Exome sequencing in a breast cancer family withoutBRCAmutation

Abstract

PurposeWe performed exome sequencing in a breast cancer family without BRCA mutations.Materials and MethodsA family that three sisters have a history of breast cancer was selected for analysis. There were no family members with breast cancer in the previous generation. Genetic testing for BRCA mutation was negative, even by the multiplex ligation-dependent probe amplification method. Two sisters with breast cancer were selected as affected members, while the mother of the sisters was a non-affected member. Whole exome sequencing was performed on the HiSeq 2000 platform with paired-end reads of 101 bp in the three members.ResultsWe identified 19,436, 19,468, and 19,345 single-nucleotide polymorphisms (SNPs) in the coding regions. Among them, 8,759, 8,789, and 8,772 were non-synonymous SNPs, respectively. After filtering out 12,843 synonymous variations and 12,105 known variations with indels found in the dbSNP135 or 1000 Genomes Project database, we selected 73 variations in the samples from the affected sisters that did not occur in the sample from the unaffected mother. Using the Sorting Intolerant From Tolerant (SIFT), PolyPhen-2, and MutationTaster algorithms to predict amino acid substitutions, the XCR1, DLL1, TH, ACCS, SPPL3, CCNF, and SRL genes were risky among all three algorithms, while definite candidate genes could not be conclusively determined.ConclusionUsing exome sequencing, we found 7 variants for a breast cancer family without BRCA mutations. Genetic evidence of disease association should be confirmed by future studies.

Locoregional Recurrence by Tumor Biology in Breast Cancer Patients after Preoperative Chemotherapy and Breast Conservation Treatment

“…These subtypes, including luminal, HER2, and basal-like, can be defined by gene expression profiling [6,20,21] or approximations to this classification using IHC [8,9]. Clinicians should consider these features for proper assessment of the relevant evidence and decide on an appropriate therapeutic course of action.…”

A Review of Whole-Exome Sequencing Efforts Toward Hereditary Breast Cancer Susceptibility Gene Discovery

“…[] and Noh et al. [], it is less favorable to include unaffected family members in the initial SA used to filter exome‐sequenced variants, since they could be nonpenetrant carriers.…”

“…As demonstrated in the two BC WES publications that exome-sequenced a large number of family members [Lynch et al, 2013;Wen et al, 2014], the shared variant list can still be taxing, but as the number of BC families that are exome-sequenced increases and investigators join BC consortiums, such as COMPLEXO [Complexo et al, 2013], genetic overlap should be identified. Noteworthy, it is possible that BC risk variants are so rare that they are "family-specific," like the authors of some of the WES studies suggested [Lynch et al, 2013;Wen et al, 2014;Noh et al, 2015], but the conclusions drawn from the corresponding papers are premature. Moreover, to highlight a concern in the papers by Lynch et al [2013] and Noh et al [2015], it is less favorable to include unaffected family members in the initial SA used to filter exome-sequenced variants, since they could be nonpenetrant carriers.…”

“…Missense variants, on the other hand, are typically classified as variants of unknown significance until functional studies and/or conservation and segregation analyses (SA) can supply further information [Easton et al, 2015]. To date, over 35 genes have been suggested to carry high and/or moderate BC risk variants [OMIM R , 2015;Shiovitz and Korde, 2015]; however, only a minority (ß11) of those genes have variants with an established association that meet stringent statistical significance and burden testing requirements [Easton et al, 2015]. Altogether, high-and moderate-risk variants in known BC susceptibility genes are present in less than 30% of BC cases with a suggestive personal or family history [Shiovitz and Korde, 2015].…”

Identification of novel hereditary cancer genes by whole exome sequencing

“…However, most of the breast cancer exome studies reported so far failed to discover genes, whose significance is similar to BRCA1, BRCA2, CHEK2, PALB2, etc. [19][20][21][22]25,28,[132][133][134][135][136]. For example, Snape et al [133] subjected to WES 50 patients with familial breast cancer; they composed the list of promising candidates, but did not communicate yet the results of subsequent case-control study or segregation analysis.…”