FEATURED , Research

Alan Stolier, MD/



BRCA1 and BRCA2 interact with the PALB2 protein to repair damaged DNA. PALB2 is located on chromosome 16. When located on both alleles, mutations in PALB2 cause Fanconi’s anemia and predispose to childhood malignancies. Monoallelic PALB2 mutations predisposed to breast cancer. Previously, PALB2 mutations are found in 1% to 4% of families (depending on the population tested) with breast cancer, testing negative for BRCA1/BRCA2. It is, therefore, one of the rarer breast cancer susceptibility genes. Because of the low frequency of PALB2, there is a lack of data for the spectrum of breast cancer in the face of these mutations. A new study by Zhou et al. from China may shed some light on this mutation. 

The researchers sequenced PALB2 genes in 21,216 unselected patients with primary breast cancer and 5890 healthy Chinese women. They then assessed the odds ratio (OR) for breast cancer associated with this mutation and explored clinical outcomes. Throughout this study, the authors chose to use OR as opposed to relative risk (RR). As most know, RR is a ratio of probabilities of an event occurring whereas OR compares the absence of an exposure given that we already know the specific outcome e.g., breast cancer. 

Of the 16,501 patients that were BRCA negative yet had developed breast cancer, 160 were PALB2 mutation-positive (0.97%). In healthy controls, 11 of 5890 had mutations (0.19%). The OR for breast cancer risk was 5.23 (CI 2.84-9.65).  In a subset analysis, the OR for women less than 30 years old with a PALB2 mutation was 10.9 (CI3.95-25.79).

Tumor characteristics

For those patients with breast cancer who also tested positive for PALB2, a significantly higher number was 30 years old or younger at diagnosis compared to those older than 30. Patients with PALB2 mutations were significantly more likely to have triple-negative breast cancers than non-carriers, though not as high as carriers of BRCA mutations (23% vs. 14%). Moreover, carriers are more likely to have bigger tumors (≥ 2cm, positive axillary lymph nodes, bilateral breast cancers, as well as a family history of breast and ovarian cancer than non-carriers. Interestingly, carriers also had an increase in the incidence of family histories of other cancers, not including breast or ovarian. 

In conclusion, studies had have found that PALB2 deficient cells might be sensitive to PARP Inhibition. This indeed suggests the potential that patients with breast cancer, carrying a PALB2 germline mutation, may be sensitive to PARP inhibitors.

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