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A germline alteration of ERBB2 increases the risk of breast cancer in Chinese Han women with a familial history of malignant tumors.

ABSTRACT: Previous studies have demonstrated that a family history of breast cancer is considered a risk factor, and hereditary factors may be involved in breast cancer pathogenesis. Next-generation sequencing techniques were used to analyze 111 cancer-associated genes in patients with breast cancer with a familial history of malignant tumors in the pre-experiment and a novel variant, receptor tyrosine-protein kinase erbB-2 (ERBB2) c.338G>A: p.R113Q was identified in two cases of breast cancer. ERBB2 is considered an important oncogene, and overexpression or mutation of the ERBB2 gene may lead to the occurrence or metastasis of tumors. To assess a potential association between rs185670819 and breast cancer, 117 patients with breast cancer and a familial history of any cancer, who were diagnosed by experienced pathologists at the Xijing Hospital (Shaanxi, China) between July 2015 and December 2016, were recruited. The presence of the missense variant was confirmed using bi-directional Sanger sequencing of samples from the patients with breast cancer and 250 healthy controls. The effects of the missense mutation on the structure and function of ERBB2 were analyzed in silico. The missense variant, R113Q, in patients with breast cancer with a familial history of malignant tumors in China, was present in 8 patients [6.8% (95% CI: 3.21-13.45)] and 3 of 250 healthy controls [1.2% (95% CI: 0.31-3.76; OR=6.04, 95% CI: 1.573-23.214, P=0.009)]. Of the 8 patients with the R113Q variant, 6 patients had a family history of cancer of the digestive system. The present study suggests that ERBB2 c.338G>A: p.R113Q may be a potential risk factor in the development and progression of breast cancer.

SUBMITTER: Ju Y

PROVIDER: S-EPMC6704318 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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A germline alteration of ERBB2 increases the risk of breast cancer in Chinese Han women with a familial history of malignant tumors.

Ju Yan Y Wang Lifeng L Ta Shengjun S Shu Rui R Yang Shanling S Gao Xican X Song Hongping H Liu Liwen L

Oncology letters 20190722 3

Previous studies have demonstrated that a family history of breast cancer is considered a risk factor, and hereditary factors may be involved in breast cancer pathogenesis. Next-generation sequencing techniques were used to analyze 111 cancer-associated genes in patients with breast cancer with a familial history of malignant tumors in the pre-experiment and a novel variant, receptor tyrosine-protein kinase erbB-2 (ERBB2) c.338G>A: p.R113Q was identified in two cases of breast canc ...[more]

PMID: 31452768

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Project description:We investigated a Spanish and Catalan family in which multiple cancer types tracked across three generations, but for which no genetic etiology had been identified. Whole-exome sequencing of germline DNA from multiple affected family members was performed to identify candidate variants to explain this occurrence of familial cancer. We discovered in all cancer-affected family members a single rare heterozygous germline variant (I654V, rs1801201) in ERBB2/HER2, which is located in a transmembrane glycine zipper motif critical for ERBB2-mediated signaling and in complete linkage disequilibrium (D' = 1) with a common polymorphism (I655V, rs1136201) previously reported in some populations as associated with cancer risk. Because multiple cancer types occurred in this family, we tested both the I654V and the I655V variants for association with cancer across multiple tumor types in 6,371 cases of Northern European ancestry drawn from The Cancer Genome Atlas and 6,647 controls, and found that the rare variant (I654V) was significantly associated with an increased risk for cancer (OR = 1.40; P = 0.021; 95% confidence interval (CI), 1.05-1.89). Functional assays performed in HEK 293T cells revealed that both the I655V single mutant (SM) and the I654V;I655V double mutant (DM) stabilized ERBB2 protein and activated ERBB2 signaling, with the DM activating ERBB2 significantly more than the SM alone. Thus, our results suggest a model whereby heritable genetic variation in the transmembrane domain activating ERBB2 signaling is associated with both sporadic and familial cancer risk, with increased ERBB2 stabilization and activation associated with increased cancer risk. PREVENTION RELEVANCE: By performing whole-exome sequencing on germline DNA from multiple cancer-affected individuals belonging to a family in which multiple cancer types track across three generations, we identified and then characterized functional common and rare variation in ERBB2 associated with both sporadic and familial cancer. Our results suggest that heritable variation activating ERBB2 signaling is associated with risk for multiple cancer types, with increases in signaling correlated with increases in risk, and modified by ancestry or family history.

Dataset Information

A germline alteration of ERBB2 increases the risk of breast cancer in Chinese Han women with a familial history of malignant tumors.

Publications

A germline alteration of <i>ERBB2</i> increases the risk of breast cancer in Chinese Han women with a familial history of malignant tumors.

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