Our estimates of cancer risk using data from families with Lynch Syndrome ascertained clinically through 2 US cancer centers reveal a cumulative risk of colorectal and endometrial cancer in male and female MMR gene mutation carriers of approximately 70% by age 70. We calculated an overall hazard ratio for CRC of 148.4 for men and 51.1 for women. CRC risk appears to be highest for male carriers of mutations in the MLH1 gene, with a HR of 342 (95% CI 264-442.1). For women, cumulative risk of endometrial cancer approaches 40% by age 70, and when combined with risk for CRC, results in a lifetime cancer risk of 73%. Our data demonstrate that the cumulative risk for colon and endometrial CA continue to increase with age, with the most dramatic elevation in age-specific hazard ratios seen in individuals age 20 to 49 years.
Our risk estimates for CRC and EC in this large cohort of U.S. families with Lynch Syndrome further clarify the cancer experience of mutation carriers. These estimates are similar to those from European familial cancer registries,[
6,
8,
10] [
9] and other more recent studies in smaller clinically ascertained cohorts[
17]. Interestingly, our risk estimates are considerably higher than those presented by other recently-published studies which sought to control for ascertainment bias, as well as a recent analysis of a fairly large series of families from England without appropriate correction for ascertainment. [
18] Using “ascertainment-corrected maximum likelihood estimation”, Quehenberger
et. al. analyzed cancer histories of 84 families with mutations in
MLH1 or
MSH2 from the Dutch HNPCC registry and found a cumulative risk of CRC by age 70 of 26% for men and 22% for women, which led them to conclude that risk of CRC in LS is considerably lower than suggested by the original reports.[
11] In examining cancer histories of 17 families with MMR mutations, Jenkins
et al. calculated cumulative risks for CRC of 45% for men and 38% for women. [
12] In addition to concluding that risks of CRC were lower than expected, they reported that while CRC risk increases to age 50, the incidence decreases to general population levels at older ages.[
12] The recently published English series of 121 families[
18] included far fewer relatives (n=1420) than our series and did not use segregation analysis to estimate penetrance, making it difficult to directly compare our results. However, the penetrance estimates derived from our series of 147 families are higher than the English series as well.
Our study, which used similar statistical methodology to control for ascertainment bias, yielded strikingly different risk estimates than those of Quehenberger and Jenkins. Our data demonstrate that the risk of CRC for MMR gene mutation carriers is already twice the population risk for males by age 30 and 4.5 times the population risk for females by age 40, and that the risks continue to increase with age. Our finding of the even more dramatic elevation in CRC risk in males with
MLH1 mutations corroborates the genotype-phenotype variability that has been observed in other cohorts of MMR mutation carriers.[
19,
20] We found that risk for endometrial cancer is similarly increased for all female MMR mutation carriers. These results provide evidence in support of current cancer screening recommendations for LS which include CRC screening every 1-2 years in all MMR gene mutation carriers beginning at age 20-25 and annual uterine cancer screening for women beginning at age 30-35 [
2] with the options of continued surveillance over the patients lifetime or prophylactic surgery. In addition, our results provide new and important data that can be easily incorporated into computational software routinely used to estimate the lifetime risk of cancer among gene carriers, such as MMRpro.[
21]
Our study has several strengths. Our cohort of 147 families with MMR gene mutations is the largest U.S. study of lifetime cancer risks associated with Lynch Syndrome. Our use of segregation analysis affords ma ny advantages to estimating cancer risk, as it calculates the probability of being a mutation carrier for all relatives whose mutation status is unknown. By conditioning the analysis on the available phenot ypic information from the pedigree, we were able to minimize ascertainment bias by excluding diagnoses of CRC in probands and first-degree relatives. Using this methodology in our large cohort of families identified through two clinical cancer genetics programs allowed us to calculate what we believe is a conservative estimate of cumulative and gene-specific cancer risk among MMR gene mutation carriers. Finally, our findings in this U.S. cohort confirm the substantially elevated risk estimates for CRC and EC presented in the original descriptions of Lynch Syndrome and demonstrate that, despite some variation by MMR genotype, these lifetime cancer risk estimates are generalizable between MMR mutation carriers seen in European cancer registries and in clinical cancer genetics programs in North America.
Even so, we recognize that our study has certain limitations. This study of families with Lynch Syndrome was not population-based. It is possible that families with MMR gene mutations that present to genetics clinics may be phenotypically different from those that do not seek genetic evaluation. However, the frequency of MMR gene mutations in the general population is so low and genetic evaluation is still so uncommon that even large, well-conducted population-based study designs have been limited by very small sample sizes of carriers.[
4] Unconfirmed cancer diagnoses were another limitation. Unfortunately a centralized reporting system for cancers does not exist in the U.S.; consequently, the cancer histories included in each family’s pedigree were obtained mostly through proband reports and only a minority of cancer diagnoses had corresponding medical record confirmation. Although a number of studies have demonstrated that patient reports of family cancer history are largely accurate [
22,
23], reports of gynecologic cancers may be less accurate [
24] and it is likely that some cancers may have been misclassified. Nevertheless, in a study of this size with such a large number of colorectal and endometrial cancers, non-differential misclassification would be expected to attenuate our findings, and would be unlikely to substantially alter our conclusions. Missing information was a limitation; however, we imputed subject ages in a conservative manner and checked these in sensitivity analyses which demonstrated no significant inflation of risk estimates. Our cohort contained only 11 families with mutations in
MSH6, which provided limited power for comparison of risk estimates for this subgroup. Our methods required that we exclude CRC diagnoses in the probands and first-degree relatives, which may have led us to underestimate cancer risk in carriers of MMR gene mutations.
In summary, in this large study of U.S. families we have quantified the elevated risks of colorectal and endometrial cancer associated with Lynch Syndrome with improved precision relative to the published literature. We have clarified that these risks are substantial, clinically meaningful, and higher than recent reports that used similar statistical methods. MMR gene mutation carriers have a lifetime risk of developing either colorectal or endometrial cancer of 70% by age 70, which provides justification for current recommendations for early and continued intensive surveillance for these cancers. While our findings suggest some phenotypic differences among
MLH1, MSH2, and
MSH6 mutation carriers, further study is needed to determine whether gene-specific cancer risks may warrant tailoring cancer screening recommendations by genoytpe, such as more intensive colorectal surveillance for male
MLH1 mutation carriers. [
20]
The publisher's final edited version of this article is available at 
