Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer

Paulo, Paula; Maia, Sofia; Pinto, Carla; Pinto, Pedro; Monteiro, Augusta; Peixoto, Ana; Teixeira, Manuel R.

doi:10.1371/journal.pgen.1007355

Cited by 58 publications

(84 citation statements)

References 77 publications

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“…CHEK2 variants have been associated with PrCa predisposition in several studies [9,10], and we found that this gene was the most frequently mutated Tier 1 gene in our study (4.1%). In a recent study of 217 metastatic PrCa patients from Sweden [31], CHEK2 was also the most frequently mutated DNA repair gene (3.8%), highlighting the importance of CHEK2 mutations for aggressive PrCa in the Nordic population.…”

Section: Discussionsupporting

confidence: 70%

“…ATM and its role in pancreatic cancer was recently reviewed [35] and germline mutations in ATM have been associated with predisposition for several cancer forms [36] including PrCa [3]. Several studies have particularly reported potentially damaging variants in ATM in aggressive PrCa cases [7,9,29,31]. We also found high frequencies of potentially damaging variants in our lethal cohort (3.28% and 1.64% for Tier 1 and 2 variants, respectively), while in the unselected cases, the frequencies of these variants were found to be very low, similar to those of the population controls.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence suggests that pathogenic germline variants in known cancer-predisposing genes such as BRCA2 can increase the risk of developing PrCa, especially the more aggressive form of the disease [7]. Likewise, several other genes that were initially implicated as high-risk genes in cancers other than PrCa, such as CHEK2 and BRIP1, have subsequently been shown to increase the risk of PrCa as well [8][9][10]. Recent studies have reported a high carrier rate of inherited DNA repair gene mutations among men with metastatic PrCa (11.8%), significantly exceeding the prevalence (4.6%) among men with localized PrCa [11].…”

Section: Introductionmentioning

confidence: 99%

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Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Rantapero

Wahlfors

Kähler

et al. 2020

Genes

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Germline variants in DNA repair genes are associated with aggressive prostate cancer (PrCa). The aim of this study was to characterize germline variants in DNA repair genes associated with lethal PrCa in Finnish and Swedish populations. Whole-exome sequencing was performed for 122 lethal and 60 unselected PrCa cases. Among the lethal cases, a total of 16 potentially damaging protein-truncating variants in DNA repair genes were identified in 15 men (12.3%). Mutations were found in six genes with CHEK2 (4.1%) and ATM (3.3%) being most frequently mutated. Overall, the carrier rate of truncating variants in DNA repair genes among men with lethal PrCa significantly exceeded the carrier rate of 0% in 60 unselected PrCa cases (p = 0.030), and the prevalence of 1.6% (p < 0.001) and 5.4% (p = 0.040) in Swedish and Finnish population controls from the Exome Aggregation Consortium. No significant difference in carrier rate of potentially damaging nonsynonymous single nucleotide variants between lethal and unselected PrCa cases was observed (p = 0.123). We confirm that DNA repair genes are strongly associated with lethal PrCa in Sweden and Finland and highlight the importance of population-specific assessment of variants contributing to PrCa aggressiveness.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Rantapero

Wahlfors

Kähler

et al. 2020

Genes

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“…Cep57 insufficiency could drive tumorigenesis in this way. Interestingly, CEP57 insufficiency correlates with tumor growth and metastasis in 2 prostate cancer patient cohorts, and monoallelic mutation was reported in early-onset familial prostate cancers ( 58 , 59 ). Irrespective of the exact mechanism of tumorigenesis, the currently available data warrant future investigations as to whether homozygous and heterozygous carriers of inactivating CEP57 mutations would benefit from intensified cancer screenings, for instance by the use of newly developed multianalyte blood tests ( 60 ).…”

Section: Discussionmentioning

confidence: 99%

Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression

Aziz¹,

Sieben²,

Jeganathan³

et al. 2018

Journal of Clinical Investigation

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A homozygous truncating frameshift mutation in CEP57 (CEP57T/T) has been identified in a subset of mosaic-variegated aneuploidy (MVA) patients; however, the physiological roles of the centrosome-associated protein CEP57 that contribute to disease are unknown. To investigate these, we have generated a mouse model mimicking this disease mutation. Cep57T/T mice died within 24 hours after birth with short, curly tails and severely impaired vertebral ossification. Osteoblasts in lumbosacral vertebrae of Cep57T/T mice were deficient for Fgf2, a Cep57 binding partner implicated in diverse biological processes, including bone formation. Furthermore, a broad spectrum of tissues of Cep57T/T mice had severe aneuploidy at birth, consistent with the MVA patient phenotype. Cep57T/T mouse embryonic fibroblasts and patient-derived skin fibroblasts failed to undergo centrosome maturation in G2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Mice heterozygous for the truncating frameshift mutation or a Cep57-null allele were overtly indistinguishable from WT mice despite reduced Cep57 protein levels, yet prone to aneuploidization and cancer, with tumors lacking evidence for loss of heterozygosity. This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation.

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“…Besides RTS patients with RECQL4 mutations, our proposed regimen maybe used for cancer patients with germline RECLQ4 mutations. For instance, recent studies reveal that a small fraction of cancer patients also have RECQL4 mutations, 55,56 and we expect that our study may partially help with the genomic diagnosis for cancer treatment in the future. RTS patients are at high risk for OS at young ages without affecting prognosis significantly.…”

Section: Discussionmentioning

confidence: 87%

Human RECQL4 represses the RAD52‐mediated single‐strand annealing pathway after ionizing radiation or cisplatin treatment

Kohzaki

Ootsuyama

Sun

et al. 2019

Intl Journal of Cancer

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Ionizing radiation (IR) and cisplatin are frequently used cancer treatments, although the mechanisms of error‐prone DNA repair‐mediated genomic instability after anticancer treatment are not fully clarified yet. RECQL4 mutations mainly in the C‐terminal region of the RECQL4 gene lead to the cancer‐predisposing Rothmund–Thomson syndrome, but the function of RECQL4ΔC (C‐terminus deleted) in error‐prone DNA repair remains unclear. We established several RECQL4ΔC cell lines and found that RECQL4ΔC cancer cells, but not RECQL4ΔC nontumorigenic cells, exhibited IR/cisplatin hypersensitivity. Notably, RECQL4ΔC cancer cells presented increased RPA2/RAD52 foci after cancer treatments. RECQL4ΔC HCT116 cells exhibited increased error‐prone single‐strand annealing (SSA) activity and decreased alternative end‐joining activities, suggesting that RECQL4 regulates the DNA repair pathway choice at double‐strand breaks. RAD52 depletion by siRNA or RAD52 inhibitors (5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside [AICAR], (−)‐epigallocatechin [EGC]) or a RAD52‐phenylalanine 79 aptamer significantly restrained the growth of RAD52‐upregulated RECQL4ΔC HCT116 cells in vitro and in mouse xenografts. Remarkably, compared to single‐agent cisplatin or EGC treatment, cisplatin followed by low‐concentration EGC had a significant suppressive effect on RECQL4ΔC HCT116 cell growth in vivo. Together, the regimens targeting the RAD52‐mediated SSA pathway after anticancer treatment may be applicable for cancer patients with RECQL4 gene mutations.

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Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer

Cited by 58 publications

References 77 publications

Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression

Human RECQL4 represses the RAD52‐mediated single‐strand annealing pathway after ionizing radiation or cisplatin treatment

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