BRCA1 germline mutations are associated with elevated risk of breast and ovarian cancers, and somatic loss of the wild-type BRCA1 allele has been thought to be a rate-limiting initiating step in tumor development. BRCA1-associated breast tumors acquire additional somatic alterations during progression, with mutations of PTEN and TP53 frequently being found in this setting. However, it also has been observed that normal cells do not survive acute loss of BRCA1, suggesting that the loss of wild-type BRCA1 may not be the initiating step in tumorigenesis. Further, loss of wild-type BRCA2 appears to occur relatively late in pancreatic tumor development in BRCA2 mutation carriers, and evidence suggests that loss of wild-type BRCA1 might occur only in preexisting TP53 mutant foci in ovarian cancer.
In a recent study, Martins and colleagues from Dana-Farber Cancer Institute in Boston, Massachusetts, analyzed BRCA1, p53, and PTEN at the single cell level in BRCA1-associated breast tumors and used computational methods to identify the relative order of somatic events on the basis of the frequency of cells with single or combined alterations.
Evaluation of 55 BRCA1-associated breast tumors showed no single obligatory order of events, but suggested distinct evolutionary pathways. Loss of PTEN was the most common first event and was followed by TP53 mutation or BRCA1 loss of heterozygosity with approximately equal frequency. TP53 mutation was the second-most common first event and was almost always followed by BRCA1 loss of heterozygosity. BRCA1 loss of heterozygosity was the least common first event, and the majority of such cases exhibited mutant p53 as the only other alteration. The order of events was strongly associated with tumor type.
PTEN loss (evolutionary path 1) was almost always the first event in triple-negative (basal-like) tumors, whereas TP53 mutation or BRCA1 loss of heterozygosity was the first event in luminal tumors (path 2). PIK3CA mutation, which is associated with the luminal subtype in sporadic breast tumors, was infrequent in the BRCA1-associated tumors. Further, loss of wild-type BRCA1 was not consistent among tumor cells within a single tumor, and increased cell proliferation and centrosome amplification were observed in normal breast epithelium of BRCA1 mutation carriers.
As concluded by the investigators, “Our combined experimental and computational approach reveals that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors.… Our results [may] have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.”
Among the potential clinical implications of these findings cited by the investigators are that agents such as PARP inhibitors, which have a synthetic lethal interaction in cells lacking wild-type BRCA–associated DNA repair function, may have reduced activity in some BRCA1 mutation carriers. They also note that AKT pathway inhibitors and agents targeting p53 mutant tumor cells may have promise for prevention and treatment of breast tumors in a subset of such carriers. ■