Abstract 4842: Hazard ratio for colorectal cancer risk in Lynch syndrome is inversely associated with age.

Abstract

Abstract Introduction: Carriers of germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) have a high risk of colorectal and other cancers (Lynch syndrome). Between 30% and 70% of carriers will be develop colorectal cancer by age 70 if they are not screened for the disease. What is not well understood is how the effect of mutations, in absolute and relative terms, varies by age. Methods: We conducted a literature review to identify studies of colorectal cancer that estimated age-specific hazard ratios for colorectal cancer for carriers of a mutation in MLH1 or MSH2 compared with the general population. Studies were excluded if they did not adjust correctly for ascertainment. We conducted a random effects meta-analysis to estimate the average age-specific hazard ratio. Annual risk (incidence) by multiplying the population incidence by the age-specific hazard ratio estimated by the meta-analysis. Results: We identified six studies comprising 673 families (282 MLH1, 391 MSH2). All studies observed that the hazard ratio for colorectal cancer was highest at young ages and decreased with age. This pattern was observed for both males and females and for both MLH1 and MSH2 mutation carriers. Overall, the hazard ratio dropped 6-8 fold over three decades (Table). Incidence of colorectal cancer for carriers increased until age 40 years for males and 50 years for females, and then plateaued (Table). Conclusion: At younger ages, in multiplicative terms, the magnitude of the increased risk conferred by the mutations is substantially greater than at older ages. The reason for this age-dependency is not known. It is, however, consistent with a multi-stage model of carcinogenesis for Lynch syndrome. These findings add to the complement of factors that complicate risk estimation for Lynch syndrome including: polygenic effects, non-genetic risk modifiers, and the possibility of a parent-of-origin effect. There is still much to learn about the clinical implications and carcinogenesis of Lynch syndrome. Meta-analysis estimates of hazard ratios and incidences for colorectal cancer by age group. 30-39 year olds 40-49 year olds 50-59 year olds 60-69 year olds Hazard ratio (95%CI): Risk of colorectal cancer in carriers/risk for the general population. Males 120 (60-243) 95 (39-226) 33 (14-78) 14 (4.2-51) Females 80 (42-154) 70 (35-139) 28 (19-41) 14 (7.4-26) Incidence: Proportion of carriers diagnosed with colorectal cancer per year. Males 1 in 146 1 in 50 1 in 39 1 in 38 Females 1 in 490 1 in 135 1 in 69 1 in 61 Citation Format: Mark A. Jenkins, Aung Ko Win, James G. Dowty, John D. Mathews, John L. Hopper. Hazard ratio for colorectal cancer risk in Lynch syndrome is inversely associated with age. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4842. doi:10.1158/1538-7445.AM2013-4842