Dataset Information

Functional germline variants as potential co-oncogenes.

ABSTRACT: Germline variants that affect the expression or function of proteins contribute to phenotypic variation in humans and likely determine individual characteristics and susceptibility to diseases including cancer. A number of high penetrance germline variants that increase cancer risk have been identified and studied, but germline functional polymorphisms are not typically considered in the context of cancer biology, where the focus is primarily on somatic mutations. Yet, there is evidence from familial cancers indicating that specific cancer subtypes tend to arise in carriers of high-risk germline variants (e.g., triple negative breast cancers in mutated BRCA carriers), which suggests that pre-existing germline variants may determine which complementary somatic driver mutations are needed to drive tumorigenesis. Recent genome sequencing studies of large breast cancer cohorts reported only a handful of highly recurrent driver mutations, suggesting that different oncogenic events drive individual cancers. Here, we propose that germline polymorphisms can function as oncogenic modifiers, or co-oncogenes, and these determine what complementary subsequent somatic events are required for full malignant transformation. Therefore, we propose that germline aberrations should be considered together with somatic mutations to determine what genes drive cancer and how they may be targeted.

SUBMITTER: Agarwal D

PROVIDER: S-EPMC5700137 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Functional germline variants as potential co-oncogenes.

Agarwal Divyansh D Nowak Christoph C Zhang Nancy R NR Pusztai Lajos L Hatzis Christos C

NPJ breast cancer 20171122

Germline variants that affect the expression or function of proteins contribute to phenotypic variation in humans and likely determine individual characteristics and susceptibility to diseases including cancer. A number of high penetrance germline variants that increase cancer risk have been identified and studied, but germline functional polymorphisms are not typically considered in the context of cancer biology, where the focus is primarily on somatic mutations. Yet, there is evidence from fam ...[more]

PMID: 29177190

Similar Datasets

Project description:BackgroundLynch syndrome (LS) is a hereditary condition characterized by a high risk of colorectal cancer, endometrial cancer, and other neoplasia associated with germline alterations in DNA mismatch repair genes. The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome. Next-generation sequencing (NGS) enables the simultaneous sequencing of a large number of hereditary cancer genes. Here, we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS.MethodsA cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture. The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants. The findings of NGS were confirmed by Sanger sequencing. When possible, genetic analyses of the new findings in the proband's relatives were also performed by Sanger sequencing.ResultsWe identified five families (6%), out of 84, with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer-predisposing genes: [MLH1-BRCA2-NBN], [MLH1-BRCA1], [MSH2-ATM], [MSH6-NF1], and [MLH1-FANCA]. Interestingly, only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants. The family with three pathogenic variants of the [MLH1-BRCA2-NBN] genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome.ConclusionsOur results showed that the co-occurrence of more than one pathogenic variant in cancer-predisposing genes was remarkable among cases of LS. In most cases, no clinicial manifestations were associated with the secondary pathogenic variants. Further studies are needed to confirm these findings and elucidate their clinical impact. Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.

Dataset Information

Functional germline variants as potential co-oncogenes.

Publications

Functional germline variants as potential co-oncogenes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets