Functionally Null <i>RAD51D</i> Missense Mutation Associates Strongly with Ovarian Carcinoma

Rivera, Bárbara; Iorio, Massimo Di; Frankum, Jessica; Nadaf, Javad; Fahiminiya, Somayyeh; Arcand, Suzanna L.; Burk, David L.; Grapton, Damien; Tomiak, Eva; Hastings, Valerie; Hamel, Nancy; Wagener, Rabea; Aleynikova, Olga; Giroux, Sylvie; Hamdan, Fadi F.; Dionne‐Laporte, Alexandre; Zogopoulos, George; Rousseau, François; Berghuis, Albert M.; Provencher, Diane; Rouleau, Guy A.; Michaud, Jacques L.; Mes-Masson, Anne-Marie; Majewski, Jacek; Bens, Susanne; Siebert, Reiner; Narod, Steven A.; Akbari, Mohammad Reza; Lord, Christopher J.; Tonin, Patricia N.; Orthwein, Alexandre; Foulkes, William D.

doi:10.1158/0008-5472.can-17-0190

Cited by 32 publications

(63 citation statements)

References 49 publications

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“…Further analysis of other members of our cancer family showed only one of five other carriers was affected by BC (unpublished data). This case is from the French Canadian population and carries a pathogenic variant in BRCA2 c.8537_8538delAG; p.Glu2846GlyfsTer22 known to be a founder pathogenic variant as reported by our group and others [84][85][86][87][88][89][90][91][92][93].…”

Section: Carriers Of a Bard1 Variant And A Pathogenic Variant In A Knsupporting

confidence: 52%

Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

Alenezi

Fierheller

Recio

et al. 2020

Genes

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Soon after the discovery of BRCA1 and BRCA2 over 20 years ago, it became apparent that not all hereditary breast and/or ovarian cancer syndrome families were explained by germline variants in these cancer predisposing genes, suggesting that other such genes have yet to be discovered. BRCA1-associated ring domain (BARD1), a direct interacting partner of BRCA1, was one of the earliest candidates investigated. Sequencing analyses revealed that potentially pathogenic BARD1 variants likely conferred a low–moderate risk to hereditary breast cancer, but this association is inconsistent. Here, we review studies of BARD1 as a cancer predisposing gene and illustrate the challenge of discovering additional cancer risk genes for hereditary breast and/or ovarian cancer. We selected peer reviewed research articles that focused on three themes: (i) sequence analyses of BARD1 to identify potentially pathogenic germline variants in adult hereditary cancer syndromes; (ii) biological assays of BARD1 variants to assess their effect on protein function; and (iii) association studies of BARD1 variants in family-based and case-control study groups to assess cancer risk. In conclusion, BARD1 is likely to be a low–moderate penetrance breast cancer risk gene.

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Section: Carriers Of a Bard1 Variant And A Pathogenic Variant In A Knsupporting

confidence: 52%

Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

Alenezi

Fierheller

Recio

et al. 2020

Genes

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“…In parallel to the genome-wide LOH analysis, OncoScan CNV SNP arrays were performed to study somatic chromosomal aberrations in 4 MNG samples from II-2, III-1, III-2, and III-3, as well as in the 2 unrelated PTCs with the DGCR8-E518K mutation as previously described (49). Array data has been included in the GEO repository (accession number GSE135374).…”

Section: Genome-wide Copy Number Analysismentioning

confidence: 99%

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis

Rivera¹,

Nadaf²,

Fahiminiya³

et al. 2020

Journal of Clinical Investigation

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BACKGROUND. DICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist. METHODS. Whole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K. RESULTS. We identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p. E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons. CONCLUSION. We identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.

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“…The increased DNA damage is much more toxic to the HR-deficient tumor cells than to the surrounding HR-proficient cells. Similar to BRCA1/2-deficient tumors, emerging studies show similar platinum sensitivities for mutations in HR genes, including RAD51C and RAD51D [135,136]. While initially effective, subsequent platinum resistance often leads to the recurrence of the tumor [116].…”

Section: Chemotherapeutics Currently In the Clinicmentioning

confidence: 99%

RAD-ical New Insights into RAD51 Regulation

Sullivan

Bernstein

2018

Genes

105

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The accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions; however, they can be repaired using homologous recombination. Homologous recombination is a high-fidelity DNA repair pathway that uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends, which is a step required for the homology search and strand invasion steps of HR. RAD51 filament formation is tightly controlled by many positive and negative regulators, which are collectively termed the RAD51 mediators. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. In model organisms, RAD51 paralogs are RAD51 mediator proteins that structurally resemble RAD51 and promote its HR activity. New functions for the RAD51 paralogs during replication and in RAD51 filament flexibility have recently been uncovered. Mutations in the human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are found in a subset of breast and ovarian cancers. Despite their discovery three decades ago, few advances have been made in understanding the function of the human RAD51 paralogs. Here, we discuss the current perspective on the in vivo and in vitro function of the RAD51 paralogs, and their relationship with cancer in vertebrate models.

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Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma

Cited by 32 publications

References 49 publications

Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis

RAD-ical New Insights into RAD51 Regulation

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