Main Article Content
Colorectal cancer (CRC) is a multifactorial disease, where both the environment and genetics play a role. It is estimated that approximately 35% of CRCs have a potentially identifiable genetic cause. Well-known and highly penetrant genetic causes make up less than 5% of all CRC, and leave many families not explained by known predisposing genes/mutations. Low penetrant alleles have also been thought to modify the risk of CRC. Linkage studies have been successful in discovering and localizing highly penetrant genes in CRC and risk loci has become possible to discover performing genome wide association studies (GWAS).
In this study we have analyzed families with CRC where individuals with CRC as well as individuals with premalignant lesions, adenomas, were codes as affected. In total 600 individuals in 121 families were included in the study.
In total three genomic regions were found with suggestive linkage located at 4p16.3, 6p24.3 and 10p14. These regions were further studied using sequencing analysis and association studies using haplotypes.
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
2. Vasen HF, van der Meulen-de Jong AE, de Vos Tot Nederveen Cappel WH, Oliveira J, Group EGW. Familial colorectal cancer risk: ESMO clinical recommendations. Annals of oncology : official journal of the European Society for Medical Oncology. 2009;20 Suppl 4:51-3.
3. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. The New England Journal of Medicine. 2000;343(2):78-85.
4. Jaeger EE, Woodford-Richens KL, Lockett M, Rowan AJ, Sawyer EJ, Heinimann K, et al. An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome. American Journal of Human Genetics. 2003;72(5):1261-7.
5. Law PJ, Timofeeva M, Fernandez-Rozadilla C, Broderick P, Studd J, Fernandez-Tajes J, et al. Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Nat Commun. 2019;10(1):2154.
6. Schmit SL, Edlund CK, Schumacher FR, Gong J, Harrison TA, Huyghe JR, et al. Novel Common Genetic Susceptibility Loci for Colorectal Cancer. Journal of the National Cancer Institute. 2019;111(2):146-57.
7. Jass JR. Serrated adenoma of the colorectum: a lesion with teeth. Am J Pathol. 2003;162(3):705-8.
8. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-67.
9. O'Brien MJ, Winawer SJ, Zauber AG, Gottlieb LS, Sternberg SS, Diaz B, et al. The National Polyp Study. Patient and polyp characteristics associated with high-grade dysplasia in colorectal adenomas. Gastroenterology. 1990;98(2):371-9.
10. Sillars-Hardebol AH, Carvalho B, van Engeland M, Fijneman RJ, Meijer GA. The adenoma hunt in colorectal cancer screening: defining the target. The Journal of Pathology. 2012;226(1):1-6.
11. Kontham V, von Holst S, Lindblom A. Linkage analysis in familial non-Lynch syndrome colorectal cancer families from Sweden. PLoS One. 2013;8(12):e83936.
12. Forsberg A, Kjellstrom L, Andreasson A, Jaramillo E, Rubio CA, Bjorck E, et al. Colonoscopy findings in high-risk individuals compared to an average-risk control population. Scand J Gastroenterol. 2015;50(7):866-74.
13. Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, et al. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. Oncology Reports. 2016;36(5):2823-35.
14. O'Connell JR, Weeks DE. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. American Journal of Human Genetics. 1998;63(1):259-66.
15. Whittemore AS, Halpern J. A class of tests for linkage using affected pedigree members. Biometrics. 1994;50(1):118-27.
16. Goode EL, Badzioch MD, Jarvik GP. Bias of allele-sharing linkage statistics in the presence of intermarker linkage disequilibrium. BMC Genetics. 2005;6 Suppl 1:S82.
17. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26(5):589-95.
18. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics. 2007;81(3):559-75.
19. Tomlinson IP, Webb E, Carvajal-Carmona L, Broderick P, Howarth K, Pittman AM, et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nature Genetics. 2008;40(5):623-30.
20. Whiffin N, Hosking FJ, Farrington SM, Palles C, Dobbins SE, Zgaga L, et al. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum Mol Genet. 2014;23(17):4729-37.
21. Zheng HT, Jinag LX, Ly ZC, Li DP, Zhou CZ and Gao JJ et al. Are there tumor suppressor genes on chromosome 4p in sporadic colorectal carcinoma. World J Gastroenterol. 7;14(1):90-94.
22. Jeon BN, Kim MK, Yoon JH, Kim MY, An H, Noh HJ, et al. Two ZNF509 (ZBTB49) isoforms induce cell-cycle arrest by activating transcription of p21/CDKN1A and RB upon exposure to genotoxic stress. Nucleic Acids Research. 2014;42(18):11447-61.
23. Liu Z, Scannell DR, Eisen MB, Tjian R. Control of embryonic stem cell lineage commitment by core promoter factor, TAF3. Cell. 2011;146(5):720-31.
24. McNulty P, Pilcher R, Ramesh R, Neucuiniate R, Hughes A, Farewell D et al. Reduced cancer incidence in Huntingtons´s disease: Analysis in the registry study. J Huntingtons Dis. 2018;7(3):209-222.
25. Jiao X, Aravidis C, Marikkannu R, Rantala J, Picelli S, Adamovic T, et al. PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1. Oncotarget. 2017;8(61):102769-82.
26. Thutkawkorapin J, Mahdessian H, Barber T, Picelli S, von Holst S, Lundin J, et al. Two novel colorectal cancer risk loci in the region on chromosome 9q22.32. Oncotarget. 2018;9(13):11170-9.
27. Liu W, Jiao X, Thutkawkorapin J, Mahdessian H, Lindblom A. Cancer risk susceptibility loci in a Swedish population. Oncotarget. 2017;8(66):110300-10.
28. von Holst S, Jiao X, Liu W, Kontham V, Thutkawkorapin J, Ringdahl J, et al. Linkage analysis revealed risk loci on 6p21 and 18p11.2-q11.2 in familial colon and rectal cancer, respectively. European Journal of Human Genetics. 2019;27(8):1286-95.
29. Jiao X, Liu W, Mahdessian H, Bryant P, Ringdahl J, Timofeeva M, et al. Recurrent, low-frequency coding variants contributing to colorectal cancer in the Swedish population. PLoS One. 2018;13(3):e0193547.
30. Thutkawkorapin J, Picelli S, Kontham V, Liu T, Nilsson D, Lindblom A. Exome sequencing in one family with gastric- and rectal cancer. BMC Genetics. 2016;17:41.