Risks of Solid Tumors in Heterozygous Carriers of Recessive Syndromes

Česká verze

Authors: Monika Koudová; Alena Puchmajerová
Authors place of work: Centrum lékařské genetiky a reprodukční medicíny GENNET, Praha
Published in the journal: Klin Onkol 2019; 32(Supplementum2): 14-23
Category: Přehled
doi: https://doi.org/10.14735/amko2019S14

Summary

Expanded gene panel testing for hereditary cancer predispositions using massive parallel sequencing can identify heterozygous pathogenic variants of genes that cause autosomal recessive inherited cancer syndromes. There are no clinical guidelines regarding assessment of the risk of developing solid tumors or for developing appropriate surveillance strategies for heterozygotes for most of these genes, nor is there delineation with respect to the management for genetic testing of relatives and partners. Based on current knowledge, our aim was to create “Czech guidelines” for these cases. Here, we present an overview of the selected genes for autosomal recessive inherited tumor syndromes. The genes were divided into two groups: genes causing Fanconi anemia and genes causing other autosomal recessive inherited tumor syndromes. A summary table was created for each group. The table shows the population frequency of heterozygotes, the cancer risk for heterozygotes, the proposed surveillance strategy, and recommendations for family prediction and genetic testing of partners. Predictive testing should be performed in the case of heterozygotes that have an increased risk of cancer and/or as prerequisite to further reproduction of heterozygotes for a given gene with significant population frequency (this allows an estimation of the risk of autosomal recessive syndrome for children of heterozygote for mutation). These suggestions and recommendations are based on current knowledge and would need to be further corrected in the future based on increasing knowledge of existing or as-yet-unidentified genes.

The authors thank to all the staff of the Molecular Genetic Laboratory of the GENNET

Medical Genetics and Reproductive Medicine Center for their cooperation.

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 recommendation for biomedical papers.
Submitted: 21. 3. 2019

Accepted: 2. 5. 2019

Keywords:

Mutation – hereditary cancer syndromes – autozomal recessive inheritance – heterozygote – risk of cancer – predictive testing

Zdroje

1. Rahman N. Mainstreaming genetic testing of cancer predisposition genes. Clin Med 2014; 14 (4): 436–439. doi: 10.7861/clinmedicine.14-4-436.

2. Soukupova J, Zemankova P, Lhotova K et al. Validation of CZECANCA (CZEch CAncer paNel for Clinical Application) for targeted NGS-based analysis of hereditary cancer syndromes. PLoS One 2018; 13 (4): e0195761. doi: 10.1371/journal.pone.0195761.

3. MRC-Holland. [online]. Available from: https: //www.mlpa.com.

4. ONCOCNV: Detection of copy number changes in deep sequencing data. [online]. Available from: http: //boevalab.com/ONCOCNV.

5. CNVkit 0.9.6. [online]. Available from: https: //pypi.org/project/CNVkit/.

6. 3. Richards S, Aziz N, Bale S et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (5): 405–424. doi: 10.1038/gim.2015.30.

7. 4. Eccles DM, Mitchell G, Monteiro AN et al. BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical signifikance. Ann Oncol 2015; 26 (10): 2057–2065. doi: 10.1093/annonc/mdv278.

8. 5. Nykamp K, Anderson M, Powers M et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 2017; 19 (10): 1105–1117. doi: 10.1038/gim.2017.37.

9. Informace pro poskytovatele hrazených služeb – laboratoř lékařské genetiky a sdílené odbornosti pro rok 2018. [online]. Dostupné na: https: //www.vzp.cz/o-nas/aktuality/informace-pro-poskytovatele-hrazenych-sluzeb-laborator-lekarske-genetiky-a-sdilene-odbornosti-pro-rok-2018.

10. Pohlreich P, Kleibl Z, Kleiblová P et al. Klinický význam analýz genů středního rizika pro hodnocení rizika vzniku karcinomu prsu a dalších nádorů v České republice. Klin Onkol 2012; 25 (Suppl): S59–S66. doi: 10.14735/amko20121S59.

11. Fanconi anemia. [online]. Dostupné z: https: //www.omim.org/search/?index=entry&start=1&limit=10&sort=score+desc%2C+prefix_sort+desc&search=FANCONI+ANEMIA.

12. Mehta PA, Tolar J. Fanconi Anemia. GeneReviews® 2018. [online]. Available from: https: //www.ncbi.nlm.nih.gov/books/NBK1401/.

13. Svojgr K, Sumerauer D, Puchmajerova A et al. Fanconi anemia with biallelic FANCD1/BRCA2 mutations – case report of a family with three affected children. Eur J Med Genet 2016; 59 (3): 152–157. doi: 10.1016/j.ejmg.2015.11.013.

14. Puchmajerová A, Švojgr K, Novotná D et al. Fanconi Anemia, Complementation Group D1 Caused by Biallelic Mutations of BRCA2 Gene – Case Report. Klin Onkol 2016; 29 (Suppl 1): S89–S92. doi: 10.14735/amko2016 S89.

15. Freire BL, Homma TK, Funari MF et al. Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report and review of previous patients. Eur J Med Genet 2018; 61 (3): 130–133. doi: 10.1016/j.ejmg.2017.11.003.

16. Sawyer SL, Tian L, Kähkönen M et al. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov 2014; 5 (2): 135–142. doi: 10.1158/2159-8290.CD-14-1156.

17. Foretová L, Navrátilová M, Svoboda M et al. Doporučení pro sledování žen se vzácnějšími genetickými příčinami nádorů prsu a ovarií. Klin Onkol 2019; 32 (Suppl 2): 2S6–2S13. doi: 10.14735/amko2019S6.

18. NCCN Guidelines 2019. Genetic/familial high-risk assessment: breast and ovarian. [online]. Available from: https: //www2.tri-kobe.org/nccn/guideline/gynecological/english/genetic_familial.pdf.

19. Ramus SJ, Song H, Dicks E et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst 2015; 107 (11). doi: 10.1093/jnci/djv214.

20. Eoh KJ, Kim JE, Park HS et al. Detection of germline mutations in patients with epithelial ovarian cancer using multi-gene panels: beyond BRCA1/2. Cancer Res Treat 2018; 50 (3): 917–925. doi: 10.4143/crt.2017.220.

21. Easton DF, Lesueur F, Decker B et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet 2016; 53 (5): 298–309. doi: 10.1136/jmedgenet-2015-103529.

22. Lu HM, Li S, Black MH et al. Association of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. JAMA Oncol 2018. doi: 10.1001/jamaoncol.2018.2956.

23. Sato K et al. Mutation status of RAD51C, PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations. Cancer Sci 2017; 108 (11): 2287–2294. doi: 10.1111/cas.13350.

24. Shimelis H, LaDuca H, Hu C et al. Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing. J Natl Cancer Inst 2018. doi: 10.1093/jnci/djy106.

25. Piffer A, Luporsi E, Mathelin C. PALB2, a major susceptibility gene for breast cancer. Gynecol Obstet Fertil Senol 2018; 46 (10–11): 701–705. doi: 10.1016/j.gofs.2018.08. 006.

26. Litim N, Labrie Y, Desjardins S et al. Polymorphic variations in the FANCA gene in high-risk non-BRCA1/2 breast cancer individuals from the French Canadian population. Mol Oncol 2013; 7 (1): 85–100. doi: 10.1016/j.molonc.2012.08.002.

27. Thompson ER, Doyle MA, Ryland GL et al. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet 2012; 8 (9): e1002894. doi: 10.1371/journal.pgen.1002894.

28. Kiiski JI, Pelttari LM, Khan S. Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. Proc Natl Acas Sci USA 2014; 111 (42): 15172–15177. doi: 10.1073/pnas.1407909111.

29. van der Heijden MS, Yeo CJ, Hruban RH et al. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res 2003; 63 (10): 2585–2588.

30. Seguí N, Mina LB, Lázaro C. Germline mutations in FAN1 cause hereditary colorectal cancer by impairing DNA repair. Gastroenterology 2015; 149 (3): 563–566. doi: 10.1053/j.gastro.2015.05.056.

31. Seemanova E, Varon R, Vejvalka J et al. The Slavic NBN Founder Mutation: a role for reproductive fitness? PLoS One 2016; 11 (12): e0167984. doi: 10.1371/journal.pone.0167984.

32. Maurer MH, Hoffmann K, Sperling K et al. High prevalence of the NBN gene mutation c.657-661del5 in Southeast Germany. J Appl Genet 2010; 51 (2): 211–214.

33. Gao P, Ma N, Li M et al. Functional variants in NBS1 and cancer risk: evidence from meta-analysis of 60 publications with 111 individual studies. Mutagenesis 2013; 28 (6): 683–697. doi: 10.1093/mutage/get048.

34. 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: 809–811. doi: 10.1007/s10549-012-2049-x.

35. di Masi A, Viganotti M, Polticelli F et al. The R215W mutation in NBS1 impairs gamma H2AX binding and affects DNA repair: molecular bases for the severe phenotype of 657del5/R215W Nijmegen breakage syndrome patients. Biochem Biophys Res Commun 2008; 369 (3): 835–840. doi: 10.1016/j.bbrc.2008.02.129.

36. Zhang Y, Zhou J, Lim CU. The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control. Cell Res 2006; 16 (1): 45–54. doi: 10.1038/sj.cr.7310007.

37. Fan C, Zhang J, Ouyang T et al. RAD50 germline mutations are associated with poor survival in BRCA1/2-negative breast cancer patients. Int J Cancer 2018; 143 (8): 1935–1942. doi: 10.1002/ijc.31579.

38. Hildebrandt F. Exome resequencing identifies novel NPHP genes, implicating DNA damage response signaling in the pathogenesis of ciliopathies. Cilia 2012; 1 (Suppl 1) O2. doi: 10.1186/2046-2530-1-S1-O2.

39. Xie S, Shan XF, Shang K et al. Relevance of LIG4 gene polymorphisms with cancer susceptibility: evidence from a meta-analysis. Sci Rep 2014; 4: 6630. doi: 10.1038/srep06630.

40. Plevova P, Štekrova J, Kohoutova M et al. Familiární adenomatózní polypóza. Klin Onkol 2009; 22 (Suppl): S16–S19.

41. Aretz S, Genuardi M, Hes FJ et al. Clinical utility gene card for: MUTYH-associated polyposis (MAP), autosomal recessive colorectal adenomatous polyposis, multiple colorectal adenomas, multiple adenomatous polyps (MAP) – update 2012. Eur J Hum Genet 2013; 21 (1). doi: 10.1038/ejhg.2012.163.

42. Rennert G, Lejbkowicz F, Cohen I et al. MutYH mutation carriers have increased breast cancer risk. Cancer 2012; 118 (8): 1989–1993. doi: 10.1002/cncr.26506.

43. Rizzolo P, Silvestri V, Bucalo A et al. Contribution of MUTYH variants to male breast cancer risk: results from a multicenter study in Italy. Front Oncol 2018; 8: 583. doi: 10.3389/fonc.2018.00583.

44. Win AK, Reece JC, Dowty JG. Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH. Int J Cancer 2016; 139 (7): 1557–1563. doi: 10.1002/ijc.30197.

45. Gatti R, Perlman S. Ataxia-telangiectasia. GeneReviews 2016. [online]. Available from: https: //www.ncbi.nlm.nih.gov/books/NBK26468.

46. van Os NJ, Roeleveld N, Weemaes C M et al. Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clin Genet 2016; 90 (2): 105–117. doi: 10.1111/cge.12710.

47. Cunniff C, Bassetti JA, Ellis NA. Bloom’s syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition. Mol Syndromol 2017; 8 (1): 4–23. doi: 10.1159/000452082.

48. Fu W, Ligabue A, Rogers KJ et al. Human RECQ helicase pathogenic variants, population variation and „missing“ diseases. Hum Mutat 2017; 38 (2): 193–203. doi: 10.1002/humu.23148.

49. Sokolenko AP, Iyevleva AG, Preobrazhenskaya EV et al. High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia. Int J Cancer 2012; 130 (12): 2867–2873. doi: 10.1002/ijc.26342.

50. Oshima J, Martin GM, Hisama FM. Werner Syndrome. GeneReviews® 2016. [online]. Available from: https: //www.ncbi.nlm.nih.gov/books/NBK1514.

51. Yokote K, Chanprasert S, Lee L. WRN mutation update: mutation spectrum, patient registries, and translational prospects. Hum Mutat 2017; 38 (1): 7–15. doi: 10.1002/humu.23128.

52. Wang Z, Xu Y, Tang J et al. A polymorphism in Werner syndrome gene is associated with breast cancer susceptibility in Chinese women. Breast Cancer Res Treat 2009; 118 (1): 169–175. doi: 10.1007/s10549-009-0327-z.

53. Ding SL, Yu JC, Chen ST et al. Genetic variation in the premature aging gene WRN: a case-control study on breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev 2007; 16 (2): 263–269. doi: 10.1158/1055-9965.EPI-06-0678.

54. Orphanet. The portal for rare diseases and orphan drugs. [online]. Available from: https: //www.orpha.net.

55. Nelson A, Myers K. Shwachman-Diamond Syndrome. Genereviews 2018. [online]. Available from: https: //www.ncbi.nlm.nih.gov/books/NBK1756/.

56. Calado RT, Graf SA, Wilkerson KL et al. Mutations in the SBDS gene in acquired aplastic anemia. Blood 2007; 110 (4): 1141–1146. doi: 10.1182/blood-2007-03-080044.

57. Aalbers AM, Calado RT, Young NS et al. Absence of SBDS mutations in sporadic paediatric acute myeloid leukaemia. Br J Haematol 2013; 160 (4): 559–561. doi: 10.1111/bjh.12134.

58. Baskin B, Steele L, Rommens JM et al. De novo mutations causing shwachman-diamond syndrome and a founder mutation in SBDS in the French Canadian population. J Invest Genom 2014. [online]. Available from: https: //medcraveonline.com/JIG/JIG-01-00008.php.

59. Rump A, Benet-Pages A, Schubert S et al. Identification and functional testing of ercc2 mutations in a multi-national cohort of patients with familial breast-and ovarian cancer. PLoS Genet 2016; 12 (8): e1006248. doi: 10.1371/journal.pgen.1006248.

60. Lehmann AR, McGibbon D, Stefanini M. Xeroderma pigmentosum Orphanet. J Rare Dis 2011; 6: 70. doi: 10.1186/1750-1172-6-70.