Evidence for Genetic Association Between Chromosome 1q Loci and Predisposition to Colorectal Neoplasia

Overview

Journal Br J Cancer

Specialty Oncology

Date 2017 Jul 26

PMID 28742792

Citations 9

Authors

Stephanie A Schubert

Dina Ruano

Fadwa A Elsayed

Arnoud Boot

Stijn Crobach

Arantza Farina Sarasqueta

Bruce Wolffenbuttel

Melanie M van der Klauw

Jan Oosting

Carli M Tops

Ronald van Eijk

Hans Fa Vasen

Rolf Ham Vossen

Maartje Nielsen

Sergi Castellvi-Bel

Clara Ruiz-Ponte

Ian Tomlinson

Malcolm G Dunlop

Pavel Vodicka

Juul T Wijnen

Frederik J Hes

Hans Morreau

Noel Fcc de Miranda

Rolf H Sijmons

Tom van Wezel

Affiliations

Soon will be listed here.

Abstract

Background: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders.

Methods: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level.

Results: Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues.

Conclusions: Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.

Citing Articles

Mutational analysis of driver genes defines the colorectal adenoma: in situ carcinoma transition.

Jungwirth J, Urbanova M, Boot A, Hosek P, Bendova P, Siskova A Sci Rep. 2022; 12(1):2570.

PMID: 35173208 PMC: 8850440. DOI: 10.1038/s41598-022-06498-9.

Identification of oral squamous cell carcinoma markers MUC2 and SPRR1B downstream of TANGO.

Sasahira T, Kurihara-Shimomura M, Shimomura H, Bosserhoff A, Kirita T J Cancer Res Clin Oncol. 2021; 147(6):1659-1672.

PMID: 33620575 DOI: 10.1007/s00432-021-03568-9.

Novel Insights Into Epigenetic Reprogramming and Destabilization of Pericentromeric Heterochromatin in Cancer.

Gjerstorff M Front Oncol. 2020; 10:594163.

PMID: 33251148 PMC: 7674669. DOI: 10.3389/fonc.2020.594163.

Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes-Considerations for Future Studies.

Te Paske I, Ligtenberg M, Hoogerbrugge N, de Voer R Int J Mol Sci. 2020; 21(22).

PMID: 33228212 PMC: 7699508. DOI: 10.3390/ijms21228757.

Digenic inheritance of MSH6 and MUTYH variants in familial colorectal cancer.

Schubert S, Ruano D, Tiersma Y, Drost M, de Wind N, Nielsen M Genes Chromosomes Cancer. 2020; .

PMID: 32615015 PMC: 7689793. DOI: 10.1002/gcc.22883.

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