GermlinePALB2Mutations in Cancers and Its Distinction From SomaticPALB2Mutations in Breast Cancers

PALB2is an important BRCAx candidate for familial breast cancers (FBC).PALB2pathogenic variants (PVs) may not to conform to two hit paradigm. However, a recent study demonstrates that in the majorityPALB2germline mutant breast cancers, the loss of heterozygosity (LOH) and somatic point mutations are the second hit. This study aimed to investigate the second hits in germlinePALB2mutations in breast cancers. We screened out 28 germlinePALB2-mutation carriers among 480 familial cancer patients (including 143 FBC patients) in Geneplus database pool. Of the 143 patients with FBC, 10 had mono-allelicPALB2germline mutations. All these germlinePALB2mutations were high-risk stop-gain, frameshift, or splicing mutations that concentrated in EX5-EX9 and might led to truncated proteins, severe functional defects and malignant phenotype. The hotspots were c.1057A[3 > 2] and c.3114-1G > A. Other mutations included c.389delA, c.2068C > T, c.2167_2168delAT, c.2629delT and c.2968G > T. Only one FBC patient hasPALB2somatic mutation and two patients had LOH ofPALB2. All germlinePALB2mutations were high-risk mutations, whereas the somaticPALB2mutations were moderate-risk missense mutations. We also distinguished PALB2 novel mutations from reported mutations. In conclusion, germlinePALB2mutation should be put into the context of future screening.