Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Rantapero, Tommi; Wahlfors, Tiina; Kähler, Anna K.; Hultman, Christina M.; Lindberg, Johan; Tammela, Teuvo L.J.; Nykter, Matti; Schleutker, Johanna; Wiklund, Fredrik

doi:10.3390/genes11030314

Cited by 17 publications

(19 citation statements)

References 43 publications

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“…Moreover, these authors also observed a significantly higher prevalence of germline alterations in the CHEK2 gene in the metastatic compared to localized form of PrCa; however no association with age at diagnosis or family history of the disease was reported. A similar prevalence of germline variants in DNA repair genes was also reported in patients with lethal PrCa in Finnish and Swedish populations unselected for family history [ 91 ]. A total of 12.3% of the lethal PrCa cases presented potentially damaging protein-truncating variants in DNA repair genes, with ATM (3.3%) and CHEK2 (4.1%) being the genes most frequently altered.…”

Section: Genetic Etiology Of Inherited Prcasupporting

confidence: 66%

“…As previously stated, the identification of pathogenic variants in genes mediating DNA-damage repair mechanisms in men with PrCa can have several therapeutic implications. The determination of defective DNA repair genes is important for providing information on disease prognosis and severity, as they have been consistently associated with a higher incidence of early-onset, more aggressive clinical behavior and cancer-specific mortality [ 13 , 90 , 91 , 158 ]. Moreover, the incidence of DNA repair alterations is significantly higher in advanced metastatic PrCa [ 90 ].…”

Section: Genetic Testingmentioning

confidence: 99%

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Hereditary Predisposition to Prostate Cancer: From Genetics to Clinical Implications

Brandão

Paulo

Teixeira

2020

IJMS

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Prostate cancer (PrCa) ranks among the top five cancers for both incidence and mortality worldwide. A significant proportion of PrCa susceptibility has been attributed to inherited predisposition, with 10–20% of cases expected to occur in a hereditary/familial context. Advances in DNA sequencing technologies have uncovered several moderate- to high-penetrance PrCa susceptibility genes, most of which have previously been related to known hereditary cancer syndromes, namely the hereditary breast and ovarian cancer (BRCA1, BRCA2, ATM, CHEK2, and PALB2) and Lynch syndrome (MLH1, MSH2, MSH6, and PMS2) genes. Additional candidate genes have also been suggested, but further evidence is needed to include them in routine genetic testing. Recommendations based on clinical features, family history, and ethnicity have been established for more cost-efficient genetic testing of patients and families who may be at an increased risk of developing PrCa. The identification of alterations in PrCa predisposing genes may help to inform screening strategies, as well as treatment options, in the metastatic setting. This review provides an overview of the genetic basis underlying hereditary predisposition to PrCa, the current genetic screening recommendations, and the implications for clinical management of the disease.

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Section: Genetic Etiology Of Inherited Prcasupporting

confidence: 66%

Section: Genetic Testingmentioning

confidence: 99%

Hereditary Predisposition to Prostate Cancer: From Genetics to Clinical Implications

Brandão

Paulo

Teixeira

2020

IJMS

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“…ATM has been implicated in increased risk of metastatic and lethal prostate cancer. [19][20][21][22][23] In most recent study, ATM mutations were detected in 0.7% of men with early onset PCa vs 0.2% in controls (OR = 4.1, P = .1). 18 In aggregate, studies to date suggest that ATM variants predispose to aggressive and early onset PCa, but each includes small number of carriers, and further research is needed.…”

Section: Resultsmentioning

confidence: 95%

“…Importantly, 50% of cancers diagnosed among ATM carriers were of Gleason score 8 to 10, compared to 22.7% in noncarriers ( P = .03). ATM has been implicated in increased risk of metastatic and lethal prostate cancer 19‐23 . In most recent study, ATM mutations were detected in 0.7% of men with early onset PCa vs 0.2% in controls (OR = 4.1, P = .1) 18 .…”

Section: Discussionmentioning

confidence: 99%

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland

Wokołorczyk

Kluźniak

Huzarski

et al. 2020

Intl Journal of Cancer

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In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency of mutations in PCa susceptibility genes in Polish familial PCa cases and to estimate gene-related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer-free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High-grade (Gleason 8-10) tumors

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“…Patients with early onset of PCa associated to family members affected with PCa or other heritable cancers are suitable candidates to undergo a genetic testing [ 6 ]. Over time, about 170 susceptibility loci for HPCa, accounting for ~33% of familial prostate cancer risks, have been identified with genome wide association studies (GWAS) [ 13 , 14 ]. Further insights have suggested that mutations in the different DNA damage repair (DDR) genes ( BRCA1 , BRCA2 , CHEK2 , ATM and PALB2 ) and in the DNA mismatch repair genes (MMR) ( MLH1 , MSH2 , MSH6 and PMS2 ), are biomarkers of HPCa [ 6 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention

Vietri

Goletti

Caliendo

et al. 2021

IJMS

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Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared to age, race, ethnicity and environmental factors for PCa development. Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5–15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits. Here, we discuss the current knowledge of the genetic basis for inherited predisposition to PCa, the potential target therapy, and the role of active surveillance as a management strategy for patients with low-risk PCa. Finally, the current PCa guideline recommendations are reviewed.

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Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Cited by 17 publications

References 43 publications

Hereditary Predisposition to Prostate Cancer: From Genetics to Clinical Implications

Hereditary Predisposition to Prostate Cancer: From Genetics to Clinical Implications

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland

Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention

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