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.

• Authors: Aung Ko Win, Jeanette C Reece, Daniel D Buchanan, Mark Clendenning, Joanne P Young, Sean P Cleary, Hyeja Kim, Michelle Cotterchio, James G Dowty, Robert J MacInnis, Katherine M Tucker, Ingrid M Winship, Finlay A Macrae, Terrilea Burnett, Loïc Le Marchand, Graham Casey, Robert W Haile, Polly A Newcomb, Stephen N Thibodeau, Noralane M Lindor, John L Hopper, Steven Gallinger, Mark A Jenkins
• Journal: Familial cancer (Fam Cancer) Vol. 14 Issue 4 Pg. 575-83 (Dec 2015) ISSN: 1573-7292 [Electronic] Netherlands
• PMID: 26202870 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• DNA-Binding Proteins
• MLH1 protein, human
• Nuclear Proteins
• DNA Glycosylases
• mutY adenine glycosylase
• Adenosine Triphosphatases
• PMS2 protein, human
• MSH2 protein, human
• Mismatch Repair Endonuclease PMS2
• MutL Protein Homolog 1
• MutS Homolog 2 Protein
• DNA Repair Enzymes

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adenosine Triphosphatases (genetics)
• Adult
• Aged
• Aged, 80 and over
• Colorectal Neoplasms (genetics, pathology)
• DNA Glycosylases (genetics)
• DNA Repair Enzymes (genetics)
• DNA-Binding Proteins (genetics)
• Female
• Follow-Up Studies
• Humans
• Male
• Middle Aged
• Mismatch Repair Endonuclease PMS2
• MutL Protein Homolog 1
• MutS Homolog 2 Protein (genetics)
• Mutation (genetics)
• Neoplasm Staging
• Nuclear Proteins (genetics)
• Prognosis
• Risk Factors