Mismatch repair gene pathogenic germline variants in a population-based cohort of breast cancer

AbstractThe advent of gene panel testing is challenging the previous practice of using clinically defined cancer family  syndromes to inform single-gene genetic screening. Individual and family cancer histories that would have previously indicated testing of a single gene or a small number of related genes are now, increasingly, leading to screening across gene panels that contain larger numbers of genes. We have a pplied a gene panel test that included four DNA mismatch repair (MMR) genes (MLH1,MSH2,MSH6 andPMS2) to an Australian population-based case –control-family study of breast cancer. Altogether, eight pathogenic variants in MMR genes were identified: six in 1421 case-families (0.4%, 4MSH6 and 2PMS2) and two in 833 control-families (0.2%, one each ofMLH1 andMSH2). This testing highlights the current and future challenges for clinical genetics in the context of anticipated gene panel-based population-based screening that includes the MMR genes. This testing is likely to provide additional opportunities for cancer prevention via cascade testing for Lynch syndrome and precision medicine for breast cancer treatment.
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research

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In this study, we performed Targeted Next-Generation Sequencing of MMR pathway genes MLH1, MSH2, MSH6, EPCAM, and PMS2 in a cohort of 711 patients with hereditary BC, 60 patients with sporadic BC, and 492 healthy donors. Sixty-nine patients (9.7%) with hereditary BC harbored at least one germline mutation in the MMR pathway genes, of them 32 patients (4.5%) harbored mutations in MMR pathway genes which we define as pathogenic or likely pathogenic, and of them 26 patients (3.6%) did not have any pathogenic mutations in DDR pathway genes, compared to two mutations in MMR pathway genes (0.4%) detected in a group of 492 health...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In conclusion, somatic mutational signatures suggest that conventional MMR status of tumor tissues is likely to underestimate the significance of the predisposing MMR defects as contributors to breast tumorigenesis in LS. PMID: 32292574 [PubMed]
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
ConclusionThe patient presented represents the first reported case where both next generation sequencing (NGS) forBRCA LOH and MMR IHC testing of her breast cancer were performed and underscores the importance of using NGS including the reported mutational allelic frequency (MAF) and IHC use to predict the likely responsiveness to the recently approved PARP inhibitors and checkpoint inhibitor therapies (Robson et al in N Engl J Med 377:523 –533, 2017, Lemery et al in 377(15):1409–1412,https://doi.org/10.1056/NEJMp1709968, 2017), key because the gatekeeper transforming event for tumors related to inherited cance...
Source: Breast Cancer Research and Treatment - Category: Cancer & Oncology Source Type: research
This report underlines the need for broad panel gene testing in lieu of single-gene or syndrome-focused gene screening and evaluation of the effects of multiple pathogenic or modifier variants on the phenotypic spectrum of the disease.
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
ConclusionsSporadic dMMR breast cancers are extremely rare (Davies et al. in Cancer Res 77:4755 –4762, 2017). It seems reasonable to conclude that identifying a dMMR breast cancer in a patient with known LS strongly suggests that her LS is breast cancer-predisposing. LS patients with dMMR breast cancers might therefore be considered for above-average breast cancer screening for the developme nt of additional breast cancers. Also, the FDA recently granted approval of checkpoint inhibitor therapy for all metastatic dMMR solid malignancies (Lemery et al. in N Engl J Med 377:1409–1412, 2017). MMR expression assays ...
Source: Breast Cancer Research and Treatment - Category: Cancer & Oncology Source Type: research
This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines. Introduction von Hippel-Lindau (VHL) disease (MIM 193300) is a rare autosomal dominant cancer syndrome caused by germline mutations in the VHL tumor suppressor gene (Latif et al., 1993; Lonser et al., 2003). Generally, the first VHL-related manifestation occurred in the third decade of patient’s life, and the penetrance is more than 90% by 70 years old (Ong et al., 2007; Nordstrom-O’brien et al., 2010). Patients may develop...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precurso...
Source: Clinical Genitourinary Cancer - Category: Cancer & Oncology Authors: Tags: Hered Cancer Clin Pract Source Type: research
ConclusionsThe CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC inpath_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs inpath_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor le...
Source: Hereditary Cancer in Clinical Practice - Category: Cancer & Oncology Source Type: research
Women developing endometrial cancer after tamoxifen treatment for breast cancer are more likely to develop tumours with poorer prognostic features and exhibit poorer survival after adjustment for these prognostic features. Results indicate the importance of longer ‐term monitoring of women treated with tamoxifen for cancer symptoms. Report of prior cancer is a significant indicator of MMR pathogenic variant status, but molecular analysis of endometrial tumors at diagnosis is warranted to detect all patients with Lynch Syndrome. AbstractWe hypothesized that endometrial carcinoma (EC) patients with a prior cancer diagnosis...
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research
CONCLUSIONS: Our study results showed BC in Japanese females with LS to be an MSI-H tumor, which was ER and PgR positive and HER2 negative. PMID: 30446972 [PubMed - as supplied by publisher]
Source: Breast Cancer - Category: Cancer & Oncology Authors: Tags: Breast Cancer Source Type: research
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