[Retrospective NGS Study in High-risk Hereditary Cancer Patients at Masaryk Memorial Cancer Institute]. / Retrospektivní NGS studie u vysoce rizikových pa-cientu s hereditární predispozicí k nádorovému onemocnení v Masarykove onkologickém ústavu.

BACKGROUND: Currently, more than 200 hereditary cancer syndromes have been described, yet, in most countries genetic testing is restricted to a narrow spectrum of genes within a limited group of people tested. METHODS: For this retrospective study we used the TruSight cancer panel (Illumina)--NGS panel targeting 94 cancer predisposition genes in order to analyze 50 high-risk cancer patients with significant personal and family history of cancer who did not carry mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6, TP53 or APC genes. All pathogenic and potentially pathogenic mutations detected by NGS technology have been confirmed by Sanger sequencing. RESULTS: There were several deleterious (frame-shift/nonsense) mutations detected in ATM, BAP1, FANCC, FANCI, PMS2, SBDS, ERCC2, RECQL4 genes. Various pathogenic or potentially pathogenic (missense, predicted splice site, in-frame insertion/deletion) mutations were detected in ATM, BRIP1, CDH1, CHEK2, ERCC2, ERCC3, ERCC4, FANCA, MC1R, MEN1, MRE11A, MUTYH, PALB2, RAD51C, RET, SDHB, STK11. These mutations affect highly conserved protein domains and affect their function as proved by the available functional assays. They were confirmed to be pathogenic as an "Parent No2 " in serious recessive diseases such as Ataxia telangiectasia or Fanconi anemia. The clinical significance of the majority of detected missense variants still remains to be identified. CONCLUSION: Moderate or low penetrance variants are of limited clinical importance. Panel genetic testing in high-risk individuals with cancer provides important information concerning the cause of the investigated cancer, and may assist in the risk assesment and optimal management of the cancer, as well as in further preventive care.

[The clinical importance of a genetic analysis of moderate-risk cancer susceptibility genes in breast and other cancer patients from the Czech Republic]. / Klinický význam analýz genu stredního rizika pro hodnocení rizika vzniku karcinomu prsu a dalsích nádoru v Ceské republice.

BACKGROUND: Analysis of the major breast cancer (BC) predisposition genes BRCA1 and BRCA2 enables identification of high-risk individuals. Specialized programs enrolling the carriers of BRCA1/2 mutations facilitate an improvement in prevention and early diagnostics in asymptomatic individuals and rationalize the selection of individualized treatment in case of a BC onset. However, the carriers of mutations in the major predisposition genes represent only approximately 25% of cases among high-risk BC patients. Numerous candidate predisposing genes for breast and other cancers have recently been identified. The risk of cancer development associated with alterations in these genes is lower, and there is a considerable population variability in different regions worldwide. AIM: We have performed mutation analyses of moderate-risk cancer susceptibility genes to evaluate their clinical importance for genetic counseling in high-risk patients suffering from breast and other cancers in the Czech population. RESULTS: Czech oncological patients were analysed for mutation in ATM, CHEK2, NBS1 (NBN) and PALB2 genes. The majority of analyzed individuals represent the population of high-risk BRCA1/2-negative BC patients. CONCLUSIONS: Based on results of this study, we recommend an analysis of recurrent truncating mutations in the CHEK2 gene (the c.1100delC mutation and a large deletion affecting exons 9-10) in BRCA1/2-negative patients from high-risk BC families. A clinical assessment of missense variants in CHEK2 is not suitable. A routine mutation analysis of the ATM and NBS1 (NBN) genes is not recommended in BC patients due to the low frequency of alterations in these genes in the Czech Republic. An identification of truncating mutations in the PALB2 gene is important in BRCA1/2-negative BC patients from families with a strong history of BC (HBC families). The frequency of PALB2 mutations may be comparable to the frequency of mutations in the BRCA2 gene in Czech HBC families.

Genetic testing and prevention of hereditary cancer at the MMCI--over 10 years of experience.

Hereditary cancer syndromes are frequently seen in young cancer patients and patients with a positive family history. Genetic testing is important for the identification of high-risk individuals, and for the early introduction of specialized preventive care or prophylactic surgeries. High-risk tumour suppressor genes (BRCA1 and BRCA2) and DNA repair genes (MLH1, MSH2 and MSH6) are responsible for a substantial part of hereditary breast, ovarian and colorectal cancer. Other hereditary cancers are seen less frequently, but genetic testing has increased for many other site-specific cancers and complex syndromes. Genetic centres and molecular genetic laboratories are located mostly within university or regional hospitals. Some genetic centres are private. It is highly recommended (Czech Society for Medical Genetics) that all laboratories are accredited according to ISO 15,189 and that genetic testing of hereditary cancer syndromes is indicated by medical geneticists. The indication criteria and prevention strategies were published in Supplement 22 of Clinical Oncology 2009 (in Czech). Preventive care for high-risk individuals is organized by thirteen Oncology Centres, which provide most of the oncology care in the Czech Republic. Genetic testing and preventive care for high-risk individuals and mutation carriers is covered by health insurance. The molecular genetic laboratory at the MMCI provides molecular genetic testing of BRCA1, BRCA2, CHEK2 for hereditary breast/ovarian cancer, MLH1, MSH2, MSH6 for Lynch syndrome,TP53 for Li-Fraumeni syndrome, CDKN2A for familial malignant melanoma syndrome and CDH1 gene for hereditary diffuse gastric cancer. Other syndromes are tested in specialized laboratories elsewhere.The use of genetic testing is increasing because of more frequent referrals from oncologists and other specialists and the increasing variety of genes tested. However, in some patients the testing is not recommended and other family members are dying because of the late diagnosis of hereditary syndrome. Greater awareness of the importance of genetic testing in oncology is needed.