We confirmed that MMR gene mutation carriers were at increased risk of a wide variety of cancers and found that there was no evidence of an increased risk of cancer for their noncarrier relatives. A major strength of our study is the prospective nature of the design, because observation time for carriers and noncarriers commenced before cancer diagnosis. This design, therefore, avoided ascertainment bias commonly present in retrospective analyses, particularly when estimates of cancer risk are made using relatives who are enrolled in cancer clinics because they have been diagnosed with cancer. A further strength of the prospective analysis is that it provides an estimate, based on empirical data, of future cancer risk at the time they come under clinical care. Our estimated 10-year risk of CRC for carriers with a median age of 49 years (8.05%; 95% CI, 4.46% to 14.29%) is comparable to our previous estimate (using an ascertainment-corrected retrospective analysis) of the 10-year risk for MSH6
mutation carriers at age 50 years (6% [95% CI, 3% to 9%] for men and 3% [95% CI, 1% to 5%] for women).27
It seems to be lower than a previous retrospective estimate of the 10-year estimates for MLH1
carriers (26% for men and 13% for women).28
An unanticipated finding of our study is the confirmation of an increased risk for cancers of the breast and pancreas for MMR gene mutation carriers. Although risk of pancreatic cancer has been investigated in Lynch syndrome,29–33
the evidence was inconsistent. The study showing evidence for an association was that of Kastrinos et al,34
which recently showed an increased risk of pancreatic cancer in Lynch syndrome (hazard ratio, 8.6; 95% CI, 4.5 to 15.7). This result is consistent with our finding (test for difference, P =
.79). However, given the limited evidence for efficacy of screening for pancreatic cancers,35
expert opinion has not yet advocated pancreatic cancer screening in the context of Lynch syndrome.
A more controversial association with Lynch syndrome is that of breast cancer. Initially raised by Lynch et al36
several decades ago, the issue of breast cancer risk in Lynch syndrome has been debated with evidence for and against this association. Multiple case reports describing MMR-deficient breast cancers, including cases of male breast cancer, have been published.37–41
Walsh et al40
showed that about half of breast cancers observed in MMR gene mutation carries have loss of expression in the tumor of the gene that is mutated in the germline. However, this and other studies were not able to address whether the MMR deficiency caused breast cancer or was a phenotype of a breast cancer caused by another factor. In this report, we observed an increased risk of breast cancer for MMR gene mutation carriers followed prospectively. Although the numbers are small, the risk was estimated to be increased four-fold above that of the general population, suggesting that MMR mutation carriers may benefit from enhanced screening. Further clarification of age-specific magnitude of risk is needed to determine whether ages at screening or methods such as use of magnetic resonance imaging should be modified in Lynch syndrome.
In addition to defining spectrum and cancer risks for MMR gene mutation carriers, it is important to clarify the risk of CRC and other cancers for noncarrier relatives. Identification of mutation noncarriers is considered to be one of the major benefits of MMR gene testing, providing reassurance that these people are at substantially lower risk than their mutation-carrying relatives and, therefore, not subject to the same costly, frequent, and invasive screening and risk-reductionstrategies. Because no cancer arises, to our knowledge, as a result of a single gene mutation, even highly penetrant disorders such as Lynch syndrome might arise on the background of multiple other genetic variants that modify cancer risks. If that is the case, then relatives who do not carry the family-specific pathogenic MMR mutation may still have a cancer risk that is elevated compared with the general population. In this study, we found no evidence of an increased risk of cancers for the noncarrier relatives, whereas carriers of an MMR gene mutation from the same families were at increased risk of a wide variety of cancers. In a similar scenario, it has been observed that there is no evidence of increased risk of breast cancer42,43
or ovarian cancer44
for noncarriers from families carrying mutations of BRCA1
Estimating penetrance for CRC is particularly challenging in the high-risk family setting because surveillance colonoscopy is likely to be offered to those with a strong family history of CRC or if Lynch syndrome has been diagnosed in a relative. The colonoscopy likely changes the natural history of the disease by removing the precursor lesion at least some of the time. We observed that those who were mutation carriers (although they may not have known about their mutation status at the time) were having frequent colonoscopies (approximately once every 3 years) yet still manifested an appreciable high risk for development of CRC. In contrast, those who were not mutation carriers (although they also may not have known of their mutation status) were also having colonoscopies almost as frequently as the carriers (approximately once every 4 years). Therefore, we cannot dismiss the possibility that noncarriers who are relatives of mutation carriers are at increased risk of CRC, but their frequent colonoscopies may have reduced their risk.
We also found no evidence of increased risk of extracolonic cancers for the noncarriers. It is unlikely that this finding can be attributed to increased screening for these cancers because, unlike CRC, screening does not alter the risk for extracolonic cancers. For example, screening for urothelial, endometrial, and ovarian cancers does not reduce the risk of these diseases, because it is done for early detection only and not for removal of precursor lesions, and therefore, screening would not influence the estimates of these cancer risks.
There are some limitations to our study, most notably the small number of events and a short follow-up duration. We do not have sufficient power to exclude a two-fold increased risk of CRC for the noncarriers. Another possible limitation is that censoring each individual at the age of polypectomy could have resulted in underestimating the true cancer risk.
In conclusion, our prospective analysis provides unbiased estimates of cancer risks for MMR gene mutation carriers, including significantly increased risks of recognized Lynch syndrome–associated cancers (colorectal, endometrial, ovarian, renal, gastric, and urinary bladder) and of breast cancer and pancreatic cancer. For the noncarrier relatives of family-specific MMR gene mutations, we found no evidence that their risks of CRC or other cancers exceed the population risks.