Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes

Giovanna D'Elia; Gemma Caliendo; Maria-Myrsini Tzioni; Luisa Albanese; Luana Passariello; Anna Maria Molinari; Maria Teresa Vietri

doi:10.3390/genes13101692

Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes

Genes (Basel). 2022 Sep 21;13(10):1692. doi: 10.3390/genes13101692.

Authors

Giovanna D'Elia¹, Gemma Caliendo¹, Maria-Myrsini Tzioni², Luisa Albanese¹, Luana Passariello¹, Anna Maria Molinari^{1

3}, Maria Teresa Vietri^{1

3}

Affiliations

¹ Unity of Clinical and Molecular Pathology, AOU, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
² Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
³ Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.

Abstract

Hereditary prostate cancer (HPCa) has the highest heritability of any cancer in men. Interestingly, it occurs in several hereditary syndromes, including breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Several gene mutations related to these syndromes have been identified as biomarkers in HPCa. The goal of this study was to screen for germline mutations in susceptibility genes by using a multigene panel, and to subsequently correlate the results with clinical and laboratory parameters. This was undertaken in 180 HBOC families, which included 217 males with prostate cancer (PCa). Mutational analysis was further extended to 104 family members of mutated patients. Screening of HBOC families revealed that 30.5% harbored germline mutations in susceptibility genes, with 21.6% harboring pathogenic variants (PVs) and 8.9% having variants of uncertain significance (VUS). We found PVs at similar frequency in BRCA1 and BRCA2 genes (8.8% and 9.4%, respectively), while 0.56% of PVs were present in well-established susceptibility genes PALB2, TP53 and RAD51C. Moreover, 0.56% of monoallelic PVs were present in MUTYH, a gene whose function in tumorigenesis in the context of PCa is still unclear. Finally, we reported double heterozygosity (DH) in BRCA1/2 genes in a single family, and found double mutation (DM) present in BRCA2 in a separate family. There was no significant difference between the mean age of onset of PCa in HBOC families with or without germline mutations in susceptibility genes, while the mean survival was highest in mutated patients compared to wild type. Furthermore, PCa is the second most recurrent cancer in our cohort, resulting in 18% of cases in both mutated and non-mutated families. Our investigation shows that PVs were located mostly in the 3' of BRCA1 and BRCA2 genes, and in BRCA2, most PVs fell in exon 11, suggesting a mutation cluster region relating to risk of HPCa. A total of 65 family members inherited the proband's mutation; of these, 24 developed cancer, with 41 remaining unaffected.

Keywords: BRCA genes; hereditary breast and ovarian cancer syndrome; hereditary prostate cancer; susceptibility genes.

MeSH terms

Female
Genetic Predisposition to Disease
Germ-Line Mutation
Hereditary Breast and Ovarian Cancer Syndrome* / genetics
Humans
Male
Neoplasm Recurrence, Local
Prostatic Neoplasms* / genetics

Supplementary concepts

Prostate cancer, familial

Grants and funding

This research received no external funding.