GermlinePALB2Mutations in Cancers and Its Distinction From SomaticPALB2Mutations in Breast Cancers

• Type of Material: Article
• Authors: Zhe-Yu Hu, Central South University; Liping Liu, Central South University; Ning Xie, Central South University; Jun Lu, Central South University; Zhentian Liu, Geneplus-Beijing Institute; Yu Tang, Central South University; Yikai Wang, Emory University; Jianbo Yang, Central South University; Quchang Ouyang, Central South University
• Language: English
• Date: 2020-08-27
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Hu, Liu, Xie, Lu, Liu, Tang, Wang, Yang and Ouyang.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fgene.2020.00829
• Title of Journal or Parent Work: FRONTIERS IN GENETICS
• Volume: 11
• Start Page: 829
• End Page: 829
• Grant/Funding Information: The funders supported the study design, data collection and the publication.; This work was support Development and Reform Commission of Hunan Province (CN) Hunan Key Research Project Nos. 2019SK20232 and 2019JJ50356 (Z-YH).
• Keywords: BRCA1; germlinePALB2mutation; hereditary breast cancer; GERMLINE MUTATIONS; Life Sciences & Biomedicine; GENE; loss of heterozygosity; somatic mutations; Genetics & Heredity; Science & Technology; FAMILIES; PREDICTOR; mutational signature; PALB2; MUTATIONAL PROCESSES
• Research Categories: Health Sciences, Oncology

Abstract

PALB2 is an important BRCAx candidate for familial breast cancers (FBC). PALB2 pathogenic variants (PVs) may not to conform to “two hit” paradigm. However, a recent study demonstrates that in the majority PALB2 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 PALB2 mutations in breast cancers. We screened out 28 germline PALB2-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 PALB2 germline mutations. All these germline PALB2 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 PALB2 somatic mutation and two patients had LOH of PALB2. All germline PALB2 mutations were high-risk mutations, whereas the somatic PALB2 mutations were moderate-risk missense mutations. We also distinguished PALB2 “novel mutations” from “reported mutations.” In conclusion, germline PALB2 mutation should be put into the context of future screening.