MTHFR Glu429Ala and ERCC5 His46His polymorphisms are associated with prognosis in colorectal cancer patients: analysis of two independent cohorts from Newfoundland.

Introduction: In this study, 27 genetic polymorphisms that were previously reported to be associated with clinical outcomes in colorectal cancer patients were investigated in relation to overall survival (OS) and disease free survival (DFS) in colorectal cancer patients from Newfoundland.

Methods: The discovery and validation cohorts comprised of 532 and 252 patients, respectively. Genotypes of 27 polymorphisms were first obtained in the discovery cohort and survival analyses were performed assuming the co-dominant genetic model.

Serotonin transporter gene (SLC6A4) variations are associated with poor survival in colorectal cancer patients.

Prognosis in colorectal cancer patients is quite variable, even after adjustment for clinical parameters such as disease stage and microsatellite instability status. It is possible that the psychological distress experienced by patients, including anxiety and depression, may be correlated with poor prognosis. In the present study, we hypothesize that genetic variations within three genes biologically linked to the stress response, namely serotonin transporter (SLC6A4), brain-derived neurotrophic factor (BDNF), and arginine vasopressin receptor (AVPR1B) genes are associated with prognosis in colorectal cancer patients.

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22.

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e.

Inherited deleterious variants in GALNT12 are associated with CRC susceptibility.

A recent report detailed the occurrence of both somatic and constitutional variants in the GALNT12 gene, located at 9q22.33, in some colorectal cancer (CRC) patients. In this study, we investigate the occurrence of inherited deleterious variants in GALNT12 in 118 families referred to a cancer genetics clinic.

Promoter methylation of Wnt antagonists DKK1 and SFRP1 is associated with opposing tumor subtypes in two large populations of colorectal cancer patients.

Aberrant activation of canonical Wnt signaling is a hallmark event in colorectal carcinogenesis. The Dickkopf-1 (DKK1) and Secreted Frizzled Related Protein 1 (SFRP1) genes encode extracellular inhibitors of Wnt signaling that are frequently silenced by promoter hypermethylation in colorectal cancer (CRC). These methylation events have been identified as prognostic markers of patient outcome and tumor subtype in several cancers but similar roles in CRC have not been comprehensively examined.

A histology-based model for predicting microsatellite instability in colorectal cancers.

Identifying colorectal cancers (CRCs) with high levels of microsatellite instability (MSI-H) is clinically important. MSI-H is a positive prognostic marker for CRC, a predictive marker for resistance to standard 5-fluorouracil-based adjuvant chemotherapy, and an important feature for identifying individuals and families with Lynch syndrome. Our aim was to compare and improve upon the existing predictive pathology models for MSI-H CRCs.

Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer.

Background: We previously identified an association between a mismatch repair gene, MLH1, promoter SNP (rs1800734) and microsatellite unstable (MSI-H) colorectal cancers (CRCs) in two samples. The current study expanded on this finding as we explored the genetic basis of DNA methylation in this region of chromosome 3. We hypothesized that specific polymorphisms in the MLH1 gene region predispose it to DNA methylation, resulting in the loss of MLH1 gene expression, mismatch-repair function, and consequently to genome-wide microsatellite instability.

Increased cancer predisposition in family members of colorectal cancer patients harboring the p.V600E BRAF mutation: a population-based study.

Background: The serrated pathway represents a distinct molecular pathway of colorectal carcinogenesis and is associated with the p.V600E BRAF mutation. The objective of this study is to characterize the cancer family history and clinicopathologic features of colorectal cancer (CRC) patients according to the microsatellite instability (MSI) and BRAF mutation status of their tumors.

dbCPCO: a database of genetic markers tested for their predictive and prognostic value in colorectal cancer.

Colorectal cancer is the third most common cancer with a 5-year survival rate of 30-65%. A portion of the interpatient variability in its clinical outcome is attributed to inherited and somatic genetic factors. Although numerous research articles have investigated these factors in colorectal cancer, there has not been a central resource, such as a public database, that compiles these findings.

Case-control study of overweight, obesity, and colorectal cancer risk, overall and by tumor microsatellite instability status.

Background: Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%-20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status.

Validity of random-digit-dialing in recruiting controls in a case-control study.

Objectives: To evaluate whether the participating controls represented the underlying population in a colorectal cancer case-control study in a geographically isolated North American population.

Methods: The characteristics of the study controls recruited through Random-digit-dialing (RDD) were compared with those in the corresponding target population estimates.

Results: Participating controls were more likely to have higher levels of education and income and were less likely to be smokers.

Prediction of Lynch syndrome in consecutive patients with colorectal cancer.

Background: Lynch syndrome is caused by inherited mutations in DNA mismatch repair genes (primarily MSH2, MLH1, MSH6, and PMS2) and is one of the most prevalent inherited cancer syndromes. Several models have been developed to predict the occurrence of Lynch syndrome in high-risk patients and families, but it is not known how these models compare with one another or how they perform for colorectal cancer patients from the general population. We used data from such patients to test the ability of four models--Leiden, MMRpredict, PREMM(1,2), and MMRpro--to distinguish between those who did and did not carry DNA mismatch repair gene mutations.

MSH2 118T>C and MSH6 159C>T promoter polymorphisms and the risk of colorectal cancer.

The most important indicator of colorectal cancer (CRC) risk is the presence of family history of the disease. Inherited genetic changes, such as single nucleotide polymorphisms, in key candidate genes may contribute to CRC risk. We investigated whether promoter polymorphisms in DNA mismatch repair (MMR) genes MSH2 and MSH6 are associated with the risk of CRC.

Cytochrome P450 17A1 and catechol O-methyltransferase polymorphisms and age at Lynch syndrome colon cancer onset in Newfoundland.

Purpose: Lynch syndrome is a cancer predisposition syndrome which includes colon cancer. It is caused by inherited defects in DNA mismatch repair genes. Sporadic colon cancers are influenced by exogenous hormones (e.

MLH1 -93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer.

Background: Although up to 30% of patients with colorectal cancer have a positive family history of colorectal neoplasia, few colorectal cancers can be explained by mutations in high-penetrance genes. We investigated whether polymorphisms in DNA mismatch repair genes are associated with the risk of colorectal cancer.

Methods: We genotyped 929 case patients and 1098 control subjects from Ontario and 430 case patients and 275 control subjects from Newfoundland and Labrador for five polymorphisms in the mismatch repair genes MLH1 and MSH2 with the fluorogenic 5' nuclease assay.

A new variant database for mismatch repair genes associated with Lynch syndrome.

Mutations in some mismatch repair (MMR) genes are associated with Lynch syndrome (LS; also called hereditary nonpolyposis colorectal cancer [HNPCC]), an autosomal dominant cancer susceptibility syndrome. Colorectal cancer (CRC) is the most frequent cancer observed in LS. However, tumors occur at a variety of extracolonic sites and individuals may have multiple primary cancers.

A comparison of multi-layer neural network and logistic regression in hereditary non-polyposis colorectal cancer risk assessment.

Hereditary non-polyposis colorectal cancer (HN-PCC) is one of the most common autosomal dominant diseases in developed countries. Here, we report on a system to identify the risk of a family having HNPCC based on its history. This is important since population-wide genetic screening for HNPCC is not currently considered feasible due to its complexity and expense.

Hereditary non-polyposis colorectal cancer risk assessment based on AI analysis of pedigree data.

Colorectal cancer (CRC) is one of the most common fatal cancers in developed countries and represents a significant public-health issue. About 3-5% of patients with CRC have hereditary non-polyposis colorectal cancer (HNPCC). Cancer morbidity and mortality can be reduced if early and intensive screening is pursued.

Cancer risk analysis in families with hereditary nonpolyposis colorectal cancer.

Colorectal cancer (CRC) is one of the most common fatal cancers in developed countries and represents a significant public-health issue. About 3%-5% of patients with CRC have hereditary nonpolyposis colorectal cancer (HNPCC). Cancer morbidity and mortality can be reduced if early and intensive screening is pursued.

High frequency of hereditary colorectal cancer in Newfoundland likely involves novel susceptibility genes.

Purpose: Newfoundland has one of the highest rates of colorectal cancer in North America. The most common hereditary form of colorectal cancer is hereditary nonpolyposis colorectal cancer caused by mutations in genes involved in mismatch repair. Our purpose was to determine the proportion of hereditary colorectal cancer and to determine the genetic basis of disease in both population and clinically referred cohorts from Newfoundland.

Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates.

Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. We identified two large pedigrees segregating the disorder in an isolated population living in Newfoundland and performed a 5-cM genome scan. Linkage analysis identified a locus mapping to 12p13.