BRCA Germline Mutations in Prostate Cancer: The Future Is Tailored

Crocetto, Felice; Barone, Biagio; Caputo, Vincenzo; Fontana, Matteo; Cobelli, O. De; Ferro, Matteo

doi:10.3390/diagnostics11050908

Cited by 30 publications

(23 citation statements)

References 20 publications

(21 reference statements)

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“…Moreover, it is possible to identify protein regions where germline pathogenic variants accumulate more than benign and VUS variants. These results together reinforce the hypothesis that there is a synergistic effect between germline and somatic variants affecting protein function and interactions 32 .…”

Section: Discussionsupporting

confidence: 85%

A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases

Magraner-Pardo

Laskowski

Pons

et al. 2021

Sci Rep

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DNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have severe consequences since failure to repair damaged DNA can result in cells turning cancerous. Here, we compare germline and somatic variants in DDR genes, specifically looking at their locations in the corresponding three-dimensional (3D) structures, Pfam domains, and protein–protein interaction interfaces. We show that somatic variants in metastatic cases are more likely to be found in Pfam domains and protein interaction interfaces than are pathogenic germline variants or variants of unknown significance (VUS). We also show that there are hotspots in the structures of ATM and BRCA2 proteins where pathogenic germline, and recurrent somatic variants from primary and metastatic tumours, cluster together in 3D. Moreover, in the ATM, BRCA1 and BRCA2 genes from prostate cancer patients, the distributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam domains. Together, these results provide a better characterisation of the most recurrent affected regions in DDRs and could help in the understanding of individual susceptibility to tumour development.

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Section: Discussionsupporting

confidence: 85%

A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases

Magraner-Pardo

Laskowski

Pons

et al. 2021

Sci Rep

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“…An association between MSI-H status and the efficacy of PD-L1/PD-1 inhibitors has been established in a range of solid tumors, including a relatively small number of PC cases; MMR deficiency was sometimes associated with favorable response to anti-PD-1 therapy or PD-L1 expression [ 29 , 37 , 61 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 ]. The 2021 NCCN guidelines have allowed immunotherapy in men with asymptomatic or minimally symptomatic mCRPCs; pembrolizumab can be administered as ≥2nd line systemic therapy to dMMR/MSI-H mCRPCs that have progressed through prior docetaxel and/or novel hormone therapy [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, the NCCN guidelines [ 4 ] do not define how to evaluate the MSI-H/dMMR or the PD-L1 status: MSI-H or dMMR can be tested by using either DNA tests or IHC. The second approach is easy to use and cost-effective, but it may be insufficient to predict PC recurrence after radical prostatectomy [ 29 , 38 , 61 , 168 , 169 , 170 , 171 , 172 , 173 , 174 ]. In case of molecular testing, validated NGS assays are preferred by the NCCN guidelines [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…About 40–50% of PCs are hereditary, frequently showing earlier onset, familial clustering, and multifocality; mutations and polymorphisms of several tumor suppressor genes and proto-oncogenes play a key role in PC onset and progression [ 10 , 169 ]. The impairment of MMR genes has been linked not only to sporadic PC cases (usually harboring MSH2 or MSH6 gene defects), but also to some hereditary forms of PC [ 4 , 10 , 169 , 178 , 179 ].…”

Section: Discussionmentioning

confidence: 99%

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What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes

et al. 2022

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Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system deficiency (MSI-H/dMMR). BRCA1/2 loss-of-function is linked to hereditary PCs and homologous recombination DNA-repair system deficiency: poly-ADP-ribose-polymerase inhibitors can be administered to BRCA-mutated PC patients. Recently, docetaxel-refractory metastatic castration-resistant PC patients with BRCA1/2 or ATM somatic mutations had higher response rates to pembrolizumab. PTEN regulates cell cycle/proliferation/apoptosis through pathways including the AKT/mTOR, which upregulates PD-L1 expression in PC. Our systematic literature review (PRISMA guidelines) investigated the potential correlations between PD-L1 and MMR/MSI/BRCA/PTEN statuses in PC, discussing few other relevant genes. Excluding selection biases, 74/677 (11%) PCs showed dMMR/MSI; 8/67 (12%) of dMMR/MSI cases were PD-L1+. dMMR-PCs included ductal (3%) and acinar (14%) PCs (all cases tested for MSI were acinar-PCs). In total, 15/39 (39%) PCs harbored BRCA1/2 aberrations: limited data are available for PD-L1 expression in these patients. 13/137 (10%) PTEN- PCs were PD-L1+; 10/29 (35%) PD-L1+ PCs showed PTEN negativity. SPOP mutations may increase PD-L1 levels, while the potential correlation between PD-L1 and ERG expression in PC should be clarified. Further research should verify how the efficacy of PD-1 inhibitors in metastatic castration-resistant PCs is related to dMMR/MSI, DNA-damage repair genes defects, or PD-L1 expression.

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“…BRCA1 (and BRCA2) have indisputable roles in maintaining genomic integrity in various cancers. At present, PARPi (specifically Olaparib and Rucaparib) have been approved for the treatment of mCRPC with germline BRCA1/2 mutations [ 101 ]. Several clinical trials are currently underway to examine the efficacy of PARPi alone and in combination with other drugs in BRCA1/2 -mutation carriers and in patients with tumors carrying mutations in other DNA repair genes in prostate and other cancers (NCT03148795, NCT04267939).…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

BRCA1 and Metastasis: Outcome of Defective DNA Repair

Krishnan

Patel

Hakem

2021

Cancers

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Heritable mutations in BRCA1 and BRCA2 genes are a major risk factor for breast and ovarian cancer. Inherited mutations in BRCA1 increase the risk of developing breast cancers by up to 72% and ovarian cancers by up to 69%, when compared to individuals with wild-type BRCA1. BRCA1 and BRCA2 (BRCA1/2) are both important for homologous recombination-mediated DNA repair. The link between BRCA1/2 mutations and high susceptibility to breast cancer is well established. However, the potential impact of BRCA1 mutation on the individual cell populations within a tumor microenvironment, and its relation to increased aggressiveness of cancer is not well understood. The objective of this review is to provide significant insights into the mechanisms by which BRCA1 mutations contribute to the metastatic and aggressive nature of the tumor cells.

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BRCA Germline Mutations in Prostate Cancer: The Future Is Tailored

Abstract: Prostate cancer (PCa) is the second most common neoplasm in men and the fifth leading cause of death worldwide [...]

Cited by 30 publications

References 20 publications

A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases

A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes

BRCA1 and Metastasis: Outcome of Defective DNA Repair

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