Like BRCA1/2, deleterious mutations in PALB2 underlie deficiencies in homologous recombination-based DNA repair (HRD) and can underlie sensitivity to platinum (Pt) therapies and PARP inhibitors (PARPi). BRCA1/2 reversion mutations have been widely reported to cause therapy resistance. We report analogous reversion mutations in PALB2 for breast, ovarian, and prostate carcinomas (Ca).
Comprehensive genomic profiling (CGP) of DNA (≥50 ng) extracted from 114,200 samples, both solid tumors and heme malignancies, was performed using hybridization-captured, adaptor ligation-based libraries (mean coverage depth >600X) for up to 315 cancer-related genes. Samples were evaluated for substitutions, indels, copy number changes and rearrangements.
PALB2 mutations were found in ∼1-3% of breast, ovarian and prostate carcinomas. Of 744 samples (0.7% of total) with likely deleterious PALB2 mutations, 7 (0.9%) harbored multiple alterations with at least one predicted to be a reversion. Of these samples, 4 were breast Ca, 1 a prostate acinar adenocarcinoma, 1 a high-grade ovarian serous Ca, and 1 an ovarian carcinosarcoma. For 3 samples the availability of multiple tests indicated the acquisition of the predicted reversion mutation(s) over time. Several reversion mutation types were observed: missense (1), compensatory frameshifts (3), overlapping small indels (2), and a deletion likely to disrupt splicing (1) that may lead to skipping of exon 4 and an in-frame deletion excising a frameshift mutation. Multiple reversion mutations were observed in 2 cases. Only 1/7 cases also showed disruption of BRCA1/2.
In addition to the commonly sequenced genes BRCA1/2, PALB2 mutation can lead to homologous recombination deficiency. As with BRCA, the acquisition of additional mutations predicted to restore at least some PALB2 function and thus potentially confer resistance to therapies dependent on HRD, can be observed in tumors such as breast, ovarian, and prostate carcinomas. CGP is a valuable tool to identify clinically significant, albeit rare, primary PALB2 mutations in BRCA-negative tumors as well as acquired secondary resistance mutations in patients who progress on Pt and PARP inhibitor based therapies.
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L.M. Gay, S. Daniel, J. Suh, S. Ramkissoon, J-A. Vergilio, E. Severson, P.J. Stephens, J.S. Ross, J.A. Elvin: Employee of and stockholder in Foundation Medicine, Inc.