Objective: To estimate risk of colorectal cancer (CRC) for first-degree relatives of CRC cases based on CRC molecular subtypes and tumour pathology features.

Design: We studied a cohort of 33,496 first-degree relatives of 4853 incident invasive CRC cases (probands) who were recruited to the Colon Cancer Family Registry through population cancer registries in the USA, Canada and Australia. We categorised the first-degree relatives into four groups: 28,156 of 4095 mismatch repair (MMR)-proficient probands, 2302 of 301 MMR-deficient non-Lynch syndrome probands, 1799 of 271 suspected Lynch syndrome probands and 1239 of 186 Lynch syndrome probands.