Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients

Koczkowska, Magdalena; Krawczyńska, Natalia; Stukan, Maciej; Kuźniacka, Alina; Brożek, Izabela; Śniadecki, Marcin; Dȩbniak, Jarosław; Wydra, Dariusz; Biernat, Wojciech; Kozlowski, Piotr; Limon, Janusz; Wasąg, Bartosz; Ratajska, Magdalena

doi:10.3390/cancers10110442

Cited by 31 publications

(40 citation statements)

References 44 publications

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“…Mutations in NF1 were absent and were extremely rare in CDH1 and PTEN, just like STK11 mutations found in a patient with nonepithelial OC, a characteristic Peutz-Jeghers syndrome manifestation [9]. Altogether, the high overall frequency of mutations in OC predisposition genes in our study is in agreement with some previous studies [4][5][6]28] and may contribute to a high OC incidence in our population.…”

Section: Discussionsupporting

confidence: 92%

“…The BRCA1 and BRCA2 mutations, present in 84.0% of all mutation carriers, were by far the most frequent alterations found in 17.9% and 7.4% of our patients, respectively. Mutations in other eight genes leaded by RAD51C/RAD51D/BRIP1 affected additional 5.0% of patients, as shown also by others recently [5,6,22]. Germline mutations in Lynch syndrome genes together associated with high OC risk.…”

Section: Discussionmentioning

confidence: 62%

“…Genetic predisposition for OC is unusually high and is reported in up to 25% of cases [4][5][6]. The most frequent germline mutations affect the BRCA1 and BRCA2 genes, conferring 24% and 8.4% OC lifetime risks, respectively [7].…”

Section: Introductionmentioning

confidence: 99%

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Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Lhotová

Zemánková

Vočka

et al. 2020

Cancers

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Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2, RAD51C/RAD51D, BARD1, and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 62%

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Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Lhotová

Zemánková

Vočka

et al. 2020

Cancers

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“…Initial studies clearly showed that founder mutations cover as little as 48-65% of the germline mutation spectrum further reinforcing the testing paradigm shift towards NGS-based approach [9,10,11]. In Poland, germline mutations are now detected in 15% of unselected ovarian cancer cases and as many as 28% for testing from tumour specimen [10,12,13]. Introduction of NGS-based tumour testing has the advantage of detection both germline and somatic mutations yet poses several challenges in the patients pathway and lab pipeline [14].…”

Section: Introductionmentioning

confidence: 99%

Somatic mutations in BRCA1&2 in 201 unselected ovarian carcinoma samples – single institution study

Kowalik¹,

Zalewski²,

Kopczyński³

et al. 2019

pjp

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Ovarian cancer (OC) is the most lethal among gynecologic malignancies worldwide. Unfortunately, in around 70% of cases cancer is diagnosed in late stages (III-IV) which decreases the 5-year survival rate to 25%. The standard of care in ovarian cancer is debulking surgery followed by chemotherapy regimens based on platinum salts. Since 2014 PARP inhibitors became available for OC patients with germline or/and somatic mutations in BRCA1/2, including maintenance therapy. BRCA1/2 Next Generation Sequencing (NGS)-based analysis of formalin-fixed paraffin-embedded (FFPE) ovarian cancer samples becomes the standard of care. The aim of the present study was to evaluate the frequency of mutations in 201 unselected ovarian cancer tissues using the NGS method. In total, pathogenic mutations in both genes were detected in 24% (49/201) of the ovarian cancer cases tested. For 41 patients the results of testing of DNA isolated from blood sample revealed that 17% (35/201) mutations were germline origin, whereas 3% (6/201) mutations were somatic. In 4% (8/201) cases blood sample was inaccessible. The presence of pathogenic mutations was correlated with younger age at diagnosis and serous subtype. Close cooperation between many specialists (gynecologist, pathologist, oncologist, clinical genetics and molecular biologist) is indispensable for efficient and on-time BRCA1/2 ovarian tumor tissue testing.

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“…Efforts to identify additional moderate-to-high-risk hereditary breast and ovarian cancer (HBOC) genes have largely been restricted to candidate gene approaches using targeted nextgeneration sequencing (NGS) panels of known cancer predisposition genes [12][13][14][15][16][17][18] , which have collectively only resolved a very small proportion of unexplained families. Although three studies utilised data from whole-exome sequencing (WES) of BRCA1 and BRCA2-negative ovarian carcinoma patients [19][20][21] , these analysed only a subset of candidate genes in the available data and included non-HGSOC tumour types in their case cohorts.…”

mentioning

confidence: 99%

Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

et al. 2020

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High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by threefold or more compared to Gno-mAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously underexplored genes and pathways.

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Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients

Cited by 31 publications

References 44 publications

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Somatic mutations in BRCA1&2 in 201 unselected ovarian carcinoma samples – single institution study

Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

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