Using Next generation Sequencing to Redefine BRCAness in Triple-Negative Breast Cancer.

Using Next generation Sequencing to Redefine BRCAness in Triple-Negative Breast Cancer.:

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Using Next generation Sequencing to Redefine BRCAness in Triple-Negative Breast Cancer.

Cancer Sci. 2020 Jan 20;:

Authors: Lin PH, Chen M, Tsai LW, Lo C, Yen TC, Huang TY, Chen CK, Fan SC, Kuo SH, Huang CS

Abstract

BRCAness is considered as a predictive biomarker to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors. However, recent trials demonstrated that its predictive value was limited in triple-negative breast cancer (TNBC) treated with platinum. Moreover, tumors with mutations of DNA damage response (DDR) genes, such as homologous recombination (HR) genes, may be sensitive to platinum and PARP inhibitors. Thus, we aim to explore the relationship between mutation status of DDR genes and BRCAness in TNBC. We sequenced 56 DDR genes in 120 TNBC and identified BRCAness by array comparative genomic hybridization (aCGH). The sequencing results showed that 13, 14, and 14 patients had BRCA, non-BRCA HR gene, and non-HR DDR gene mutations, respectively. aCGH revealed that BRCA-mutated and HR gene-mutated TNBC shared similar BRCAness features, both having higher numbers and longer length of large-scale structural aberration (LSA, >10Mb) and similar altered chromosomal regions of LSA. These suggested non-BRCA HR gene-mutated TNBC shared similar characteristics with BRCA-mutated TNBC, indicating non-BRCA HR gene-mutated TNBC sensitive to platinum and PARP inhibitors. Among tumors with mutation of non-HR DDR genes, 3 PTEN and 1 MSH6-mutation also contained significant LSAs (BRCAness); however, they had different regions of genomic alteration to BRCA and HR gene-mutated tumors, might explaining prior findings that PTEN and MSH6-mutated cancer cells not sensitive to PARP inhibitors. Therefore, we hypothesize that the heterogeneous genomic background of BRCAness indicates different responsiveness to platinum and PARP inhibitors. Direct sequencing DDR genes in TNBC should be applied to predict their sensitivity toward platinum and PARP inhibitors.

PMID: 31958182 [PubMed - as supplied by publisher]