Pathogenic germline or somatic loss-of-function alterations in BRCA1/2 tumor suppressor genes are associated with tumorigenesis in only a few types of cancer, with these alterations unlikely to be either related to tumor pathogenesis or clinically actionable in most patients with other cancer types, according to results of a study published in Nature.

Prior to the past 6 to 7 years, genetic testing of cancer patients was primarily restricted to those at high risk of specific germline mutations (eg, pathogenic BRCA1/2 mutations). However, the practice of performing comprehensive genomic profiling of matched tumor and normal DNA in unselected cancer patients has become increasingly common.

In addition, consideration of particular molecular alterations as “tissue-agnostic” biomarkers predictive of benefit from specific types of targeted therapy, including off-label use of PARP inhibitors in the setting of cancers characterized by pathogenic BRCA1/2 alterations, is becoming more widely accepted. Nevertheless, the association of BRCA1/2 mutations with response to specific therapies in most cancer types, as well as their effect on the phenotype of cancers other than those previously associated with BRCA1/2 alterations (ie, breast, ovarian, prostate, and pancreatic cancers), has not been well defined.

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In this study, comprehensive targeted DNA sequencing involving up to 468 cancer-associated genes was performed on matched blood and tumor specimens from 17,152 patients with 55 different types of advanced cancer. In this cohort, 2.7% of patients had a germline pathogenic BRCA1/2 alteration, and 1.8% of patients with a non-hypermutated cancer exhibited a somatic (ie, tumor) loss-of-function alteration in BRCA1/2. These alterations were found in 38 different cancer types, including the 4 aforementioned BRCA1/2-associated cancers.

Regarding the latter subgroup, the study authors noted that “strikingly, these were the only 4 cancer types that upon ancestry-adjusted association testing were significantly enriched among BRCA1/2 germline carriers, so all other cancer types were considered non–BRCA-associated for subsequent analyses.”

Since both alleles of BRCA1 or BRCA2 must be inactivated or lost for BRCA1/2 dysfunction to occur, the study authors speculated that the rate of deleterious “second hits” in BRCA1/2 (ie, loss of the remaining BRCA1/2 wild-type allele) would be higher in cancers driven by dysregulation of BRCA1/2 genes. To investigate this hypothesis, they compared the rate of BRCA1/2 “second hits” in tumors characterized by pathogenic germline BRCA1/2 alterations with those characterized by germline or somatic BRCA1/2 variants of unknown significance across cancer types.

Interestingly, for the 4 BRCA-associated cancers, the “second hit” rate was significantly higher if the disease was characterized by a pathogenic germline BRCA1/2 compared with a germline or somatic BRCA1/2 variant of unknown significance (P <.01). However, the BRCA1/2 “second hit” rate was similar in patients with germline pathogenic BRCA1/2 alterations and those with germline or somatic BRCA1/2 variants of unknown significance in the setting of non-small cell lung cancer, melanoma, bladder cancer, and colorectal cancer.

Furthermore, somatic loss of a BRCA1/2 pathogenic germline allele was shown to occur in 8% of BRCA1/2 carriers of a pathogenic germline mutation. Such a finding would be expected to occur more frequently in the setting of cancer not driven by a BRCA1/2 alteration. While this situation occurred in only 5% of BRCA-associated cancers, 20% of lung cancers associated with a pathogenic BRCA1/2 germline alteration exhibited this phenomenon (P =.003).

In commenting on these results, the study authors noted that “these data suggest that selection for loss of wild-type BRCA was tumor lineage-dependent, while varying both by the affected gene and the origin of the first BRCA hit, and that the pathogenesis of some cancers arising in BRCA1/2 carriers is likely independent of mutant BRCA.

Another finding from this study was that the degree of homologous recombination deficiency, which results in impairment in double-stranded DNA break repair and is considered to be a marker of sensitivity to platinum agents and PARP inhibitors, was significantly higher in BRCA-associated compared with non–BRCA-associated tumors (P =10-10).

Not surprisingly, a subsequent review of the subgroup of patients in this cohort treated with a PARP inhibitor showed the clinical benefit rate was significantly improved in patients with BRCA-associated cancers characterized by a pathogenic germline or somatic BRCA1/2 alteration (110 individuals) compared with those without these alterations (73 individuals) (hazard ratio [HR], 0.58; 95% CI 0.46-0.73). However, no significant difference in clinical outcome was observed when PARP inhibitor therapy was administered to patients with non–BRCA-associated cancers with (14 individuals) and without (20 individuals) these alterations were compared (HR, 1.02; 95% CI, 0.6-1.7).

In their concluding remarks, the study authors stated that “despite the recent emergence of tissue-agnostic biomarkers of cancer therapy response such as NTRK fusions and microsatellite instability, our data suggest that mutant BRCA1/2 is unlikely to be of similar therapeutic relevance in all cancer types in which it is found. While the identification of germline carriers will continue to be important for broader cancer risk reduction, we caution that the integration of both germline and somatic BRCA1/2 mutational status with broader somatic tumor profiles will ultimately be necessary to identify the subset of non–BRCA-associated cancers with true phenotypic dependence on mutant BRCA.”


Jonsson P, Bandlamudi C, Cheng ML, et al. Tumour lineage shapes BRCA-mediated phenotypes [published online July 10, 2019]. Nature. doi: 10.1038/s41586-019-1382-1