Our results demonstrate that the prevalence of MSI among individuals of Hispanic origin with CRC diagnosed at a large, urban, US County hospital is approximately 10%. Data from a comparable study from Puerto Rico are consistent with our findings. De Jesus-Monge et al. evaluated prevalence of abnormal IHC for the MMR proteins MLH1 and MSH2 among 164 individuals in Puerto Rico14
. The prevalence of abnormal expression of either MLH1 or MSH2 was 4.3%, but immunohistochemistry for PM2 and MS6 was not performed, and MSI testing was restricted to those with abnormal IHC, perhaps leading to an underestimation of CRC attributable to MMR protein dysfunction. The single patient with abnormal IHC for MLH1 had MSI but normal testing for a BRAFV600E
mutation. Consistent with our study, the pattern of molecular abnormalities suggested that the prevalence of sporadic MSI among Hispanics was low, and that the abnormalities seen were suspicious for underlying Lynch syndrome. Similar to our study, germline testing for confirmation was precluded by the retrospective nature of the study. Overall, in considering other studies the estimated prevalence of MSI CRC found in our study is similar to the 7 to 13% prevalence reported in population-studies from Italy, Spain, and other parts of the US1–3, 15, 16
, but lower than the 20% prevalence reported in a previous large US study17
, suggesting that our reported prevalence is similar to non-Hispanic populations. Interestingly, 10 of 11 subjects with MSI had clinical and/or molecular characteristics that raise suspicion for Lynch syndrome, suggesting that sporadic MSI may be uncommon among Hispanics. The one exception was an individual most likely to have sporadic MSI secondary to hypermethylation associated with age and type of MMR abnormality, as he was age 81 at diagnosis with abnormal MLH1 and PMS2 expression18
. If true, a low prevalence of CRC attributable to sporadic MSI among Hispanics may be explained by a lower frequency of exposure (or resistance to) environmental carcinogens, or a lower frequency of a genetic predisposition to develop the alterations that result in sporadic MSI CRC in the non-Hispanic population.
Our findings may have implications for clinical care and future research. While adaptation of universal screening for MSI and Lynch syndrome for all individuals with CRC is under debate on a national level19, 20
, on a local level, if the prevalence of MSI CRC is indeed 10%, then universal screening may be worthwhile, as identification of individuals with MSI may result in more optimized surgical care, planning of post-resection surveillance, and family risk counseling, and help reduce disparities between Hispanics and Whites in CRC survival21, 22
. Indeed, while survival was not statistically significantly different between Hispanic individuals with MSI and MSS CRC in our study, the curves are clearly divergent and approach significance (). We postulate that with a larger sample size, the favorable survival observed for individuals with MSI as compared to those with MSS CRC in other studies may have been observed, extending the potential importance of MSI testing for prognosis and management of Hispanic individuals with CRC. From a research perspective, if the prevalence of sporadic MSI CRC is indeed low, comparative studies of environmental and lifestyle factors between Hispanic and non-Hispanic individuals may offer insight into exposures that may be important to the development of sporadic MSI CRC. For example, our findings may reflect lower exposure to “Western” lifestyle factors associated with MSI CRC, such as tobacco 2, 4, 23, 24
, that may be less prevalent but increasing over time and across generations among Hispanics in the United States25–27
. Further study of these factors and others is warranted, particularly if the prevalence of sporadic MSI is low.
We recognize several potential limitations to our findings and conclusions. First, due to the retrospective nature of our study, detailed family history and pedigree data were not available for analyses, and blood samples for sequencing to identify germline mutations in MMR genes were not obtainable. We can therefore only speculate as to whether the MSI cases identified were a result of hereditary or acquired genetic changes. It is well known that while the Bethesda criteria and presence of abnormal MMR expression are associated with increased likelihood of Lynch syndrome, the specificity of these characteristics are suboptimal, and thus insufficient to make definitive conclusions regarding the presence/absence of Lynch syndrome among our MSI cases 16
. Second, neither the country of origin, nor birth generation relative to immigration to the US was available. It has been observed that CRC incidence is highly modified by degree of industrialization and country of origin presumably due to country specific differences in lifestyle and environmental risk factors 28
. If risk for MSI CRC differs by country of origin based up on diet, lifestyle, or hereditary risk, it is possible that our findings are not generalizeable to all individuals of Hispanic origin living in the US. Third, Parkland Memorial Hospital serves a disproportionate number of uninsured patients in the Dallas area, perhaps resulting in selection bias towards a younger population with CRC. Sporadic MSI is generally associated with an age at presentation above 65, when the likelihood of access to insurance is higher in the US, while Lynch syndrome related MSI CRC is more common among younger individuals who may be more likely to be uninsured and present to Parkland if residing in Dallas County 29
. This may have resulted in under-estimation of the prevalence of sporadic MSI (and perhaps overall MSI), and over-estimation of the prevalence of suspected hereditary MSI CRC. Fourth, identification of individuals of Hispanic ethnicity was based on retrospective review of demographic data collected through the course of usual clinical care, perhaps leading to decreased sensitivity or specificity for identifying individuals of Hispanic origin with CRC through our tumor registry. Finally, direct comparisons to non-Hispanic whites and African-Americans were not performed; therefore, prevalence relative to these groups could not be assessed.
The strengths of our study include the use of a large, comprehensive, American College of Surgeons certified cancer registry to identify cases that resulted in a large sample size, analysis of MSI in all cases, analysis for abnormal MMR expression in nearly all cases, and abstraction of detailed clinical information from clinical and cancer registry records. Extensive efforts were taken to include every potential case, without bias towards selection from the potential study pool.
In conclusion, the prevalence of MSI CRC among Hispanic individuals may be similar to other races and ethnicities, but clinical and molecular characteristics, including age at diagnosis and type of abnormal MMR protein expression, suggests that sporadic MSI may be less common in individuals of Hispanic ethnicity, and that much MSI observed in this situation may be attributable to Lynch syndrome. Further exploration of the causes of disparate disease presentations of CRC by ethnicity and race, including characterization of sporadic and hereditary MSI, is warranted.