Research Papers:

Two novel colorectal cancer risk loci in the region on chromosome 9q22.32

Jessada Thutkawkorapin, Hovsep Mahdessian, Tom Barber, Simone Picelli, Susanna von Holst, Johanna Lundin, Laura Valle, Vinaykumar Kontham, Tao Liu, Daniel Nilsson, Xiang Jiao and Annika Lindblom _

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Oncotarget. 2018; 9:11170-11179. https://doi.org/10.18632/oncotarget.24340

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Jessada Thutkawkorapin1, Hovsep Mahdessian1, Tom Barber2, Simone Picelli1, Susanna von Holst1, Johanna Lundin1, Laura Valle3, Vinaykumar Kontham1, Tao Liu1, Daniel Nilsson1, Xiang Jiao1 and Annika Lindblom1

1Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden

2The Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA

3Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL and CIBERONC, Barcelona 08908, Spain

Correspondence to:

Annika Lindblom, email: [email protected]

Keywords: familial colorectal cancer; risk haplotype; cancer predisposition; association study; next generation sequencing

Received: November 26, 2017     Accepted: January 23, 2018     Published: January 29, 2018


Highly penetrant cancer syndromes account for less than 5% of all cases with familial colorectal cancer (CRC), and other genetic contribution explains the majority of the genetic contribution to CRC. A CRC susceptibility locus on chromosome 9q has been suggested. In this study, families where risk of CRC was linked to the region, were used to search for predisposing mutations in all genes in the region. No disease-causing mutation was found. Next, haplotype association studies were performed in the region, comparing Swedish CRC cases (2664) and controls (4782). Two overlapping haplotypes were suggested. One 10-SNP haplotype was indicated in familial CRC (OR 1.4, p = 0.00005) and one 25-SNP haplotype was indicated in sporadic CRC (OR 2.2, p = 0.0000012). The allele frequencies of the 10-SNP and the 25-SNP haplotypes were 13.7% and 2.5% respectively and both included one RNA, RP11-332M4.1 and RP11-l80l4.2, in the non-overlapping regions. The sporadic 25-SNP haplotype could not be studied further, but the familial 10-SNP haplotype was analyzed in 61 additional CRC families, and 6 of them were informative for all markers and had the risk haplotype. Targeted sequencing of the 10-SNP region in the linked families identified one variant in RP11-332M4.1, suggestive to confer the increased CRC risk on this haplotype. Our results support the presence of two loci at 9q22.32, each with one RNA as the putative cause of increased CRC risk. These RNAs could exert their effect through the same, or different, genes/pathways, possibly through the regulation of neighboring genes, such as PTCH1, FANCC, DKFZP434H0512, ERCC6L2 or the processed transcript LINC00046.

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