Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain)

Sánchez-Bermúdez, A.I.; Sarabia-Meseguer, M.D.; García-Aliaga, Ángeles; Marín-Vera, Miguel; Macías-Cerrolaza, José Antonio; Henaréjos, Pilar Sánchez; Castillo-Guardiola, Verónica; Peña, Francisco Ayala-De La; Alonso-Romero, José Luis; Noguera-Velasco, José Antonio; Ruíz-Espejo, Francisco

doi:10.1016/j.ejmg.2018.01.015

Cited by 18 publications

(11 citation statements)

References 21 publications

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“…A number of rare variants have previously been reported as likely pathogenic, including p.Gln143Arg 7,8 , p.Arg258His 7,9,10 , p.Cys135Tyr 7,8,15 , p.Ile144Thr 7,16 and p.Val169Ala 4,5 . In this study, p.Gln143Arg was detected in 0.7% of cases (n = 4), including one TN BC and two with a family history of ovarian cancer, and 0.2% of controls (n = 3), consistent with the observed RAD51C phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Integration of tumour sequencing and case–control data to assess pathogenicity of RAD51C missense variants in familial breast cancer

Lim

Rowley

et al. 2022

npj Breast Cancer

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While protein-truncating variants in RAD51C have been shown to predispose to triple-negative (TN) breast cancer (BC) and ovarian cancer, little is known about the pathogenicity of missense (MS) variants. The frequency of rare RAD51C MS variants was assessed in the BEACCON study of 5734 familial BC cases and 14,382 population controls, and findings were integrated with tumour sequencing data from 21 cases carrying a candidate variant. Collectively, a significant enrichment of rare MS variants was detected in cases (MAF < 0.001, OR 1.57, 95% CI 1.00–2.44, p = 0.05), particularly for variants with a REVEL score >0.5 (OR 3.95, 95% CI 1.40–12.01, p = 0.006). Sequencing of 21 tumours from 20 heterozygous and 1 homozygous carriers of nine candidate MS variants identified four cases with biallelic inactivation through loss of the wild-type allele, while six lost the variant allele and ten that remained heterozygous. Biallelic loss of the wild-type alleles corresponded strongly with ER- and TN breast tumours, high homologous recombination deficiency scores and mutational signature 3. Using this approach, the p.Gly264Ser variant, which was previously suspected to be pathogenic based on small case–control analyses and loss of activity in in vitro functional assays, was shown to be benign with similar prevalence in cases and controls and seven out of eight tumours showing no biallelic inactivation or characteristic mutational signature. Conversely, evaluation of case–control findings and tumour sequencing data identified p.Ile144Thr, p.Arg212His, p.Gln143Arg and p.Gly114Arg as variants warranting further investigation.

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Section: Discussionmentioning

confidence: 99%

Integration of tumour sequencing and case–control data to assess pathogenicity of RAD51C missense variants in familial breast cancer

Lim

Rowley

et al. 2022

npj Breast Cancer

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“…RAD51D mutation carriers were more likely to suffer from premenopausal ovarian tumors. [20] Song et al found more mutation carriers were diagnosed at ages 40 to 49 years than noncarriers, and no mutation carrier was diagnosed with ovarian cancer before age 40 years. [5] Our present observations are in agreement with these ndings.…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and survival analysis of Chinese ovarian cancer patients with RAD51D germline mutations

Yuan

2022

Preprint

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ObjectivesWe aimed to describe the behavior among Chinese ovarian cancer patients with RAD51D germline mutations at our institution. MethodsNext-generation sequencing (NGS) was conducted for the entire coding regions and exon/intron boundaries of the RAD51D genes in 781 Chinese ovarian cancer patients treated at our institution from January 1, 2015 to August 1, 2021. Clinicopathological characteristics, treatment modalities, and outcomes were assessed for ovarian cancerpatients with RAD51D germline mutations. ResultsRAD51D germline pathogenic mutations were detected in 1.7% (13/781) of patients in this cohort. RAD51D c. 270_271dup (p. Lys91fs) mutation was the most common mutation which was found in 7 patients (7/13, 53.1%). Patients median age at diagnosis was 58 years (range: 45-69 years). 46.2% (6/13) of them were diagnosed after 60 years. Only 1 patient (1/13, 7.7%) had a family history of ovarian or breast cancer. And 1 patient (1/13, 7.7%) had a personal history of breast cancer. The FIGO 2014 distribution by stage was: stage II in 1 patient (7.7%), stage III in 9 patients (69.2%) and stage IV in 3 patient (23.1%).92.3% (12/13) patients had high-grade serous carcinoma. 2 patients (2/13, 15.4%) had a primary peritoneal cancer. The majority of patients in the entire cohort were reported to be platinum sensitive (92.3%, 12/13) with a platinum-free interval (PFI) of > 6 months.For patients who received PARPis for 2ndline maintenance treatment (n=5), 2 patients discontinued PARPis treatment after 33.5 and 8.1 months of duration. Other 3 patients are still on therapy with a duration of 2.4, 13.8 and 30.1 months at the date of data cutoff. 1 patient received PARPi as salvage treatment with a duration of only 1.2 months. 9 patients (9/13, 69.2%) relapsed during follow up and all of them relapsed within 2 years after diagnosis, among which 88.9% (8/9) were classi ed as platinum-sensitive recurrence (PSR), and only 1 patient was classi ed as platinum-resistant recurrence (PRR). Median PFS for the entire cohort was 17.3 months. Median PFS for the PSR subgroup was 15.9 months. 2 patients died during follow-up. The OS of these 2 patients was 17.2 and 39.6 months. The 5-year OS rate was 67.5%. ConclusionsRAD51D germline mutations are more frequent in Chinese ovarian cancer patients than other population. Few patients have a family history of ovarian or breast cancer, and personal history of breast cancer. Most patients are diagnosed after 50 years and tend to be associated with particularly aggressive phenotype. The sensitivity to PARP inhibitors of patients with RAD51D germline mutations need a further analysis.

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“…Given the rarity of RAD51D mutations, there is limited data about the clinical characteristics and survival of mutation carriers. RAD51D mutation carriers were more likely to suffer from premenopausal ovarian tumors [ 35 ]. Song et al found more mutation carriers were diagnosed at ages 40 to 49 years than noncarriers, and no mutation carrier was diagnosed with ovarian cancer before age 40 years [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and survival analysis of Chinese ovarian cancer patients with RAD51D germline mutations

Yao

Yuan

2022

BMC Cancer

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Objectives We aimed to describe the behavior among Chinese ovarian cancer patients with RAD51D germline mutations at our institution. Methods Next-generation sequencing (NGS) was conducted for the entire coding regions and exon/intron boundaries of the RAD51D genes in 781 Chinese ovarian cancer patients treated at our institution from January 1, 2015 to August 1, 2021. Clinicopathological characteristics, treatment modalities, and outcomes were assessed for ovarian cancer patients with RAD51D germline mutations. Results RAD51D germline pathogenic mutations were detected in 1.7% (13/781) of patients in this cohort. RAD51D c. 270_271dup (p. Lys91fs) mutation was the most common mutation which was found in 7 patients (7/13, 53.1%). Patients median age at diagnosis was 58 years (range: 45–69 years). 46.2% (6/13) of them were diagnosed after 60 years. Only 1 patient (1/13, 7.7%) had a family history of ovarian or breast cancer. And 1 patient (1/13, 7.7%) had a personal history of breast cancer. The FIGO 2014 distribution by stage was: stage II in 1 patient (7.7%), stage III in 9 patients (69.2%) and stage IV in 3 patient (23.1%). 92.3% (12/13) patients had high-grade serous carcinoma. 2 patients (2/13, 15.4%) had a primary peritoneal cancer. The majority of patients in the entire cohort were reported to be platinum sensitive (92.3%, 12/13) with a platinum-free interval (PFI) of > 6 months. For patients who received PARPis for 2nd line maintenance treatment (n = 5), 2 patients discontinued PARPis treatment after 33.5 and 8.1 months of duration. Other 3 patients are still on therapy with a duration of 2.4, 13.8 and 30.1 months at the date of data cutoff. 1 patient received PARPi as salvage treatment with a duration of only 1.2 months. Nine patients (9/13, 69.2%) relapsed during follow up and all of them relapsed within 2 years after diagnosis, among which 88.9% (8/9) were classified as platinum-sensitive recurrence (PSR), and only 1 patient was classified as platinum-resistant recurrence (PRR). Median PFS for the entire cohort was 17.3 months. Median PFS for the PSR subgroup was 15.9 months. 2 patients died during follow-up. The OS of these 2 patients was 17.2 and 39.6 months. The 5-year OS rate was 67.5%. Conclusions RAD51D germline mutations are more frequent in Chinese ovarian cancer patients than other population. Few patients have a family history of ovarian or breast cancer, and personal history of breast cancer. Most patients are diagnosed after 50 years. The sensitivity to PARP inhibitors of patients with RAD51D germline mutations need a further analysis.

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Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain)

Cited by 18 publications

References 21 publications

Integration of tumour sequencing and case–control data to assess pathogenicity of RAD51C missense variants in familial breast cancer

Integration of tumour sequencing and case–control data to assess pathogenicity of RAD51C missense variants in familial breast cancer

Clinical characteristics and survival analysis of Chinese ovarian cancer patients with RAD51D germline mutations

Clinical characteristics and survival analysis of Chinese ovarian cancer patients with RAD51D germline mutations

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