Research Article - Journal of Gastroenterology and Digestive Diseases (2018) Volume 3, Issue 2
Racial difference in DNA mismatch repair deficiency associated with Lynch syndrome among colorectal cancer patients.
- *Corresponding Author:
- Yize R. Wang, MD, PhD
Division of Gastroenterology and Liver Diseases
Department of Medicine
Cooper Medical School of Rowan University
Cooper Digestive Health Institute
501 Fellowship Road, Suite 101, Mount Laurel, Camden, NJ-08054, USA
Tel: (856) 642-2133
E-mail: [email protected]
Accepted on March 28, 2018
Citation: Contino K, Irons FR, Behling CK, et al. Racial difference in DNA mismatch repair deficiency associated with Lynch syndrome among colorectal cancer patients. J Gastroenterol Dig Dis. 2018;3(2):38-40.
Introduction: Lynch syndrome accounts for approximately 3% of all colorectal cancers (CRC) in the United States. African American (AA) patients are at a higher risk for CRC and diagnosed at a younger age and more advanced stage. The prevalence of LS among AAs has not been well studied. We hypothesized that AAs differ from non-Hispanic Whites (NHWs) in the prevalence of CRC secondary to DNA mismatch repair (MMR) deficiency.
Methods: We retrospectively studied 91 CRC patients screened for MMR deficiency between 03/2014 and 03/2016 at our institution. Immunohistochemistry staining was used to examine expression of MLH1, MSH2, MSH6 and PMS2. The Student’s t-test, chi-square test, and Fisher’s exact test were used in statistical analysis.
Results: Compared to NHW patients (n=68), AA patients (n=23) trended toward younger age (mean ± standard deviation [SD]: 54.0 ± 13.6 vs. 59.3 ± 10.7 years, p=0.06) and tumor location in the right colon (56.5 vs. 36.9%, p=0.10) and were similar in percentage of female patients, body mass index, and TNM stage. Among NHWs, 8 (11.7%) had loss of MLH1/PMS2, 1 (1.5%) had loss of MSH2/MSH6, and 1 (1.5%) had loss of PMS2 only. In contrast, all AAs had intact MMR protein expression. The difference in MMR deficiency between NHW (14.7%) and AA (0%) patients was statistically significant (p<0.05).
Conclusion: We found that the rate of MMR deficiency is lower in AA CRC patients compared to NHW patients. This finding warrants further study as it has significant implications for Lynch Syndrome screening in AA patients.
Colorectal cancer, Lynch syndrome.
Identification of DNA mismatch repair (MMR) deficiency has become particularly important in the diagnosis and treatment of colorectal cancer and more recently an even broader spectrum of tumors [1-4]. Originally identified as an indicator of Lynch Syndrome, MMR status also has prognostic significance for treatment [5-7]. CRC patients with high microsatellite instability tumors, a molecular hallmark of MMR deficiency, have longer survival times than those without high microsatellite instability [8-11].
Several MMR proteins are involved, including MLH1, MSH2, MSH6 and PMS2 . In CRC, MMR deficiency is seen in approximately 15% of patients, with most cases due to acquired loss of MLH1 expression caused by methylation of the MLH1 promotor. In about 3% of CRC patients, MMR deficiency is due to inherited mutations or Lynch Syndrome. Historically, patients were selected for screening for Lynch syndrome based on clinico-pathologic criteria, including the Amsterdam and Bethesda criteria [13-15]. Due to the poor sensitivity of these criteria and ready availability of immunohistochemical staining, many institutions have moved to universal or near universal screening protocols.
In the United States, African Americans (AAs) have the highest rate of CRC followed by non-Hispanic whites (NHWs) and Hispanics . AA patients are diagnosed at a younger age and more advanced stage, contributing to worse outcomes. The prevalence of MMR deficiency among AA CRC patients has not been well studied . In this study, we aimed to compare the rates of MMR deficiency between AA and NHW patients diagnosed with CRC at our institution.
This study was approved by the Institutional Review Board at Cooper University Hospital in Camden, New Jersey, USA. We performed a retrospective chart review of 106 consecutive patients (none from the same family) who underwent CRC resection and were screened for MMR deficiency between March 2014 and March 2016 at our institution. Patients with familial adenomatous polyposis or inflammatory bowel disease were excluded. Indications for MMR deficiency testing at the time of the study were age ≤ 70 at the time of CRC diagnosis (with the primary goal of Lynch syndrome screening) or stage II CRC irrespective of age (with the intent of providing guidance for adjuvant treatment decisions). The 15 patients with other race/ethnicity (4 Asians, 11 Hispanics) were excluded from the final study sample because their number was too small for statistical analysis.
Immunohistochemical testing for MLH1, MSH2, MSH6, and PMS2 was performed by a reference laboratory and interpreted at Cooper University Hospital. In addition to patient race and MMR deficiency status, age, sex, body mass index, CRC location (right vs. left colon [including rectum]), and TNM stage were collected from the electronic medical record system. The Student’s T-test, chi-square test, and Fisher’s exact test were used in statistical analysis (SAS Version 9.4, Cary, NC).
Compared to NHW patients (n=68), AA patients (n=23) trended toward younger age (mean ± standard deviation [SD]: 54.0 ± 13.6 vs. 59.3 ± 10.7 years, p=0.06) and more right colon cancer (56.5 vs. 36.9%, p=0.10) and were similar in percentage of female patients, body mass index, and TNM stage (Table 1).
|Variables||Non-Hispanic White (n=68)||African American (n=23)||P-value|
mean (standard deviation)
|59.3 (10.7)||54.0 (13.6)||0.06|
|Body Mass Index, mean (standard deviation)||29.7 (7.9)||28.8 (7.0)||0.66|
|Right Colon (vs. Left Colon/ Rectum), %||36.9||56.5||0.10|
|TNM Stage III or IV (vs. I or II), (%*)||72.1||73.9||0.86|
Notes: *There were 3 NHW patients without information on TNM stage
Table 1. Patient characteristics by race.
Among NHW patients, 8 (11.7%) had loss of MLH1/PMS2, 1 (1.5%) had loss of MSH2/MSH6, and 1 (1.5%) had loss of PMS2 only (Table 2). In contrast, all AAs had intact MMR protein expression. The difference in overall MMR deficiency between NHW (14.7%) and AA (0%) patients was statistically significant (p<0.05).
|Variables||Non-Hispanic White (n=68)||African American (n=23)||P-value|
|Loss of MLH1/PMS2, %||11.7||0||0.09|
|Loss of MSH2/MSH6, %||1.5||0||0.75|
|Loss of PMS2 only, %||1.5||0||0.75|
|MMR deficiency, %||14.7||0||0.045|
Notes: The Fisher’s exact test was used in the above analyses comparing NHW and AA patients.
Table 2. DNA mismatch repair (MMR) deficiency by race.
Comparing AA and NHW CRC patients at our institution, we found that the rate of MMR deficiency was significantly lower in AA patients. This finding is interesting considering that the AA patients were slightly younger and tended to have more right-sided CRCs. In fact, none of the 23 AA patients had MMR deficiencies, although we would expect 3 AA patients to test positive if their rate of MMR deficiency is similar to that of NHW patients (10 out of 68). In contrast, the NHW rate of MMR deficiency and the predominance of MLH1/PMS2 loss for NHW patients at our institution are similar to previous studies [1,10,17-19], confirming the compatibility and validity of our MMR deficiency test.
The current literature on racial difference in MMR deficiency is limited. The rate of MMR deficiency was reportedly similar in Latino patients compared to patients of European descent [17- 19]. Different from our study, one study of 253 CRC patients showed that the rate of MMR deficiency was similar among AA, NHW and Hispanics in the Miami area , while another study of 25 young (≤ 40 years) Jamaican CRC patients showed a higher rate of microsatellite instability and Lynch syndrome compared to previous studies . It is possible that the genetic risk factors for CRC are different for AA patients at our institution in the Northeast compared to those in Miami (South) and Jamaica (Caribbean), or that most of the CRCs in AAs at our institution are due to non-genetic or environmental factors.
The major limitation of our study is the small sample size of AA and other minority patients, and the latter group was excluded from this study. The 10 patients tested positive for MMR deficiency were recommended to undergo genetic testing for Lynch Syndrome (either at our institution or locally), but their genetic testing results were not available to us. Our small sample size would preclude a comparison of Lynch Syndrome diagnosis between NHW and minority patients.
In conclusion, we found that the rate of MMR deficiency is lower in AA CRC patients compared to NHW patients at our institution. This finding warrants further study as it has significant implications for Lynch Syndrome screening in AA patients. We found that the rate of MMR deficiency is lower in AA CRC patients compared to NHW patients. This finding warrants further study as it has significant implications for Lynch Syndrome screening in AA patients.
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