Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Lhotová, Klára; Zemánková, Petra; Vočka, Michal; Janatová, Markéta; Borecká, Marianna; Černá, Marta; Jelínková, Sandra; Král, J; Volková, Z; Urbanová, Markéta; Kleiblová, Petra; Foretová, Lenka; Házová, Jana; Vašíčková, Petra; Lhota, Filip; Koudová, Monika; Cerna, Leona; Tavandzis, Spiros; Indrakova, Jana; Hrušková, Lucie; Kosařová, Marcela; Vrtěl, Radek; Stránecký, Viktor; Kmoch, Stanislav; Zikán, Michal; Macůrek, Libor; Kleibl, Zdeněk; Soukupová, Jana

doi:10.3390/cancers12040956

Cited by 28 publications

(36 citation statements)

References 55 publications

(68 reference statements)

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“…We found the most frequent, Slavic founder germ-line hypomorphic variant c.657del5 in five patients [ 48 ]. Two of them also developed ovarian cancer, which was associated with NBN germline mutations in our population [ 49 ]. An increased melanoma prevalence among NBN c.657del5 mutation carriers was reported from Poland (with a frequency comparable to our patients) and southern Germany (with lower prevalence) [ 50 , 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

et al. 2020

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Cutaneous melanoma is the deadliest skin malignity with a rising prevalence worldwide. Patients carrying germline mutations in melanoma-susceptibility genes face an increased risk of melanoma and other cancers. To assess the spectrum of germline variants, we analyzed 264 Czech melanoma patients indicated for testing due to early melanoma (at <25 years) or the presence of multiple primary melanoma/melanoma and other cancer in their personal and/or family history. All patients were analyzed by panel next-generation sequencing targeting 217 genes in four groups: high-to-moderate melanoma risk genes, low melanoma risk genes, cancer syndrome genes, and other genes with an uncertain melanoma risk. Population frequencies were assessed in 1479 population-matched controls. Selected POT1 and CHEK2 variants were characterized by functional assays. Mutations in clinically relevant genes were significantly more frequent in melanoma patients than in controls (31/264; 11.7% vs. 58/1479; 3.9%; p = 2.0 × 10−6). A total of 9 patients (3.4%) carried mutations in high-to-moderate melanoma risk genes (CDKN2A, POT1, ACD) and 22 (8.3%) patients in other cancer syndrome genes (NBN, BRCA1/2, CHEK2, ATM, WRN, RB1). Mutations in high-to-moderate melanoma risk genes (OR = 52.2; 95%CI 6.6–413.1; p = 3.2 × 10−7) and in other cancer syndrome genes (OR = 2.3; 95%CI 1.4–3.8; p = 0.003) were significantly associated with melanoma risk. We found an increased potential to carry these mutations (OR = 2.9; 95%CI 1.2–6.8) in patients with double primary melanoma, melanoma and other primary cancer, but not in patients with early age at onset. The analysis revealed affected genes in Czech melanoma patients and identified individuals who may benefit from genetic testing and future surveillance management of mutation carriers.

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Section: Discussionmentioning

confidence: 99%

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

et al. 2020

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“…Loss-of-function variants in RAD51C and RAD51D increase the risk of breast and ovarian cancer, but the same has not been demonstrated for other RAD51 paralogs, or for RAD51 itself that plays a major role in HR repair [ 7 , 8 , 9 , 10 , 11 ]. Likewise, bi-allelic RAD51C (or FANCO ) deleterious variants have been found in Fanconi Anemia patients [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Functional Characterization and Clinical Interpretation of 20 Splice-Site Variants of the RAD51C Gene

Sanoguera-Miralles

Valenzuela-Palomo

Bueno-Martínez

et al. 2020

Cancers

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Hereditary breast and/or ovarian cancer is a highly heterogeneous disease with more than 10 known disease-associated genes. In the framework of the BRIDGES project (Breast Cancer Risk after Diagnostic Gene Sequencing), the RAD51C gene has been sequenced in 60,466 breast cancer patients and 53,461 controls. We aimed at functionally characterizing all the identified genetic variants that are predicted to disrupt the splicing process. Forty RAD51C variants of the intron-exon boundaries were bioinformatically analyzed, 20 of which were selected for splicing functional assays. To test them, a splicing reporter minigene with exons 2 to 8 was designed and constructed. This minigene generated a full-length transcript of the expected size (1062 nucleotides), sequence, and structure (Vector exon V1- RAD51C exons_2-8- Vector exon V2). The 20 candidate variants were genetically engineered into the wild type minigene and functionally assayed in MCF-7 cells. Nineteen variants (95%) impaired splicing, while 18 of them produced severe splicing anomalies. At least 35 transcripts were generated by the mutant minigenes: 16 protein-truncating, 6 in-frame, and 13 minor uncharacterized isoforms. According to ACMG/AMP-based standards, 15 variants could be classified as pathogenic or likely pathogenic variants: c.404G > A, c.405-6T > A, c.571 + 4A > G, c.571 + 5G > A, c.572-1G > T, c.705G > T, c.706-2A > C, c.706-2A > G, c.837 + 2T > C, c.905-3C > G, c.905-2A > C, c.905-2_905-1del, c.965 + 5G > A, c.1026 + 5_1026 + 7del, and c.1026 + 5G > T.

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“…There were performed several other smaller studies, in which only single cases of BRCA1/2 mutations among BOT patients were detected, and the cumulative prevalence in all tested patients was 1.3% for BRCA1 and 0.2% for BRCA2 genes [ 33 ]. In contrary to the reports mentioned above, in a study of 1333 Czech ovarian cancer patients and 152 borderline ovarian tumor cases recruited from seven centers, the prevalence of BRCA1/2 mutations was similar in high-grade ovarian cancers and BOT cases (30.9% and 28.9%) [ 14 ]. There is no obvious explanation for such a high frequency of BRCA1/2 mutations among patients with BOT.…”

Section: Discussionmentioning

confidence: 91%

“…Mutations in BRCA1, BRCA2, RAD51C, and PALB2 genes were already shown to correlate with the risk of ovarian cancer [ 5 – 9 ], but not with BOTs [ 10 – 14 , 33 ]. The two studies conducted on the Jewish population (including 117 BOT and 161 ovarian cancer cases, as well as 46 BOT and 59 ovarian cancer cases, respectively) showed a much lower incidence of thfoundersnder BRCA1/2 mutations in BOT patients than in invasive early-stage ovarian carcinoma patients—the prevalence varied between 2.2 and 4.3% in BOT cases and 24.2–32% in ovarian cancer cases [ 10 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

Association of recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2, and CHEK2 with the risk of borderline ovarian tumor

Ogrodniczak

Menkiszak

Gronwald

et al. 2022

Hered Cancer Clin Pract

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Background There are several genes associated with ovarian cancer risk. Molecular changes in borderline ovarian tumor (BOT) indicate linkage of this disease to type I ovarian tumors (low-grade ovarian carcinomas). This study determined the prevalence and association of mutations in BRCA1, BRCA2, PALB2, RAD51C, and CHEK2 with the risk of BOTs. Methods The study group consisted of 102 patients with histologically confirmed BOT and 1743 healthy controls. In addition, 167 cases with ovarian cancer G1 were analyzed. The analyses included genotyping of 21 founder and recurrent mutations localized in 5 genes (BRCA1, BRCA2, PALB2, RAD51C, and CHEK2). The risk for developing BOT and low-grade ovarian cancer, as well as the association of tested mutations with survival, was estimated. Results The CHEK2 missense mutation (c.470T>C) was associated with 2-times increased risk of BOT (OR=2.05, p=0.03), at an earlier age at diagnosis and about 10% worse rate of a 10-year survival. Mutations in BRCA1 and PALB2 were associated with a high risk of ovarian cancer G1 (OR=8.53, p=0.005 and OR=7.03, p=0.03, respectively) and were related to worse all-cause survival for BRCA1 carriers (HR=4.73, 95%CI 1.45–15.43, p=0.01). Conclusions Results suggest that CHEK2 (c.470T>C) may possibly play a role in the pathogenesis of BOT, but due to the low number of BOT patients, obtained results should be considered as preliminary. Larger more in-depth studies are required.

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Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Cited by 28 publications

References 55 publications

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

Comprehensive Functional Characterization and Clinical Interpretation of 20 Splice-Site Variants of the RAD51C Gene

Association of recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2, and CHEK2 with the risk of borderline ovarian tumor

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