The Clinical Importance of a Genetic Analysis of Moderate-Risk Cancer Susceptibility Genes in Breast and Other Cancer Patients from the Czech Republic
Authors:
P. Pohlreich 1; Z. Kleibl 1; P. Kleiblová 1; M. Janatová 1; J. Soukupová 1; E. Macháčková 2; J. Hazova 2; P. Vašíčková 2; E. Sťahlová Hrabincová 2; M. Navratilova 2; M. Svoboda 2,3; L. Foretová 2
Authors place of work:
Ústav biochemie a experimentální onkologie, 1. LF UK a VFN v Praze
1; Oddělení epidemiologie a genetiky nádorů, Masarykův onkologický ústav, Brno
2; Klinika komplexní onkologické péče, Masarykův onkologický ústav, Brno
3
Published in the journal:
Klin Onkol 2012; 25(Supplementum): 59-66
Summary
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.
Key words:
hereditary cancer – genetic testing – ATM – CHEK2 – NBS1 (NBN) – PALB2
This study was supported by IGa MZ ČR NT/13343 grant and by the European Regional Development Fund and by the National budget of the Czech republic (OP VaVpI - RECaMO, CZ.1.05/2.1.00/03.0101).
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
Submitted:
15. 5. 2012
Accepted:
26. 5. 2012
Zdroje
1. Oldenburg RA, Meijers-Heijboer H, Cornelisse CJ et al. Genetic susceptibility for breast cancer: how many more genes to be found? Crit Rev Oncol Hematol 2007; 63(2): 125–149.
2. Bartkova J, Tommiska J, Oplustilova L et al. Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. Mol Oncol 2008; 2(4): 296–316.
3. Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med 2008; 359(20): 2143–2153.
4. Soukupova J, Pohlreich P, Seemanova E. Characterisation of ATM mutations in Slavic Ataxia telangiectasia patients. Neuromolecular Med 2011; 13(3): 204–211.
5. Bartek J, Bartkova J, Lukas J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 2007; 26(56): 7773–7779.
6. Prokopcova J, Kleibl Z, Banwell CM et al. The role of ATM in breast cancer development. Breast Cancer Res Treat 2007; 104(2): 121–128.
7. Soukupova J, Dundr P, Kleibl Z et al. Contribution of mutations in ATM to breast cancer development in the Czech population. Oncol Rep 2008; 19(6): 1505–1510.
8. Renwick A, Thompson D, Seal S et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 2006; 38(8): 873–875.
9. Matsuoka S, Huang M, Elledge SJ. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 1998; 282(5395): 1893–1897.
10. Bell DW, Varley JM, Szydlo TE et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 1999; 286(5449): 2528–2531.
11. Cybulski C, Górski B, Huzarski T et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 2004; 75(6): 1131–1135.
12. Brennan P, McKay J, Moore L et al. Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers: case control study. Hum Mol Genet 2007; 16(15): 1794–1801.
13. Seppälä EH, Ikonen T, Mononen N et al. CHEK2 variants associate with hereditary prostate cancer. Br J Cancer 2003; 89(10): 1966–1970.
14. Thompson D, Seal S, Schutte M et al. A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer Epidemiol Biomarkers Prev 2006; 15(12): 2542–2545.
15. Nevanlinna H, Bartek J. The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 2006; 25(43): 5912–5919.
16. Kleibl Z, Novotny J, Bezdickova D et al. The CHEK2 c.1100delC germline mutation rarely contributes to breast cancer development in the Czech Republic. Breast Cancer Res Treat 2005; 90(2): 165–167.
17. Walsh T, Casadei S, Coats KH et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 2006; 295(12): 1379–1388.
18. Kleibl Z, Novotny J, Malik R et al. Výskyt a význam mutace CHEK2*1100delC u pacientek s karcinomem prsu a v kontrolní skupině zdravých žen v České republice. Klin Onkol 2005; 18(3): 98–101.
19. Kleibl Z, Havranek O, Hlavata I et al. The CHEK2 gene I157T mutation and other alterations in its proximity increase the risk of sporadic colorectal cancer in the Czech population. Eur J Cancer 2009; 45(4): 618–624.
20. Kleibl Z, Havránek O, Novotny J et al. Analýza mutace c.1100delC genu CHEK2 v populaci pacientů se sporadickým karcinomem kolorekta a familiární adenomatózní polypózou. Klin Onkol 2007; 20(2): 224–226.
21. Mohelnikova-Duchonova B, Havranek O, Hlavata I et al. CHEK2 gene alterations in the forkhead-associated domain, 1100delC and del5395 do not modify the risk of sporadic pancreatic cancer. Cancer Epidemiol 2010; 34(5): 656–658.
22. Kleibl Z, Havranek O, Novotny J et al. Analysis of CHEK2 FHA domain in Czech patients with sporadic breast cancer revealed distinct rare genetic alterations. Breast Cancer Res Treat 2008; 112(1): 159–164.
23. Havranek O, Spacek M, Hubacek P et al. Alterations of CHEK2 forkhead-associated domain increase the risk of Hodgkin lymphoma. Neoplasma 2011; 58(5): 392–395.
24. Cybulski C, Wokołorczyk D, Kładny J et al. Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations? Eur J Hum Genet 2007; 15(2): 237–241.
25. Kilpivaara O, Vahteristo P, Falck J et al. CHEK2 variant I157T may be associated with increased breast cancer risk. Int J Cancer 2004; 111(4): 543–547.
26. Kilpivaara O, Alhopuro P, Vahteristo P et al. CHEK2 I157T associates with familial and sporadic colorectal cancer. J Med Genet 2006; 43(7): e34.
27. Cybulski C, Masojc B, Oszutowska D et al. Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers. Carcinogenesis 2008; 29(4): 762–765.
28. Antoni L, Sodha N, Collins I et al. CHK2 kinase: cancer susceptibility and cancer therapy – two sides of the same coin? Nat Rev Cancer 2007; 7(12): 925–936.
29. Weischer M, Bojesen SE, Ellervik C et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 2008; 26(4): 542–548.
30. Narod SA. Testing for CHEK2 in the cancer genetics clinic: ready for prime time? Clin Genet 2010; 78(1): 1–7.
31. Macháčkova E, Vašíčková P, Sťahlová Hrabincová E et al. Zárodečné mutace v genu CHEK2 u českých pacientů s nádorovou predispozicí. Abstrakt 005. In: Edukační sborník. Brno: XXXVI Brněnské onkologické dny a XXVI Konference pro sestry a laboranty 2012.
32. Varon R, Vissinga C, Platzer M et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 1998; 93(3): 467–476.
33. Williams RS, Dodson GE, Limbo O et al. NBS1 flexibly tethers Ctp1 and Mre11-RAD50 to coordinate DNA double-strand break processing and repair. Cell 2009; 139(1): 87–99.
34. Seemanova E, Sperling K, Neitzel H et al. Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability. J Med Genet 2006; 43(3): 218–224.
35. Seemanova E, Jarolim P, Seeman P et al. Increased risk of malignancies in heterozygotes in families of patients with Nijmegen breakage syndrome. Čas Lék Česk 2006; 145(2): 138–143.
36. Pardini B, Naccarati A, Polakova V et al. NBN 657del5 heterozygous mutations and colorectal cancer risk in the Czech Republic. Mutat Res 2009; 666(1–2): 64–67.
37. Mateju M, Kleiblova P, Kleibl Z et al. Germline mutations 657del5 and 643C>T (R215W) in NBN are not likely to be associated with increased risk of breast cancer in Czech women. Breast Cancer Res Treat 2012; 133(2): 809–811.
38. Xia B, Sheng Q, Nakanishi K et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 2006; 22(6): 719–729.
39. Xia B, Dorsman JC, Ameziane N et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 2007; 39(2): 159–161.
40. Rahman N, Seal S, Thompson D et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 2007; 39(2): 165–167.
41. Hellebrand H, Sutter C, Honisch E et al. Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. Hum Mutat 2011; 32(6): E2176–E2188.
42. Casadei S, Norquist BM, Walsh T et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res 2011; 71(6): 2222–2229.
43. Erkko H, Dowty JG, Nikkilä J et al. Penetrance analysis of the PALB2 c.1592delT founder mutation. Clin Cancer Res 2008; 14(14): 4667–4671.
44. Tischkowitz M, Capanu M, Sabbaghian N et al. Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum Mutat 2012; 33(4): 674–680.
45. Janatova M, Pohlreich P, Kotlas J. PALB2 mutations in familial breast cancer in the Czech republic. Eur J Cancer 2011; 47 (Suppl 1): S133.
46. Walsh T, King MC. Ten genes for inherited breast cancer. Cancer Cell 2007; 11(2): 103–105.
47. Walsh T, Casadei S, Lee MK et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 2011; 108(44): 18032–18037.
48. Brownstein Z, Friedman LM, Shahin H et al. Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in middle eastern families. Genome Biol 2011; 12(9): R89.
Štítky
Paediatric clinical oncology Surgery Clinical oncologyČlánok vyšiel v časopise
Clinical Oncology
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Najčítanejšie v tomto čísle
- Birt-Hogg-Dubé Syndrome
- The Clinical Importance of a Genetic Analysis of Moderate-Risk Cancer Susceptibility Genes in Breast and Other Cancer Patients from the Czech Republic
- Hereditary Diffuse Gastric Cancer
- Clinical Dysmorphic Syndromes with Tumorigenesis