Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer

Holečková, Klaudia Híveš; Baluchova, Katarina; Híveš, Márk; Musak, Ludovit; Kliment, J.; Škereňová, Mária

doi:10.21873/invivo.11971

Cited by 4 publications

(4 citation statements)

References 31 publications

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“…Three germline pathogenic variants (PVs), eight variants of unknown significance (VUSs), and one benign (B) variant (Figure 1), classified according to the ACMG criteria [11], were studied by comparing them with an ATM wild-type control. The p.Met1484fs PV, which we previously described in patients diagnosed with multiple primary melanoma and pancreatic cancer [7,12], has never been detected in patients with AT, but was found in a patient with Metastatic Castration-resistant Prostate Cancer [13].…”

Section: Classification and Distribution Of Germline Atm Variantsmentioning

confidence: 71%

Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma

Pastorino

Dalmasso

Allavena

et al. 2022

IJMS

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ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was to functionally characterize 13 germline ATM variants found in high-risk melanoma patients—and classified by in silico tools as pathogenic, uncertain significance, or benign—using multiple assays evaluating ATM/pATM expression and/or LOH in melanoma tissues and cell lines. We assessed ATM status by Immunohistochemistry (IHC), Western Blot, Whole-Exome Sequencing/Copy Number Variation analysis, and RNA sequencing, supported by Sanger sequencing and microsatellite analyses. For most variants, IHC results matched those obtained with in silico classification and LOH analysis. Two pathogenic variants (p.Ser1135_Lys1192del and p.Ser1993ArgfsTer23) showed LOH and complete loss of ATM activation in melanoma. Two variants of unknown significance (p.Asn358Ile and p.Asn796His) showed reduced expression and LOH, suggestive of a deleterious effect. This study, showing a classic two-hit scenario in a well-known tumor suppressor gene, supports the inclusion of melanoma in the ATM-related cancer spectrum.

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Section: Classification and Distribution Of Germline Atm Variantsmentioning

confidence: 71%

Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma

Pastorino

Dalmasso

Allavena

et al. 2022

IJMS

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“…Our results will be useful when planning future trial protocols for CRPC. Furthermore, the present study provides important information to elucidate the detailed pathological characteristics of CRPC and identify effective therapies for CRPC, which have been examined by other investigators (33)(34)(35).…”

Section: Correlation Between E-type Prostanoid (Ep) 2 Receptor (Ep2r)...mentioning

confidence: 90%

Pathological Roles of Prostaglandin E2-specific E-type Prostanoid Receptors in Hormone-sensitive and Castration-resistant Prostate Cancer

et al. 2021

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Background/Aim: Prostaglandin (PG) E 2 mediates malignant aggressiveness by binding to four specific E-type prostanoid receptors (EP1R -4R). This study aimed to clarify the pathological significance of EPRs in hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). Materials and Methods: EP1R -4R expression was examined in 102 HSPC and 27 CRPC specimens. The relationships between their expression and proliferation index (PI), apoptotic index (AI), and vascular endothelial growth factor (VEGF)-A expression were analyzed. Results: EP4R expression in CRPC was significantly higher compared to that in HSPC, even in advanced disease (T3/4, N1, and/or M1). EP4R expression was significantly correlated with PI, AI, and VEGF-A expression in CRPC. Such significant relationshipswere not detected between EP1R -3R and CRPC. Conclusion: EP4R expression in CRPC was significantly higher than that in HSPC and was associated with cancer cell proliferation, apoptosis, and pro-angiogenetic potential.

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“…Germline mutations in certain genes, such as DNA repair genes, may involve different tissues in multiple organs, including the breasts, ovaries, and prostate. [38,39] Further, presence or absence of germline mutations may influence risk for distant metastasis or poor prognosis.…”

Section: Role Of Genetic and Genomic Factors In Pcmentioning

confidence: 99%

Prostate cancer genotyping for risk stratification and precision treatment

Kumar

2024

Curr Urol

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Prostate cancer (PC) is the most frequently diagnosed cancer and second leading cause of cancer-related deaths in men. It is heterogeneous, as is evident from the wide spectrum of therapeutic approaches. Most patients with PC are initially responsive to androgen deprivation therapy; however, the majority of cases are either hormone-sensitive PC or castration-resistant PC. Current therapeutic protocols follow the evolution of PC, a continuously progressive process involving a combination of widespread genomic alterations. These genomic alterations are either hereditary germline mutations, such as mutations in BRCA2, or specific only to tumor cells (somatic). Tumor-specific genomic spectra include genomic structural rearrangements, canonical androgen response genes, and many other specific genes such as TMPRSS2-ERG fusion, SPOP/FOXA1, TP53/RB1/PTEN, and BRCA2. New evidence indicates the involvement of signaling pathways including PI3K, WNT/β-catenin, SRC, and IL-6/STAT, which have been shown to promote epithelial-mesenchymal transition cancer stem cell–like features/stemness, and neuroendocrine differentiation in PC. Over the last decade, our understanding of the genotype-phenotype relationships has been enhanced considerably. The genetic background of PC related to canonical genetic alterations and signaling pathway activation genes has shed more insight into the molecular subtype and disease landscape, resulting in a more flexible role of individual therapies targeting diverse genotypes and phenotypes.

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Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer

Cited by 4 publications

References 31 publications

Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma

Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma

Pathological Roles of Prostaglandin E2-specific E-type Prostanoid Receptors in Hormone-sensitive and Castration-resistant Prostate Cancer

Prostate cancer genotyping for risk stratification and precision treatment

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