NEW YORK (GenomeWeb) – Some of the tumors that form in individuals with germline mutations affecting just one copy of the BRCA1 or BRCA2 genes may be more apt to respond to DNA-damaging treatments if the remaining copy of BRCA1/2 becomes impaired through loss of heterozygosity (LOH), new research suggests.
Researchers from the University of Pennsylvania Perelman School of Medicine and elsewhere analyzed tumor sequence and patient survival data for 160 individuals with germline mutations in BRCA1 or BRCA2 who had developed breast or ovarian cancer. As described in the past, LOH altered the activity of non-mutated BRCA1/2 alleles in many individuals with heterozygous germline mutations affecting BRCA1 or BRCA2.
But LOH was not universal in heterozygous BRCA1/2 germline mutation carriers, the team found. On the contrary, a significant subset of breast and ovarian tumors retained some BRCA1 or BRCA2 function, apparently leading to poorer response to DNA-damaging platinum chemotherapy and shorter overall survival times in the ovarian cancer cases. The findings appeared online today in Nature Communications.
"Identifying the LOH status of BRCA1/2 carriers may be useful to predict who might be at risk for primary resistance to DNA-damaging agents such as platinum, which has important implications for treatment of patients with these mutations," first author Kara Maxwell, a hematology and oncology researcher at UPenn, said in a statement.
The findings hint that it might be possible to predict response to DNA-damaging treatment based on LOH at a single locus, Maxwell explained — an approach that is "more cost effective than sequencing a patient's whole genome" and "compatible with standard testing."
The team developed a computational pipeline to examine LOH and BRCA1/2 functional deficiency, dubbed BRCAness, in 41 breast tumors with BRCA1 mutations, 35 BRCA2-mutant breast tumors, 52 ovarian tumors with BRCA1 mutations, and 32 BRCA2-mutant ovarian tumors that had been exome-sequenced for the Cancer Genome Atlas project or newly sequenced at the University of Pennsylvania.
In the breast cancers considered, the researchers found that LOH was missing in 10 percent of the BRCA1-mutant tumors and in a whopping 46 percent of tumors marked by BRCA2 mutations. Roughly 7 percent of ovarian cancers with BRCA1 mutations were LOH-negative, they reported, as were 16 percent of the BRCA2-mutant ovarian tumors.
Along with analyses of genes that were co-mutated in these tumors, the team went on to examine homologous recombination deficiency, clinical features, and survival patterns for individuals with germline BRCA1/2 mutations who had LOH-negative tumors.
In particular, the authors noted that "both BRCA1 and BRCA2 ovarian tumors without locus-specific LOH treated with adjuvant platinum based chemotherapy have lower overall survival than tumors with locus-specific LOH."
The results were less clear-cut in the breast cancer cases, perhaps due to the inclusion of LOH-negative and -positive cancers from different stages, the researchers noted. Even so, they argued that results so far "provide support for the use of a BRCA locus-specific LOH assay to predict primary response to [platinum chemotherapies], and potentially PARP inhibitors, in patients with germline BRCA1 and BRCA2 mutations."