N67: Penetrance For Carriers Of A DNA Mismatch Repair Gene Specific Variant

A. K. Win1, 2, J. G. Dowty1, D. D. Buchanan2, 3, J. C. Reece1, G. Lee1, J. P. Plazzer2, G. Moslein4, R. W. Haile5, F. A. Macrae6, 7, I. M. Winship2, 7, M. A. Jenkins1, International Mismatch Repair Consortium (IMRC)

1 – Centre for Epidemiology & Biostatistics, The University of Melbourne, Parkville, Victoria, Australia. 2 – Genetic Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia. 3 -Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. 4 – Helios St. Josefs Hospital Bochum-Linden, Linden, Germany. 5 – Cedars-Sinai Medical Center, Los Angeles, CA, USA. 6 – Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Victoria, Australia. 7 – Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.

 

Aim: Previous estimates of colorectal cancer risk for Lynch syndrome are averages over hundreds of different mutations in these genes. Reason for heterogeneity of cancer risk within specific variants in each gene is unknown.

Method: We estimated colorectal cancer risk for MSH2 c.942+3A>T variant using 234 families from the International Mismatch Repair Consortium. Age-specific cumulative risks (penetrance) and 95% confidence intervals were estimated using a modified segregation analysis with appropriate ascertainment conditioning and allowing for risk to vary between families by fitting a polygenic effect.

Results: The estimated average cumulative risks to age 70 years (95% confidence intervals), were 56% (38%-78%) for males carriers and 45% (28%-67%) for female carriers.  However, the lifetime risks for different people were estimated to vary widely about these average risks (p=0.001). For carriers of this specific variant, 26% of males and 16% of females had colorectal cancer risk less than 20%; and 24% of males and 37% of females had risk greater than 70%.

Conclusion: Even for a specific variant in a DNA mismatch repair gene, there is a wide range of colorectal cancer risks. This is consistent with the existence of strong modifiers of risk, that if known, could be used to provide personalized risk of colorectal cancer for Lynch syndrome.

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