{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T08:37:04Z","timestamp":1773995824009,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004047","name":"Karolinska Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Swedish Cancer Society","award":["21 1443 Pj 02 H"],"award-info":[{"award-number":["21 1443 Pj 02 H"]}]},{"name":"Radiumhemmet\u2019s Cancer Research Funds","award":["191203"],"award-info":[{"award-number":["191203"]}]},{"name":"Stockholm County Council and Karolinska Institutet","award":["RS2022-0674"],"award-info":[{"award-number":["RS2022-0674"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetic variants specific to anatomical subsites of colorectal cancer are known to play a crucial role in its prognosis and treatment. We undertook a haplotype-based genome-wide association study (GWAS) to identify specific genetic risk loci for three sites: cecum, right colorectum, and left colorectum. Six different haplotype GWAS were performed using familial and sporadic colorectal cancer cases with tumors at three different sites. The studies included 2358 CRC cases and 1642 healthy controls. A logistic regression model using PLINK v.1.07 software was employed, and risk loci with a p-value of 5 \u00d7 10\u22128 were considered statistically significant. In total, 29 distinct risk loci were identified in the analyses of familial and sporadic cases of cecal and proximal colon cancer. The results from the analyses of familial and sporadic left-sided colorectal cancer did not meet the strict criteria for significance. Among the loci that were associated with cecal cancer, 14 were familial, and seven were sporadic. Among the other right-sided colon cancer loci, six were familial, and two were sporadic. Coding genes were found at 18 of the 29 loci. Our findings of site-specific genetic risk loci support the growing evidence for divergent pathways in familial and sporadic colorectal cancer across different colorectal sites. The data support a model where the rise in proximal tumors, both familial and sporadic, is influenced by genetic risk to a higher degree than that of distal tumors. These findings are important for understanding colorectal carcinogenesis and could, after future studies, lead to new applications in cancer prevention, treatment, and prognosis.<\/jats:p>","DOI":"10.3390\/ijms27062758","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T11:14:14Z","timestamp":1773832454000},"page":"2758","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Swedish Haplotype GWAS in Familial and Sporadic Site-Specific Colorectal Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Litika","family":"Vermani","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden"},{"name":"Department of Clinical Genetics and Genomics, Karolinska University Hospital, 171 64 Stockholm, Sweden"},{"name":"Dr. S Krishnamurthi Centre for Research and Education in Cancer, Cachar Cancer Hospital and Research Centre, Silchar 788015, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4558-5325","authenticated-orcid":false,"given":"Shabane","family":"Barot","sequence":"additional","affiliation":[{"name":"Department of Clinical Science and Education, S\u00f6dersjukhuset, Karolinska Institutet, 118 83 Stockholm, Sweden"},{"name":"Department of Oncology, S\u00f6dersjukhuset, 118 83 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7675-7569","authenticated-orcid":false,"given":"Annika","family":"Lindblom","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden"},{"name":"Department of Clinical Genetics and Genomics, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"ref_1","first-page":"87","article-title":"Global cancer statistics, 2012","volume":"65","author":"Torre","year":"2015","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"27","article-title":"Large intestine embryogenesis: Molecular pathways and related disorders","volume":"46","author":"Kostouros","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Waldstein, S., Spengler, M., Pinchuk, I.V., and Yee, N.S. (2023). Impact of colorectal cancer sidedness and location on therapy and clinical outcomes: Role of blood-based biopsy for personalized treatment. J. Pers. Med., 13.","DOI":"10.3390\/jpm13071114"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1001\/jamaoncol.2016.4227","article-title":"Prognostic survival associated with left-sided vs right-sided colon cancer: A systematic review and meta-analysis","volume":"3","author":"Petrelli","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1136\/gutjnl-2020-321534","article-title":"Genetic architectures of proximal and distal colorectal cancer are partly distinct","volume":"70","author":"Huyghe","year":"2021","journal-title":"Gut"},{"key":"ref_6","first-page":"189","article-title":"A simple model for carcinogenesis of colorectal cancers with microsatellite instability","volume":"77","author":"Janin","year":"2000","journal-title":"Adv. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"748","DOI":"10.4251\/wjgo.v14.i4.748","article-title":"Regulatory RNAs, microRNA, long-non coding RNA and circular RNA roles in colorectal cancer stem cells","volume":"14","author":"Chao","year":"2022","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/ng2085","article-title":"A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21","volume":"39","author":"Tomlinson","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/ng.133","article-title":"Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21","volume":"40","author":"Tenesa","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1038\/ng.262","article-title":"Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer","volume":"40","author":"Houlston","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/ng.670","article-title":"Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33","volume":"42","author":"Houlston","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1093\/carcin\/bgq146","article-title":"Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility","volume":"31","author":"Lascorz","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tomlinson, I.P.M., Carvajal-Carmona, L.G., Dobbins, S.E., Tenesa, A., Jones, A.M., Howarth, K., Palles, C., Broderick, P., Jaeger, E.E.M., and Farrington, S. (2011). Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002105"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1136\/gut.2010.215947","article-title":"Common variant in 6q26\u2013q27 is associated with distal colon cancer in an Asian population","volume":"60","author":"Cui","year":"2011","journal-title":"Gut"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s00439-011-1055-0","article-title":"Meta-analysis of new genome-wide association studies of colorectal cancer risk","volume":"131","author":"Peters","year":"2012","journal-title":"Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gaj, P., Maryan, N., Hennig, E.E., Ledwon, J.K., Paziewska, A., Majewska, A., Karczmarski, J., Nesteruk, M., Wolski, J., and Antoniewicz, A.A. (2012). Pooled sample-based GWAS: A cost-effective alternative for identifying colorectal and prostate cancer risk variants in the Polish population. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035307"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/ng.2293","article-title":"Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk","volume":"44","author":"Dunlop","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1053\/j.gastro.2012.12.020","article-title":"Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis","volume":"144","author":"Peters","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/ng.2985","article-title":"Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk","volume":"46","author":"Zhang","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Real, L.M., Ruiz, A., Gay\u00e1n, J., Gonz\u00e1lez-P\u00e9rez, A., S\u00e1ez, M.E., Ram\u00edrez-Lorca, R., Mor\u00f3n, F.J., Velasco, J., Marginet-Flinch, R., and Musul\u00e9n, E. (2014). A colorectal cancer susceptibility new variant at 4q26 in the Spanish population identified by genome-wide association analysis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101178"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4729","DOI":"10.1093\/hmg\/ddu177","article-title":"Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis","volume":"23","author":"Whiffin","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"40327","DOI":"10.18632\/oncotarget.5530","article-title":"Genome-wide association study identifies two new susceptibility loci for colorectal cancer at 5q23.3 and 17q12 in Han Chinese","volume":"6","author":"Jiang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17369","DOI":"10.1038\/srep17369","article-title":"Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1","volume":"5","author":"Cheng","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10442","DOI":"10.1038\/srep10442","article-title":"A new GWAS and meta-analysis with 1000 Genomes imputation identifies novel risk variants for colorectal cancer","volume":"5","author":"Whiffin","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4613","DOI":"10.1038\/ncomms5613","article-title":"Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A","volume":"5","author":"Wang","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7138","DOI":"10.1038\/ncomms8138","article-title":"Genome-wide association study of colorectal cancer identifies six new susceptibility loci","volume":"6","author":"Schumacher","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1053\/j.gastro.2016.02.076","article-title":"Identification of susceptibility loci and genes for colorectal cancer risk","volume":"150","author":"Zeng","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1093\/jnci\/djy099","article-title":"Novel common genetic susceptibility loci for colorectal cancer","volume":"111","author":"Schmit","year":"2019","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1093\/carcin\/bgy026","article-title":"GWAS identifies two novel colorectal cancer loci at 16q24.1 and 20q13.12","volume":"39","author":"Tanikawa","year":"2018","journal-title":"Carcinogenesis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/s41588-018-0286-6","article-title":"Discovery of common and rare genetic risk variants for colorectal cancer","volume":"51","author":"Huyghe","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1053\/j.gastro.2020.08.062","article-title":"Identifying novel susceptibility genes for colorectal cancer risk from a transcriptome-wide association study of 125,478 subjects","volume":"160","author":"Guo","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1038\/s41467-019-09775-w","article-title":"Association analyses identify 31 new risk loci for colorectal cancer susceptibility","volume":"10","author":"Law","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/s41588-022-01222-9","article-title":"Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and East Asian ancestries","volume":"55","author":"Timofeeva","year":"2023","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3557","DOI":"10.1038\/s41467-024-47399-x","article-title":"Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes","volume":"15","author":"Chen","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_35","first-page":"179","article-title":"Lentivirus-mediated RNA interference targeting WWTR1 in human colorectal cancer cells inhibits cell proliferation in vitro and tumor growth in vivo","volume":"28","author":"Pan","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/gcc.22539","article-title":"Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers","volume":"57","author":"Wolff","year":"2018","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ning, J., Cai, X., Su, Y., Fan, X., and Shen, M. (2025). Inhibitory effect and mechanism of the downregulation of TRIM32 in colorectal cancer. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115047"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mohammed, M., Mboya, I.B., Mwambi, H., Elbashir, M.K., and Omolo, B. (2021). Predictors of colorectal cancer survival using Cox regression and random survival forests models based on gene expression data. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0261625"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00790","DOI":"10.14309\/ctg.0000000000000790","article-title":"Candidate genetic loci modifying the colorectal cancer risk caused by lifestyle risk factors","volume":"16","author":"Barot","year":"2025","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chen, S., and Allgayer, H. (2023). Epigenetically downregulated breast cancer gene 2 through acetyltransferase lysine acetyltransferase 2B increases the sensitivity of colorectal cancer to olaparib. Cancers, 15.","DOI":"10.3390\/cancers15235580"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"26685","DOI":"10.1038\/s41598-025-05151-5","article-title":"RBM47 functions as an anti-oncogene by regulating expression and alternative splicing of cell proliferation and apoptosis associated genes in colorectal cancer cells","volume":"15","author":"Liu","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Vermani, L., Winnberg, J.S., Liu, W., Soller, V., Sj\u00f6din, T., Lindblad, M., and Lindblom, A. (2025). A haplotype GWAS in syndromic familial colorectal cancer. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26020817"},{"key":"ref_43","first-page":"129","article-title":"Fas, fas ligand, immune tolerance, and cancer: Implications in cancer of the colon","volume":"85","author":"Berger","year":"1998","journal-title":"Bull. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.7150\/thno.24284","article-title":"Aspirin cooperates with p300 to activate the acetylation of H3K9 and promote FasL-mediated apoptosis of cancer stem-like cells in colorectal cancer","volume":"8","author":"Chen","year":"2018","journal-title":"Theranostics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1002\/kjm2.12647","article-title":"DNMT3b affects colorectal cancer development by regulating FLI1 through DNA hypermethylation","volume":"39","author":"Zhou","year":"2023","journal-title":"Kaohsiung J. Med. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.21873\/anticanres.11518","article-title":"Defining new colorectal cancer syndromes in a population-based cohort of the disease","volume":"37","author":"Forsberg","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/mc.23366","article-title":"Colorectal cancer risk susceptibility loci in a Swedish population","volume":"61","author":"Liu","year":"2022","journal-title":"Mol. Carcinog."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: A tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_49","first-page":"921","article-title":"Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population","volume":"12","author":"Excoffier","year":"1995","journal-title":"Mol. Biol. Evol."},{"key":"ref_50","unstructured":"Purcell, S. (2010). PLINK (1.07) Documentation, The University of Chicago."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/gepi.20297","article-title":"Estimation of significance thresholds for genomewide association scans","volume":"32","author":"Dudbridge","year":"2008","journal-title":"Genet. Epidemiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2758\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T05:23:22Z","timestamp":1773984202000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2758"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,18]]},"references-count":51,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062758"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062758","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,18]]}}}