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Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene.
- Source :
-
Familial cancer [Fam Cancer] 2015 Dec; Vol. 14 (4), pp. 575-83. - Publication Year :
- 2015
-
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.
- Subjects :
- Adult
Aged
Aged, 80 and over
Colorectal Neoplasms pathology
Female
Follow-Up Studies
Humans
Male
Middle Aged
Mismatch Repair Endonuclease PMS2
MutL Protein Homolog 1
Neoplasm Staging
Prognosis
Risk Factors
Adaptor Proteins, Signal Transducing genetics
Adenosine Triphosphatases genetics
Colorectal Neoplasms genetics
DNA Glycosylases genetics
DNA Repair Enzymes genetics
DNA-Binding Proteins genetics
MutS Homolog 2 Protein genetics
Mutation genetics
Nuclear Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1573-7292
- Volume :
- 14
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Familial cancer
- Publication Type :
- Academic Journal
- Accession number :
- 26202870
- Full Text :
- https://doi.org/10.1007/s10689-015-9824-x