PALB2 mutations and prostate cancer risk and survival

Wokołorczyk, Dominika; Kluźniak, Wojciech; Stempa, Klaudia; Rusak, Bogna; Huzarski, Tomasz; Gronwald, Jacek; Gliniewicz, Katarzyna; Kashyap, Aniruddh; Morawska, Sylwia; Dębniak, Tadeusz; Jakubowska, Anna; Szwiec, Marek; Domagała, Paweł; Lubiński, Jan; Narod, Steven A.; Akbari, Mohammad Reza; Cybulski, Cezary

doi:10.1038/s41416-021-01410-0

Cited by 24 publications

(15 citation statements)

References 34 publications

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“…However, considering that our cohort is neither enriched in patients with aggressive disease nor in carriers of P/LP variants in BRCA2, associated with aggressive disease in multiple studies (14,17,38,40), we cannot discard the possible effect of a "cumulative bias" driving this lack of association, eventually conditioned by a population-speci c effect. P/LP variants in ATM, NBN and PALB2 have also been associated with aggressive PrCa (40,41), however the low frequency of carriers in our cohort does not allow to reach statistical power.…”

Section: Discussionmentioning

confidence: 76%

Genetic landscape of homologous recombination repair genes in early-onset/familial prostate cancer patients

Teixeira

Paulo

Cardoso

et al. 2023

Preprint

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Prostate cancer (PrCa) is among the three top most frequent and deadlier cancers worldwide. The discovery of PARP inhibitors for the treatment of tumors having deleterious variants in homologous recombination repair (HRR) genes has placed PrCa in the roadmap of precision medicine. Still, the overall contribution of HRR genes for the 10-20% of the carcinomas arising in men with early-onset/familial PrCa has not been fully clarified. We used Targeted Next Generation Sequencing (T-NGS) covering eight HRR genes (ATM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2 and RAD51C) and an analysis pipeline querying both small and large genomic variations, to clarify both their global and relative contribution for hereditary PrCa predisposition in a series of 462 early-onset/familial PrCa cases. Deleterious variants were found in 3.9% of the patients, with CHEK2 and ATM being the most frequently mutated genes (38.9% and 22.2% of the carriers, respectively), followed by PALB2 and NBN (11.1% of the carriers, each), and then by BRCA2, RAD51C, and BRIP1 (5.6% of the carriers each). Using the same NGS data, exonic rearrangements were found in two patients, one pathogenic in BRCA2 and one of unknown significance in BRCA1. Additionally, 5.4% of the patients were carriers of variants of unknown significance (VUS). These results support the utility of T-NGS to clarify the genetic heterogeneity that underlies PrCa predisposition, allowing to detect both small and large genomic variations, and unveil CHEK2 and ATM as the major HRR genes associated with early-onset and familial PrCa, respectively.

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Section: Discussionmentioning

confidence: 76%

Genetic landscape of homologous recombination repair genes in early-onset/familial prostate cancer patients

Teixeira

Paulo

Cardoso

et al. 2023

Preprint

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“…In 2020, Yang et al reported the results of a multicentric study conducted on 523 families and did not reveal any correlation between PALB2 germline pathogenic variants and increased risk for prostate cancer [ 14 ]. In contrast, Wokolorczyk et al have shown in 2021 that the two founder mutations of PALB2 in the Polish population (c.509_510delGA and c.172_175delTTGT), which represent ~80% of all PALB2 mutations, were commonly diagnosed within aggressive cancers of a high Gleason score (8–10) rather than middle Gleason score tumors (7) [ 15 ]. Other studies have established the occurrence of germline PALB2 mutations in prostate cancer as well as the sensitivity of other PALB2 -deficient tumor entities to Poly(ADP-ribose)polymerase (PARP) inhibition [ 16 , 17 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of an Exonic Duplication in PALB2 in a Man with Synchronous Breast and Prostate Cancer

Bouras

Lafaye

Léoné

et al. 2022

IJMS

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PALB2 (partner and localizer of BRCA2), as indicated by its name, is a BRCA2-interacting protein that plays an important role in homologous recombination (HR) and DNA double-strand break (DSB) repair. While pathogenic variants of PALB2 have been well proven to confer an increased risk of breast cancer, data on its involvement in prostate cancer (PrC) have not been clearly demonstrated. We investigated, using targeted next generation sequencing (NGS), a 59-year-old Caucasian man who developed synchronous breast and prostate cancers. This genetic investigation allowed to identify an intragenic germline heterozygous duplication in PALB2, implicating intronic repetitive sequences spanning exon 11. This variant was confirmed by multiplex ligation probe amplification (MLPA), and genomic breakpoints have been identified and characterized at the nucleotide level (c.3114-811_3202-1756dup) using an approach based on walking PCR, long range PCR, and Sanger sequencing. RT-PCR using mRNA extracted from lymphocytes and followed by Sanger sequencing revealed a tandem duplication r.3114_3201dup; p.(Gly1068Glufs * 14). This duplication results in the synthesis of a truncated, and most-likely, non-functional protein. These findings expand the phenotypic spectrum of PALB2 variants and may improve the yield of genetic diagnoses in this field.

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“…The control group included 10,252 cancer-free adults from the genetically homogeneous population of Poland. The control group consisted of 5545 cancer-free men (age 19–97 years, mean 59.0 years; 1486 men below age 50 years and 4059 men at age 50 or above) and 4707 cancer-free women (age 18 to 94 years, mean 54.0 years; 1865 women below age of 50 years and 2842 women at age 50 or above) from the International Hereditary Cancer Center (IHCC) cohort (Szczecin, Poland) [ 40 , 41 , 42 , 43 ]. The aim of the control group was to estimate the frequency of the three BARD1 variants in the Polish population.…”

Section: Methodsmentioning

confidence: 99%

Do BARD1 Mutations Confer an Elevated Risk of Prostate Cancer?

Stempa

Wokołorczyk

Kluźniak

et al. 2021

Cancers

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The current cancer testing gene panels tend to be comprehensive rather than site-specific. BARD1 is one of the genes commonly included in the multi-cancer testing panels. Mutations in BARD1 confer an increase in the risk for breast cancer, but it is not studied whether or not they predispose to prostate cancer. To establish if BARD1 mutations also predispose to prostate cancer, we screened BARD1 in 390 Polish patients with hereditary prostate cancer. No truncating mutations were identified by sequencing. We also genotyped 5715 men with unselected prostate cancer, and 10,252 controls for three recurrent BARD1 variants, including p.Q564X, p.R658C and p.R659=. Neither variant conferred elevated risk of prostate cancer (ORs between 0.84 and 1.15, p-values between 0.57 and 0.93) nor did they influence prostate cancer characteristics or survival. We conclude that men with a BARD1 mutation are not at elevated prostate cancer risk. It is not justified to inform men about increased prostate cancer risk in case of identification of a BARD1 mutation. However, a female relative of a man with a BARD1 mutation may benefit from this information and be tested for the mutation, because BARD1 is a breast cancer susceptibility gene.

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PALB2 mutations and prostate cancer risk and survival

Cited by 24 publications

References 34 publications

Genetic landscape of homologous recombination repair genes in early-onset/familial prostate cancer patients

Genetic landscape of homologous recombination repair genes in early-onset/familial prostate cancer patients

Identification and Characterization of an Exonic Duplication in PALB2 in a Man with Synchronous Breast and Prostate Cancer

Do BARD1 Mutations Confer an Elevated Risk of Prostate Cancer?

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