Dataset Information

A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ER? expression.

ABSTRACT: Breast cancer is the most frequent tumor in women, and in nearly two-thirds of cases, the tumors express estrogen receptor ? (ER?, encoded by ESR1). Here, we performed whole-exome sequencing of 16 breast cancer tissues classified according to ESR1 expression and 12 samples of whole blood, and detected 310 somatic mutations in cancer tissues with high levels of ESR1 expression. Of the somatic mutations validated by a different deep sequencer, a novel nonsense somatic mutation, c.2830?C>T; p.Gln944*, in transcriptional regulator switch-independent 3 family member A (SIN3A) was detected in breast cancer of a patient. Part of the mutant protein localized in the cytoplasm in contrast to the nuclear localization of ER?, and induced a significant increase in ESR1 mRNA. The SIN3A mutation obviously enhanced MCF7 cell proliferation. In tissue sections from the breast cancer patient with the SIN3A c.2830?C>T mutation, cytoplasmic SIN3A localization was detected within the tumor regions where nuclear enlargement was observed. The reduction in SIN3A mRNA correlates with the recurrence of ER-positive breast cancers on Kaplan-Meier plots. These observations reveal that the SIN3A mutation has lost its transcriptional repression function due to its cytoplasmic localization, and that this repression may contribute to the progression of breast cancer.

SUBMITTER: Watanabe K

PROVIDER: S-EPMC6207735 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression.

Watanabe Kenji K Yamamoto Shigeru S Sakaguti Syuiti S Isayama Keishiro K Oka Masaaki M Nagano Hiroaki H Mizukami Yoichi Y

Scientific reports 20181030 1

Breast cancer is the most frequent tumor in women, and in nearly two-thirds of cases, the tumors express estrogen receptor α (ERα, encoded by ESR1). Here, we performed whole-exome sequencing of 16 breast cancer tissues classified according to ESR1 expression and 12 samples of whole blood, and detected 310 somatic mutations in cancer tissues with high levels of ESR1 expression. Of the somatic mutations validated by a different deep sequencer, a novel nonsense somatic mutation, c.2830 C>T; p.Gln94 ...[more]

PMID: 30375428

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Project description:BackgroundNext-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the value of clinical whole-exome sequencing (WES) and whole-genome sequencing (WGS) for cancer care is less defined, specifically as the majority of variants found using these technologies are of uncertain significance.Patients and methodsWe used the Cancer Genome Interpreter and WGS in 726 tumours spanning 10 cancer types to identify drug repurposing opportunities. We compare the ability of WGS to detect actionable variants, tumour mutation burden (TMB) and microsatellite instability (MSI) by using in silico down-sampled data to mimic WES, a comprehensive sequencing panel and a hotspot mutation panel.ResultsWe reveal drug repurposing opportunities as numerous biomarkers are shared across many solid tumour types. Comprehensive panels identify the majority of approved actionable mutations, with WGS detecting more candidate actionable mutations for biomarkers currently in clinical trials. Moreover, estimated values for TMB and MSI vary when calculated from WGS, WES and panel data, and are dependent on whether all mutations or only non-synonymous mutations were used. Our results suggest that TMB and MSI thresholds should not only be tumour-dependent, but also be sequencing platform-dependent.ConclusionsThere is a large opportunity to repurpose cancer drugs, and these data suggest that comprehensive sequencing is an invaluable source of information to guide clinical decisions by facilitating precision medicine and may provide a wealth of information for future studies. Furthermore, the sequencing and analysis approach used to estimate TMB may have clinical implications if a hard threshold is used to indicate which patients may respond to immunotherapy.

Dataset Information

A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ER? expression.

Publications

A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression.

Similar Datasets

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