Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene

Abstract

The base excision repair protein, MUTYH, functionally interacts with the DNA mismatch repair (MMR) system. As genetic testing moves from testing one gene at a time, to gene panel and whole exome next generation sequencing approaches, understandin g the risk associated with co-existence of germline mutations in these genes will be important for clinical interpretation and management. From the Colon Cancer Family Registry, we identified 10 carriers who had both a MUTYH mutation (6 with c.1187G>A p.(Gly396Asp), 3 with c.821G>A p.(Arg274Gln), and 1 with c.536A>G p.(Tyr179Cys)) and a MMR gene mutation (3 in MLH1, 6 in MSH2, and 1 in PMS2), 375 carriers of a single (monoallelic) MUTYH mutation alone, and 469 carriers of a MMR gene mutation alone. Of the 10 carriers of both gene mutations, 8 were diagnosed with colorectal cancer. Using a weighted cohort analysis, we estimated that risk of colorectal cancer for carriers of both a MUTYH and a MMR gene mutation was substantially higher than that for carriers of a MUTYH mutation alone [hazard ratio (HR) 21.5, 95 % confidence interval (CI) 9.19–50.1; p < 0.001], but not different from that for carriers of a MMR gene mutation alone (HR 1.94, 95 % CI 0.63–5.99; p = 0.25). Within the limited power of this study, there was no evidence that a monoallelic MUTYH gene mutation confers additional risk of colorectal cancer for carriers of a MMR gene mutation alone. Our finding suggests MUTYH mutation testing in MMR gene mutation carriers is not clinically informative.

DOI: 10.1007/s10689-015-9824-x

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Cite this paper

@article{Win2015RiskOC, title={Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene}, author={Aung Ko Win and Jeanette C. Reece and Daniel D Buchanan and Mark Clendenning and Joanne P. Young and Sean P. Cleary and Hyeja Kim and Michelle Cotterchio and James G. Dowty and Robert J. Macinnis and Katherine M. Tucker and Ingrid Winship and Finlay A. Macrae and Terrilea Burnett and Lo{\"{i}c Le Le Marchand and Graham R Casey and Robert W. Haile and Polly A Newcomb and Stephen N. Thibodeau and Noralane M. Lindor and John L. Hopper and Steven Gallinger and Mark Jenkins}, journal={Familial Cancer}, year={2015}, volume={14}, pages={575-583} }