Eleven Candidate Susceptibility Genes for Common Familial Colorectal Cancer

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Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes.

Vyšlo v časopise: Eleven Candidate Susceptibility Genes for Common Familial Colorectal Cancer. PLoS Genet 9(10): e32767. doi:10.1371/journal.pgen.1003876
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003876

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Zdroje

1. ParkinDM, BrayF, FerlayJ, PisaniP (2005) Global cancer statistics, 2002. CA Cancer J Clin 55: 74–108.

2. American Cancer Society (2013) Cancer Facts & Figures 2013. Available: http://www.cancer.org/acs/groups/content/epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed 26 July 2013.

3. LichtensteinP, HolmNV, VerkasaloPK, IliadouA, KaprioJ, et al. (2000) Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from sweden, denmark, and finland. N Engl J Med 343: 78–85.

4. AaltonenLA, SalovaaraR, KristoP, CanzianF, HemminkiA, et al. (1998) Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 338: 1481–1487.

5. PallesC, CazierJB, HowarthKM, DomingoE, JonesAM, et al. (2012) Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 45: 136–144.

6. PearsonP, FrancomanoC, FosterP, BocchiniC, LiP, et al. (1994) The status of online mendelian inheritance in man (OMIM) medio 1994. Nucleic Acids Res 22: 3470–3473.

7. LakenSJ, PetersenGM, GruberSB, OddouxC, OstrerH, et al. (1997) Familial colorectal cancer in ashkenazim due to a hypermutable tract in APC. Nat Genet 17: 79–83.

8. ClearySP, ZhangW, Di NicolaN, AronsonM, AubeJ, et al. (2003) Heterozygosity for the BLM(ash) mutation and cancer risk. Cancer Res 63: 1769–1771.

9. GudaK, MoinovaH, HeJ, JamisonO, RaviL, et al. (2009) Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers. Proc Natl Acad Sci U S A 106: 12921–12925.

10. LubbeSJ, Di BernardoMC, BroderickP, ChandlerI, HoulstonRS (2012) Comprehensive evaluation of the impact of 14 genetic variants on colorectal cancer phenotype and risk. Am J Epidemiol 175: 1–10.

11. DunlopMG, DobbinsSE, FarringtonSM, JonesAM, PallesC, et al. (2012) Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nat Genet 44: 770–776.

12. DunlopMG, TenesaA, FarringtonSM, BallereauS, BrewsterDH, et al. (2013) Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals. Gut 62: 871–881.

13. NiittymakiI, KaasinenE, TuupanenS, KarhuA, JarvinenH, et al. (2010) Low-penetrance susceptibility variants in familial colorectal cancer. Cancer Epidemiol Biomarkers Prev 19: 1478–1483.

14. PeltonenL, PalotieA, LangeK (2000) Use of population isolates for mapping complex traits. Nat Rev Genet 1: 182–190.

15. JakkulaE, RehnstromK, VariloT, PietilainenOP, PaunioT, et al. (2008) The genome-wide patterns of variation expose significant substructure in a founder population. Am J Hum Genet 83: 787–794.

16. Genomes Project Consortium (2012) AbecasisGR, AutonA, BrooksLD, DePristoMA, et al. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491: 56–65.

17. KuCS, NaidooN, PawitanY (2011) Revisiting mendelian disorders through exome sequencing. Hum Genet 129: 351–370.

18. SalovaaraR, LoukolaA, KristoP, KaariainenH, AhtolaH, et al. (2000) Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 18: 2193–2200.

19. FletcherO, HoulstonRS (2010) Architecture of inherited susceptibility to common cancer. Nat Rev Cancer 10: 353–361.

20. BodmerW, BonillaC (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 40: 695–701.

21. GibsonG (2012) Rare and common variants: twenty arguments. Nat Rev Genet 13: 135–145.

22. LiuL, SakaiT, SanoN, FukuiK (2004) Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with nuclear factor kappaB signalling. Biochem J 380: 31–41.

23. MoravcikovaE, KrepelaE, ProchazkaJ, RousalovaI, CermakJ, et al. (2012) Down-regulated expression of apoptosis-associated genes APIP and UACA in non-small cell lung carcinoma. Int J Oncol 40: 2111–2121.

24. ChangC, HoltzmanDA, ChauS, ChickeringT, WoolfEA, et al. (2001) Twisted gastrulation can function as a BMP antagonist. Nature 410: 483–487.

25. TzachanisD, LiL, LafuenteEM, BerezovskayaA, FreemanGJ, et al. (2007) Twisted gastrulation (tsg) is regulated by tob and enhances TGF-beta signaling in activated T lymphocytes. Blood 109: 2944–2952.

26. MeachamF, BoffelliD, DhahbiJ, MartinDI, SingerM, et al. (2011) Identification and correction of systematic error in high-throughput sequence data. BMC Bioinformatics 12: 451-2105-12-451.

27. TuupanenS, NiittymakiI, NousiainenK, VanharantaS, MecklinJP, et al. (2008) Allelic imbalance at rs6983267 suggests selection of the risk allele in somatic colorectal tumor evolution. Cancer Res 68: 14–17.