Germline PALB2 Mutations in Cancers and Its Distinction From Somatic PALB2 Mutations in Breast Cancers

Abstract

<i>PALB2</i> is an important BRCAx candidate for familial breast cancers (FBC). <i>PALB2</i> pathogenic variants (PVs) may not to conform to "two hit" paradigm. However, a recent study demonstrates that in the majority <i>PALB2</i> germline 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 germline <i>PALB2</i> mutations in breast cancers. We screened out 28 germline <i>PALB2-</i>mutation carriers among 480 familial cancer patients (including 143 FBC patients) in Geneplus database pool. Of the 143 patients with FBC, 10 had mono-allelic <i>PALB2</i> germline mutations. All these germline <i>PALB2</i> mutations 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 has <i>PALB2</i> somatic mutation and two patients had LOH of <i>PALB2</i>. All germline <i>PALB2</i> mutations were high-risk mutations, whereas the somatic <i>PALB2</i> mutations were moderate-risk missense mutations. We also distinguished PALB2 "novel mutations" from "reported mutations." In conclusion, germline <i>PALB2</i> mutation should be put into the context of future screening.