SAN ANTONIO – Bi-allelic inactivation of BRCA1 and BRCA2 are frequent events in BRCA1 breast cancers and BRCA2 breast cancers, respectively, a study presented at the 2016 San Antonio Breast Cancer Symposium (SABCS) has shown.1

BRCA1 and BRCA2 are both tumor suppressor genes,” said Felipe Geyer, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. “They are key players in homologous recombination (HR) DNA repair, with HR deficiency being caused by 2 ‘hits.’ The second hit can be LOH or a somatic mutation.”

Therefore, researchers aimed to define the somatic genetic alterations of BRCA1 and BRCA2 breast cancers and determine whether LOH of BRCA1/2 wild-type alleles and/or mutations affecting additional tumor suppressor genes would be present and clonal in these cancers.

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For the study, investigators extracted DNA from 29 BRCA1 and 10 BRCA2 microdissected breast cancer samples and conducted high-depth targeted capture massively parallel sequencing, as well as a state-of-the-art mutation and copy number analysis of 111 genes present in sequencing assays.

Results showed bi-allelic inactivation of BRCA1 in 28 of the 29 BRCA1 breast cancers, with 93% harboring LOH of the BRCA1 wild-type allele and 3% harboring a second somatic BRCA1 pathogenic mutation.

“There were no differences in the frequency of bi-allelic inactivation according to ER status,” Dr Geyer noted.

Researchers also found that 50% of BRCA1 breast cancers displayed bi-allelic BRCA1 inactivation and clonal TP53 mutation, and 29% showed clonal bi-allelic BRCA1 inactivation, with subclonal or no TP53 mutations; 1 of which displayed a clonal PTEN mutation, coupled with LOH. In addition, 21% displayed subclonal bi-allelic BRCA1 inactivation, which Dr Geyer noted was likely preceded by mutations affecting other tumor suppressor genes.

“In BRCA1 breast cancers, TP53 is the single gene highly recurrently mutated,” said Dr Geyer. “BRCA1 second hit is present in most ER-positive and ER-negative tumors and is mainly by LOH of the wild-type allele.

“BRCA2 breast cancers are genetically heterogenous, without a highly recurrent altered gene,” Dr Geyer added. “They harbor less frequent PIK3CA mutations than sporadic ER-positive breast cancers and all cases of BRCA2 second hit analyzed displayed clonal LOH of the wild-type allele.


1. Burke KA, Macedo GS, Piscuoglio S, et al. The landscape of somatic genetic alterations in BRCA1 and BRCA2 breast cancers. Paper presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX.