paywalled: Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation - Wiley Online Library

Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation

Abstract

Mismatch repair (MMR) malfunction causes the accumulation of mismatches in the genome leading to genomic instability and cancer. The inactivation of an MMR gene (MSH2, MSH6, MLH1 or PMS2) with an inherited mutation causes Lynch syndrome (LS), a dominant susceptibility to cancer. MMR gene variants of uncertain significance (VUS) may be pathogenic mutations which cause LS, may result in moderately increased cancer risks, or may be harmless polymorphisms. Our study suggests that an inherited MMR VUS individually assessed as proficient may, however, in a pair with another MMR VUS found in the same colorectal cancer (CRC) patient have a concomitant contribution to the MMR deficiency. Here, eight pairs of MMR gene variants found in cancer patients were functionally analyzed in an in vitro MMR assay. Although the other pairs do not suggest a compound deficiency, the MSH2 VUS pair c.380A>G/c.982G>C (p.Asn127Ser/p.Ala328Pro), which nearly halves the repair capability of the wild type MSH2 protein, is presumed to increase the cancer risk considerably. Moreover, two MSH6 variants, c.1304T>C (p.Leu435Pro) and c.1754T>C (p.Leu585Pro), were shown to be MMR deficient. The role of one of the most frequently reported MMR gene VUS, MSH2 c.380A>G (p.Asn127Ser), is especially interesting, since its concomitant defect with another variant could finally explain its recurrent occurrence in CRC patients.

Genetic Variations in Stem Cell-Related Genes and Colorectal Cancer Prognosis

Genetic Variations in Stem Cell-Related Genes and Colorectal Cancer Prognosis:

Abstract

Background  

Many properties of cancer cells are reminiscent of those in normal stem cells. Genes important to stem cell development have been significantly implicated in the etiology and clinical outcome of colorectal cancer (CRC). However, the associations of genetic variations in these genes with CRC prognosis have not yet been elucidated.

Methods  

We analyzed the effects of eight potentially functional single nucleotide polymorphisms (SNPs) in six stem cell-related genes on the prognosis of a well-characterized population of 380 Chinese CRC patients diagnosed from February 2006 to January 2010.

Results 

The most significant finding was related to rs879882, a variant in the 5′ region of POU5F1 gene which encodes a protein essential for embryonic stem cell self-renewal and pluripotency, and induced pluripotent stem cell reprogramming. The variant-containing genotypes of rs879882 were associated with an increased risk of recurrence (hazard ratio [HR] = 2.10, 95 % confidence interval [CI] 1.17–3.76, P = 0.01). In chemotherapy-stratified analysis, the association remained borderline significant in patients receiving chemotherapy (HR = 1.97, 95 % CI 0.89–4.34, P = 0.09). In addition, a nonsynonymous SNP of APC gene was also significantly associated with recurrence risk in chemotherapy-treated patients (HR = 2.63, 95 % CI 1.14–6.06 P = 0.02). Further analyses showed a combined effect of the two SNPs in predicting CRC recurrence in patients receiving chemotherapy (P = 0.04) but not in those without chemotherapy (P = 0.43). Moreover, an exploratory multivariate assessment model indicated that these two variants enhanced the power to predict recurrence after chemotherapy.

Conclusion 

We presented one of the first epidemiologic studies showing that stem cell-related genetic variants may impact CRC clinical outcomes, especially in chemotherapy-treated patients.

• Journal Journal of Gastrointestinal Cancer

open access: Apr 2012 -Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC) - Journal of Internal Medicine (BRCA, Lynch, high/low penetrance mutations....)

Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC) -  Journal of Internal Medicine

open access pdf file


 "In this article, we review the current knowledge of the inherited genetics of epithelial ovarian cancer (EOC) susceptibility and clinical outcome. We focus on recent developments in identifying low-penetrance susceptibility genes and the role of the ovarian cancer association consortium (OCAC) in these discoveries. The OCAC was established to facilitate large-scale replication analyses for reported genetic associations for EOC. Since its inception, the OCAC has conducted both candidate gene and genome-wide association studies (GWAS); the latter has identified six established loci for EOC susceptibility, most of which showed stronger association with the serous histological subtype. Future GWAS and sequencing studies are likely to result in the discovery of additional susceptibility loci and may result in established associations with clinical outcome. Additional rare and uncommon ovarian cancer loci will likely be uncovered from high-throughput next-generation sequencing studies. Applying these novel findings to establish improved preventative and clinical intervention strategies will be one of the major challenges of future work....

abstract: Shared Genetic Basis for Breast Cancer and Breast Density

Shared Genetic Basis for Breast Cancer and Breast Density:

" Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants."

Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer.