Male breast cancer (mBC) is a rare cancer diagnosis that constitutes less than 1 % of all breast cancer cases globally. Genetic factors play an important role in the mBC risk. Germline pathogenic variants (PVs) in cancer predisposition genes could be identified in about 15 % of cases. We performed germline genetic testing in 248 Czech mBC patients and 3,626 non-cancer male controls using next-generation sequencing by the CZECANCA panel (226 genes). We identified 46/248 (18.5 %) carriers of PVs in the established mBC predisposition genes, primarily in BRCA2 (N = 34), less frequently in BRCA1 (N = 7) and PALB2 (N = 5). The presence of a PV in these genes significantly increased the mBC risk (OR 44.04; 5.82; and 8.26, respectively). Additionally, we identified 16 carriers of PVs in candidate mBC genes, but only PVs in CHEK2 were significantly associated with increased mBC risk (OR = 4.98). The significance of 26 germline alterations in 23/192 additionally analysed genes remained uncertain. The carriers of PVs in BRCA1 and CHEK2 were significantly younger (55.8 and 52.6 years, respectively) than non-carriers (64.8 years), and all carriers of PVs in the established genes had more frequently grade G3 tumours and positive family cancer history. Our study underscores the critical role of BRCA2 in mBC predisposition while also highlighting the potential contributions of additional genes that warrant further investigation. Moreover, it supports and justifies universal genetic testing for all mBC patients to generally improve early cancer detection and tailored treatment.

• Klíčová slova
• NGS, germline genetic testing, hereditary cancer predisposition, male breast cancer,
• MeSH
• checkpoint kinasa 2 genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• genetické testování MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu u mužů * genetika   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• senioři MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• checkpoint kinasa 2 MeSH
• CHEK2 protein, human MeSH Prohlížeč
• protein BRCA1 MeSH
• protein BRCA2 MeSH

Recent studies have conferred that the RAD51C and RAD51D genes, which code for the essential proteins involved in homologous recombination, are ovarian cancer (OC) susceptibility genes that may explain genetic risks in high-risk patients. We performed a mutation analysis in 171 high-risk BRCA1 and BRCA2 negative OC patients, to evaluate the frequency of hereditary RAD51C and RAD51D variants in Czech population. The analysis involved direct sequencing, high resolution melting and multiple ligation-dependent probe analysis. We identified two (1.2%) and three (1.8%) inactivating germline mutations in both respective genes, two of which (c.379_380insG, p.P127Rfs*28 in RAD51C and c.879delG, p.C294Vfs*16 in RAD51D) were novel. Interestingly, an indicative family cancer history was not present in four carriers. Moreover, the ages at the OC diagnoses in identified mutation carriers were substantially lower than those reported in previous studies (four carriers were younger than 45 years). Further, we also described rare missense variants, two in RAD51C and one in RAD51D whose clinical significance needs to be verified. Truncating mutations and rare missense variants ascertained in OC patients were not detected in 1226 control samples. Although the cumulative frequency of RAD51C and RAD51D truncating mutations in our patients was lower than that of the BRCA1 and BRCA2 genes, it may explain OC susceptibility in approximately 3% of high-risk OC patients. Therefore, an RAD51C and RAD51D analysis should be implemented into the comprehensive multi-gene testing for high-risk OC patients, including early-onset OC patients without a family cancer history.

• MeSH
• DNA vazebné proteiny genetika   MeSH
• exony genetika   MeSH
• genetická predispozice k nemoci * MeSH
• geny nádorové * MeSH
• introny genetika   MeSH
• komplementární DNA genetika   MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• mutační analýza DNA MeSH
• nádory vaječníků genetika   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• rizikové faktory MeSH
• rodina MeSH
• sekvence nukleotidů MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• komplementární DNA MeSH
• protein BRCA1 MeSH
• protein BRCA2 MeSH
• RAD51C protein, human MeSH Prohlížeč
• RAD51D protein, human MeSH Prohlížeč

BACKGROUND: Several reports indicate that inherited mutations in the PALB2 gene predispose to breast cancer. However, there is little agreement about the clinical relevance and usefulness of mutation screening in this gene. We analyzed the prevalence and spectrum of germline mutations in PALB2 to estimate their contribution to hereditary breast and/or ovarian cancer in the Czech Republic. METHODS: The entire PALB2 coding region was sequenced in 409 breast/ovarian cancer patients negative for BRCA1 and BRCA2 mutations. Testing for large genomic rearrangements (LGR) was performed by multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS: We have identified 13 different pathogenic alterations including 10 truncating mutations and three LGRs in 16 of 409 patients (3.9%), whereas one truncating mutation was found in a group of 1,226 controls (0.08%; P = 2.6 × 10(-9)). Three novel LGRs included deletions involving exons 7-8 and 9-10, respectively, and a duplication spanning exons 9-11. Five frameshift and two nonsense mutations were novel, whereas three truncating mutations were described previously. The only recurrent mutation was the c.172_175delTTGT detected in four unrelated breast cancer individuals. CONCLUSIONS: Our analyses demonstrated the significant role of the PALB2 gene in breast cancer susceptibility. The highest frequency of PALB2 mutations (comparable with that previously reported for BRCA2) was found in a subgroup of patients with hereditary breast cancer (HBC) (13/235; 5.5%). IMPACT: Our results show that mutation analysis of the PALB2 gene, including the analysis of LGRs, is primarily indicated in patients with HBC in case of their BRCA1 and BRCA2 negativity.

• MeSH
• delece genu MeSH
• genetická predispozice k nemoci MeSH
• geny BRCA1 * MeSH
• geny BRCA2 * MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• mutační analýza DNA metody   MeSH
• nádorové supresorové proteiny genetika   MeSH
• nádory prsu genetika   patologie   MeSH
• nádory vaječníků genetika   patologie   MeSH
• prevalence MeSH
• protein FANCN MeSH
• rizikové faktory MeSH
• rodokmen MeSH
• sekvence nukleotidů MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• jaderné proteiny MeSH
• nádorové supresorové proteiny MeSH
• PALB2 protein, human MeSH Prohlížeč
• protein FANCN MeSH

Germline mutations in two major susceptibility genes BRCA1 and BRCA2 contribute to the majority of inherited breast and ovarian cancers. Besides the germline mutation, tumor progression depends on the loss of a wild-type allele. Allelic losses in the BRCA1 and BRCA2 loci have also been detected in a high proportion of sporadic breast tumors, suggesting the role of these genes in the development of non-inherited breast cancer. Forty unselected breast tumors were analyzed for the loss of heterozygosity (LOH) at BRCA1 and BRCA2 regions and tumors with allelic deletions were screened for the presence of acquired genetic alterations in respective genes. 21.1% of 38 informative tumor samples carried LOH at the BRCA1 locus whereas 33.3% of 39 informative samples showed LOH at the BRCA2 locus. Pathogenic truncating mutations in the BRCA1 gene were found in two tumor samples with allelic losses, whereas no mutations were identified in the BRCA2 gene. Mutations were not detected in non-tumor samples from the same individuals, which indicated that the BRCA1 allele was inactivated by somatic mutations in tumor tissue. The c.1116G>A (1235G>A) nonsense mutation (p.W372X) belongs to the genetic abnormalities detected infrequently in hereditary tumors; the c.3862delG (3981delG) frameshift mutation (p.E1288fsX1306) is a novel gene alteration. The occurrence of inactivating somatic mutations in sporadic breast tumors suggested the role of the BRCA1 gene in tumorigenesis in at least a minor group of patients with non-familial breast cancer.

• MeSH
• DNA nádorová genetika   MeSH
• dospělí MeSH
• duktální karcinom prsu genetika   MeSH
• geny BRCA1 * MeSH
• geny BRCA2 MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikrosatelitní repetice MeSH
• mutační analýza DNA MeSH
• nádorová transformace buněk genetika   MeSH
• nádory prsu genetika   MeSH
• nesmyslný kodon MeSH
• posunová mutace * MeSH
• protein BRCA1 fyziologie   MeSH
• sekvenční analýza DNA MeSH
• senioři MeSH
• ztráta heterozygozity MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA nádorová MeSH
• nesmyslný kodon MeSH
• protein BRCA1 MeSH