2nd ed. xxii, 441 s. : il. ; 28 cm
Část karcinomů prsu a vaječníků vzniká na základě zděděné genetické dispozice, mutace, v některém z predisponujících genů. Ačkoliv je tato část relativně malá, 5–10 % všech mammárních a ovariálních karcinomů, tvoří skupinu s jasně definovaným etiologickým faktorem. Prediktivní vyšetření dosud zdravých osob z rodin s genetickou dispozicí umožňuje identifikovat vysoce ohrožené jedince a zařadit je do programu primární i sekundární prevence malignit. Následující článek podává základní přehled o hereditární dispozici ke vzniku karcinomu prsu a ovaria a zaměřuje se především na geny BRCA1 a BRCA2, které jsou zodpovědné za téměř tři čtvrtiny těchto hereditárních nádorů.
Part of breast and ovarian cancer cases develops on the hereditary predisposition, i.e. mutation in one of predisposing genes. Although this proportion is relatively small, 5–10%of all breast and ovarian carcinomas, it represents a group with clearly defined etiologic factor. Predictive analysis of unaffected family members allows to identify individuals at high risk of cancer and to include them into the programme of primary and secondary cancer prevention. Following article presents basic review of the hereditary predisposition to breast and ovarian cancer focusing especially on BRCA1 and BRCA2 genes, which are responsible for almost three-quarters of those hereditary tumours.
- MeSH
- Genetic Predisposition to Disease MeSH
- Genes, BRCA1 MeSH
- Genes, BRCA2 MeSH
- Carcinoma diagnosis genetics prevention & control MeSH
- Mutation MeSH
- Breast Neoplasms diagnosis genetics prevention & control MeSH
- Ovarian Neoplasms diagnosis genetics prevention & control MeSH
- Publication type
- Review MeSH
Hereditární nádorové syndromy s možnou manifestací v oblasti ženského vnitřního genitálu představují heterogenní skupinu onemocnění. Mezi dva nejčastější syndromy patří syndrom hereditárního karcinomu prsu a ovarií a Lynchův syndrom. Méně časté syndromy zahrnují syndrom predispozice k maligním rabdoidním nádorům, Cowdenův syndrom, komplex tuberózní sklerózy, DICER1 syndrom, syndrom névoidního bazocelulárního karcinomu, Peutz-Jeghersův syndrom, von Hippelova-Lindauova choroba a syndrom hereditární leiomyomatózy a renálního karcinomu. Cílem následujícího sdělení je podat přehled problematiky hereditárních nádorových syndromů s manifestací v oblasti ženského genitálu se zaměřením na jejich přehled, charakteristiky nádorů, které se v souvislosti s jednotlivými syndromy vyskytují, postup při vyšetřování profylakticky odstraněných tkání a orgánů a problematiku screeningu Lynchova syndromu.
Hereditary tumor syndromes with a possible manifestation in the female internal genital tract represent a heterogeneous group of diseases. The two most common entities are the hereditary breast and ovarian cancer syndrome, and the Lynch syndrome. The less common syndromes include the rhabdoid tumor predisposition syndrome, Cowden syndrome, tuberous sclerosis complex, DICER1 syndrome, nevoid basal cell carcinoma syndrome, Peutz-Jeghers syndrome, von Hippel-Lindau disease, and hereditary leiomyomatosis and renal cell cancer syndrome. The goal of this manuscript is to provide a comprehensive overview of those hereditary tumor syndromes which can manifest in the area of the female genital system, with an emphasis on their summary, the characteristics of the tumors which can develop in association with these syndromes, and the approach to the processing of prophylactically removed tissues and organs. The issue of Lynch syndrome screening is also discussed.
- MeSH
- Neoplastic Syndromes, Hereditary * diagnosis genetics MeSH
- Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis genetics MeSH
- Hereditary Breast and Ovarian Cancer Syndrome * diagnosis genetics MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Testing MeSH
- Immunohistochemistry MeSH
- Humans MeSH
- Mutation genetics MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Hematology/oncology clinics of North America, ISSN 0889-8588 vol. 24, no 5, October 2010
xii, 793-1004 s. : il.
- MeSH
- Genetic Predisposition to Disease MeSH
- Genes, Neoplasm MeSH
- Neoplasms genetics MeSH
- Publication type
- Collected Work MeSH
- Conspectus
- Patologie. Klinická medicína
- NML Fields
- onkologie
- genetika, lékařská genetika
Cíl: Shrnutí poznatků v oblasti karcinomu ovaria a genetické dispozice. Výsledky: Nádory ovarií jsou obvykle dia gnostikovány v pokročilých stadiích nemoci a prognóza těchto nemocných je všeobecně špatná. Pětileté celkové přežití bez ohledu na histopatologický typ nádoru se pohybuje kolem 44 %. Na vzniku epiteliálního ovariálního nádoru se majoritně podílejí germinální mutace způsobující dědičné nádorové syndromy. Nejčastější je dědičný nádorový syndrom prsu a vaječníku, který je zapříčiněn germinální mutací v tumor supresorových genech BRCA1 a BRCA2. Je známo i několik dalších tumor supresorových genů a onkogenů, které jsou asociovány s ovariálními nádory a způsobují jiné typy nádorových syndromů. Z dědičných nádorových syndromů je to např. Lynchův syndrom, Peutz-Jegersův syndrom, Gorlinův syndrom, Li-Fraumeniho syndrom a další. Indikaci ke genetickému vyšetření germinálních mutací dává klinický genetik na základě doporučení ošetřujícího lékaře. V současné době je každý ovariální nádor, primární peritoneální nádor a nádor tuby diagnostikovaný v jakémkoliv věku indikován ke genetickému vyšetření. Závěr: Časná identifikace genů dědičných nádorových syndromů díky rychle se rozvíjejícím molekulárně genetickým metodám představuje důležitý krok k personalizované léčbě nádorů ovaria a k preventivním opatřením u rizikových rodin. Důležité je si zároveň uvědomit, že negativní výsledek molekulárně genetického vyšetření není vyloučením genetického rizika.
Objective: Summary of knowledge in the field of ovarian cancer and genetic predisposition. Results: Ovarian tumors are usually diagnosed at advanced stages of the disease and the prognosis for these patients is generally poor. The 5-year overall survival rate, regardless of the histopathological type of tumor, is around 44%. Germline mutations causing hereditary tumor syndromes are predominantly involved in the development of epithelial ovarian tumors. The most common is hereditary breast and ovarian cancer syndrome, which is caused by germline mutations in the tumor suppressor genes BRCA1 and BRCA2. Several other tumor suppressor genes and oncogenes are known to be associated with ovarian tumors and cause other types of tumor syndromes. Inherited tumor syndromes include Lynch syndrome, Peutz-Jegers syndrome, Gorlin syndrome, Li-Fraumeni syndrome and others. The indication for genetic examination of germline mutations is given by a clinical geneticist on the basis of the recommendation of the attending physician. At present, every ovarian tumor, primary peritoneal tumor and tube tumor diagnosed at any age is indicated for genetic testing. Conclusion: Early identification of genes for hereditary cancer syndromes, thanks to rapidly developing molecular genetic methods, is an important step towards personalized treatment of ovarian cancer and preventive measures in families at risk. It is also important to note that a negative molecular genetic test result does not exclude genetic risk.
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.
- MeSH
- Checkpoint Kinase 2 genetics MeSH
- Adult MeSH
- Genetic Predisposition to Disease * MeSH
- Genetic Testing MeSH
- Middle Aged MeSH
- Humans MeSH
- Breast Neoplasms, Male * genetics MeSH
- BRCA1 Protein genetics MeSH
- BRCA2 Protein genetics MeSH
- Aged MeSH
- Germ-Line Mutation genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
XIX, 407 s. : fot., grafy, tab. ; 24 cm
The genes predisposing to familial breast cancer are largely unknown, but 5 of the 6 known genes are involved in DNA damage repair. RAD50 is part of a highly conserved complex important in recognising, signalling and repairing DNA double-strand breaks. Recently, a truncating mutation in the RAD50 gene, 687delT, was identified in 2 Finnish breast cancer families. To evaluate the contribution of RAD50 to familial breast cancer, we screened the whole coding region for mutations in 435 UK and 46 Finnish familial breast cancer cases. We identified one truncating mutation, Q350X, in one UK family. We screened a further 544 Finnish familial breast cancer cases and 560 controls for the 687delT mutation, which was present in 3 cases (0.5%) and 1 control (0.2%). Neither Q350X nor 687delT segregated with cancer in the families in which they were identified. Functional analyses suggested that RAD50 687delT is a null allele as there was no detectable expression of the mutant protein. However, the wild-type allele was retained and expressed in breast tumors from mutation carriers. The abundance of the full-length RAD50 protein was reduced in carrier lymphoblastoid cells, suggesting a possible haploinsufficiency mechanism. These data indicate that RAD50 mutations are rare in familial breast cancer and either carry no, or a very small, increased risk of cancer. Altogether, these results suggest RAD50 can only be making a very minor contribution to familial breast cancer predisposition in UK and Finland.
- MeSH
- DNA-Binding Proteins MeSH
- DNA Repair Enzymes MeSH
- Genetic Predisposition to Disease * MeSH
- Middle Aged MeSH
- Humans MeSH
- DNA Mutational Analysis MeSH
- Breast Neoplasms etiology genetics MeSH
- DNA Repair MeSH
- DNA Damage MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Geographicals
- Finland MeSH
- United Kingdom MeSH
Nádory ledvin jsou podmíněny hereditární predispozicí mnohem vzácněji, než karcinom prsu nebo tlustého střeva. Je známo několik autosomálně dominantně dědičných onemocnění, kde nádor ledviny patří do klinického obrazu, ne však jako hlavní nebo dokonce diagnostický příznak. Mezi významné patří von Hippel- Lindauova choroba podmíněná mutací genu VHL a tuberózní skleróza podmíněná mutacemi genů TSC1 nebo TSC2. Mezi velmi vzácné syndromy patří hereditární papilární karcinom ledviny, jehož příčinou jsou mutace genu MET, hereditární leiomyomatóza/ karcinom ledviny, onemocnění způsobené mutacemi genu FH a syndrom Birt-Hogg-Dubé, způsobený mutacemi genu BHD. Genetické testování se rutinně provádí jen u von Hippel-Lindauovy choroby a u tuberózní sklerózy. Některé další kandidátní lokusy byly identifikovány analýzou chromosomových translokací u nemocných s nádory ledvin.
Hereditary predisposition to renal cancer is less frequent than predisposition to breast or colon cancer. Few autosomal dominant disorders are known where renal cancer is a part of clinical manifestation, but not as a key diagnostic sign. The most important syndromes are von Hippel-Lindau disease caused by mutations in VHL gene and tuberous sclerosis caused by mutations in TSC1 or TSC2 genes. Rare syndromes include hereditary papillary renal cancer, caused by mutations in MET gene, hereditary leiomyomatosis/renal cell cancer, caused by mutations in FH gene, and Birt-Hogg-Dubé syndrome caused by mutations in BHD gene. Genetic testing is routinely performed only in von Hippel-Lindau disease and tuberous sclerosis. Some new candidate loci have been identified by the analysis of breakpoints of chromosomal translocations observed in renal cancer.
- MeSH
- Neoplastic Syndromes, Hereditary diagnosis etiology genetics MeSH
- Financing, Organized MeSH
- Genetic Predisposition to Disease genetics prevention & control MeSH
- Carcinoma, Renal Cell diagnosis etiology genetics MeSH
- Leiomyomatosis diagnosis etiology genetics MeSH
- Medical Oncology methods trends MeSH
- Humans MeSH
- DNA Mutational Analysis methods trends utilization MeSH
- Von Hippel-Lindau Tumor Suppressor Protein genetics isolation & purification MeSH
- Kidney Neoplasms diagnosis etiology genetics MeSH
- Tuberous Sclerosis diagnosis etiology genetics MeSH
- von Hippel-Lindau Disease diagnosis etiology genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Tables MeSH
The subset of ovarian cancer (OC) diagnosed ≤ 30yo represents a distinct subgroup exhibiting disparities from late-onset OC in many aspects, including indefinite germline cancer predisposition. We performed DNA/RNA-WES with HLA-typing, PRS assessment and survival analysis in 123 early-onset OC-patients compared to histology/stage-matched late-onset and unselected OC-patients, and population-matched controls. Only 6/123(4.9%) early-onset OC-patients carried a germline pathogenic variant (GPV) in high-penetrance OC-predisposition genes. Nevertheless, our comprehensive germline analysis of early-onset OC-patients revealed two divergent trajectories of potential germline susceptibility. Firstly, overrepresentation analysis highlighted a connection to breast cancer (BC) that was supported by the CHEK2 GPV enrichment in early-onset OC(p = 1.2 × 10-4), and the presumably BC-specific PRS313, which successfully stratified early-onset OC-patients from controls(p = 0.03). The second avenue pointed towards the impaired immune response, indicated by LY75-CD302 GPV(p = 8.3 × 10-4) and diminished HLA diversity compared with controls(p = 3 × 10-7). Furthermore, we found a significantly higher overall GPV burden in early-onset OC-patients compared to controls(p = 3.8 × 10-4). The genetic predisposition to early-onset OC appears to be a heterogeneous and complex process that goes beyond the traditional Mendelian monogenic understanding of hereditary cancer predisposition, with a significant role of the immune system. We speculate that rather a cumulative overall GPV burden than specific GPV may potentially increase OC risk, concomitantly with reduced HLA diversity.
- MeSH
- Checkpoint Kinase 2 genetics MeSH
- Adult MeSH
- Genetic Predisposition to Disease * MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Ovarian Neoplasms * genetics MeSH
- Case-Control Studies MeSH
- Age of Onset * MeSH
- Germ-Line Mutation * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
