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Keywords:

  • colorectal neoplasms;
  • Hispanic Americans;
  • genomic instability;
  • microsatellite instability;
  • DNA mismatch repair

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

Although the presence of microsatellite instability (MSI) in patients with colorectal cancer (CRC) may have implications for prognosis, therapy, and family counseling, to the authors' knowledge, the prevalence of MSI has not been well described among individuals of Hispanic origin with CRC residing in the United States.

METHODS:

A retrospective cohort study using a hospital-based tumor registry to identify individuals of Hispanic origin who were diagnosed with CRC was conducted. Clinical data and tumor samples were retrieved. Molecular analyses included testing for MSI using a panel of 5 mononucleotide markers (BAT25, BAT26, NR21, NR24, and NR27) in a pentaplex polymerase chain reaction assay, as well as immunohistochemistry for the mismatch repair (MMR) proteins mutL homolog (MLH) 1, mutS homolog (MSH) 2, MSH6, and postmeiotic segregation increased 2 (PMS2) 2 on representative tissue.

RESULTS:

A total of 111 individuals of Hispanic origin with CRC were identified. Approximately 41.4% were women, and the median age was 57 years (interquartile range [IQR], 47.1-63.5 years). Eleven patients (9.9%; 95% confidence interval [95% CI], 4.2%-15.6%) had MSI CRC, whereas 14 patients (12.6%; 95% CI, 7.3%-21.8%) had CRC with ≥1 MMR protein abnormality. Ten of 11 individuals with MSI had clinical or molecular characteristics suspicious for Lynch syndrome such as abnormal expression of MSH2 and/or MSH6 (n = 7) or age <50 years at the time of diagnosis (n = 7).

CONCLUSIONS:

The prevalence of MSI CRC among Hispanic individuals may be similar to that of other races and ethnicities, but clinicopathological characteristics, including age at diagnosis and pattern of abnormal MMR protein expression, suggest that sporadic MSI CRC may be less common in individuals of Hispanic origin, and that much of the MSI observed in this situation may be attributable to Lynch syndrome. Further exploration of the causes of disparate presentations of CRC by ethnicity and race is warranted. Cancer 2010. © 2010 American Cancer Society.

Approximately 7% to 14% of colorectal cancer (CRC) is associated with microsatellite instability (MSI).1-4 MSI is due to either acquired (sporadic MSI) or inherited (Lynch syndrome) defects in DNA mismatch repair (MMR) mechanisms. Knowledge of MSI CRC may have clinical implications for prognosis, therapy, and family counseling. Individuals with MSI CRC may have more favorable survival compared with those with microsatellite stable (MSS) CRC, and require more tailored clinical care.1, 5-8 The prevalence of MSI CRC has been described among white and African American individuals in the United States.2, 4, 9 However, to our knowledge, the prevalence of MSI among individuals of Hispanic origin in the United States has not been well described. CRC is the third leading cause of cancer death among Hispanic men and women, accounting for 16.1 deaths per 100,000 men and 10.7 deaths per 100,000 women, rates that are somewhat lower than those reported for non-Hispanic men and women.10, 11 Given the significant burden of CRC among Hispanics, the scarcity of data regarding MSI among Hispanics with CRC, and the emerging importance of MSI status in the clinical management of patients with CRC, the prevalence of MSI among individuals of Hispanic origin requires further characterization.1, 5-8 In the current study, we hypothesized that the prevalence of MSI and MMR protein abnormalities among Hispanic individuals with CRC may play a role in the clinical presentation of patients of this ethnicity. Therefore, the primary aim of the current study was to examine the prevalence and clinical presentation of MSI CRC in a series of individuals of Hispanic origin diagnosed and/or treated for CRC at a large, urban hospital in the United States.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Study Subjects and Materials

Study subjects were identified by using a hospital-based, American College of Surgeons-certified tumor registry at Parkland Memorial Hospital, a large, urban county hospital serving residents of Dallas County, Texas. Included study subjects were of Hispanic origin, with a primary adenocarcinoma of the colon or rectum diagnosed and/or treated at Parkland Memorial Hospital at any time between 1997 and 2007, with sufficient archived, paraffin-embedded tissue for MSI analysis. Hispanic ethnicity was designated based on ethnicity recorded in the demographic section of the medical record through the course of usual medical care. It is our observation that at Parkland Memorial Hospital, Hispanic ethnicity is generally assigned to individuals whose primary language is Spanish, or whose family origin is from Mexico or any country in Central America, South America, or those areas of the Caribbean in which the primary spoken language is Spanish. Subjects were excluded if sufficient tissue for MSI analysis was not available, if the primary cancer was not adenocarcinoma of the colon, if the cancer was recurrent rather than diagnosed at the time of first presentation, or for the presence of a known genetic cancer syndrome other than Lynch syndrome. Clinical data, including age, sex, Surveillance, Epidemiology, and End Results (SEER) summary stage, date/survival status at time of last contact, and right-sided CRC location (defined as proximal to the descending colon), as well as archived, paraffin-embedded tumor samples were retrieved. Pedigrees were not routinely generated as part of usual clinical care, and therefore detailed family history data were not available. Histology of the primary tumor was re-reviewed by a dedicated pathologist for the presence of characteristics consistent with MSI, including histological type, degree of differentiation, tumor-infiltrating lymphocytes, and a Crohn-like lymphocytic reaction.12 The study was approved by the University of Texas Southwestern Medical Center Institutional Review Board.

Molecular Analyses for MSI and Abnormal MMR Protein Expression

After microdissection and capture of representative CRC tissue, MSI analyses were performed using a panel of 5 mononucleotide markers (BAT25, BAT26, NR21, NR24, and NR27) in a pentaplex polymerase chain reaction assay as described previously.13 Mutations of ≥2 markers as positive were considered evidence of MSI.

All immunostaining was performed at room temperature on the Dako Autostainer (DakoCytomation, Carpinteria, Calif). Reagents were used as supplied in the Mach 4 Universal HRP-Polymer Kit (BioCare Medical, Walnut Creek, Calif). BioCare Diva (pH 6.6) was used. Optimum primary antibody dilutions were predetermined using known positive control tissues. A known positive control section was included in each run to ensure proper staining. Antibody dilutions were as follows: mutL homolog (MLH) 1, 1:600 (G168-728; BD Pharmigen, Franklin Lakes, NJ); MLH2, 1:800 (FE11; BD Pharmigen); mutS homolog (MSH) 6, 1:800 (GTBP; BD Transduction Laboratories, Franklin Lakes, NJ); and postmeiotic segregation (PMS) 2, 1:150 (A16-4; BD Sciences, Franklin Lakes, NJ). Paraffin sections (5 μm) were cut on a rotary microtome, mounted on positively charged glass slides (Superfrost; Fisher Scientific, Pittsburgh, Pa), and baked for 1 hour at 65°C. Sections were then deparaffinized in xylene followed by ethanol and then placed in 200 mL of BioCare Diva (pH 6.6). The buffer was brought to 95°C for 40 minutes. Sections were allowed to cool in buffer for 5 minutes, and then rinsed in deionized water. The sections were then loaded onto the Dako Autostainer. Sections were first quenched with 3% hydrogen peroxide for 5 minutes, rinsed in buffer, and incubated with primary antibody at the concentrations highlighted earlier. After washing of the primary antibody, sections were incubated for 15 minutes in BioCare Mach 4 Mouse Probe, rinsed in buffer, and then incubated for 15 minutes in the MR HRP-Polymer Kit. After rinsing in buffer, the sections were then incubated in a freshly prepared mixture of diaminobenzidine and buffer substrate solution for 5 minutes. Sections were then counterstained with hematoxylin and blued in bluing reagent (Richard-Allan Scientific, Kalamazoo, Mich), dehydrated in a graded series of ethanols and xylene, and coverslipped. Slide analysis was performed on the Automated Cellular Imaging System (Dako Corporation, Carpinteria, Calif) by choosing 10 random tumor fields to determine the percentage of positive tumor cells and the intensity of staining. For primary analyses, a staining expression of <10% positive cells or a staining intensity of <2 for any proteins was considered evidence of abnormal (decreased) protein expression.

Statistical Analyses

Descriptive statistical calculations, including means (and medians when data were non-normally distributed) were performed. Chi-square tests (or Fisher exact tests for comparisons with <5 observations for cells) were used for comparisons of proportion. Survival analyses, comparing individuals with MSI with those with no evidence of MSI (MSS) were performed, censoring individuals at the time of last follow-up or death. Although family history data were not available for analyses, we assessed whether cases with MSI and/or abnormal expression of an MMR protein were suspicious for Lynch syndrome based on clinical or molecular characteristics more likely to be associated with Lynch syndrome rather than sporadic MSI CRC, such as an age at presentation of <50 years, the presence of abnormal MSH2 and/or MSH6 expression, and synchronous CRC. All analyses were performed with STATA 9.0 statistical software (StataCorp, College Station, Tex).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Of a total of 933 individuals of all races and ethnicities with a colon or rectal neoplasm diagnosed and/or treated at Parkland Memorial Hospital between 1997 and 2007, we identified 161 potential study subjects who were of Hispanic origin (Fig. 1). A total of 50 subjects were excluded for the reasons highlighted in Figure 1; the most common reasons for exclusion were the presence of a nonprimary adenocarcinoma (n = 24 subjects) such as anal carcinoma, and the absence of tissue for analysis (n = 22 subjects), usually because of pathologic diagnosis at another facility. Thus, 111 individuals with primary adenocarcinoma of the colon or rectum and sufficient tissue for MSI analyses were included for analysis. The median age of the cohort was 57 years and approximately 41.4% of subjects were women (n = 46) (Table 1). Approximately 32% of the subjects were aged <50 years at the time of diagnosis (n = 36). Nearly 68% presented with SEER summary stage regional or distant CRC (n = 75 subjects). Greater than half of the study subjects were alive at the time of last follow-up. The median follow-up time ranged from >9 months for those subjects who had died at the time of last follow-up to nearly 54 months for those still alive at the time of last follow-up.

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Figure 1. Study flow is shown. A total of 161 patients of Hispanic origin with a neoplasm of the colon or rectum who were diagnosed and/or treated at Parkland Memorial Hospital at any time between 1997 and 2007 were identified. Fifty patients were excluded from analysis, leaving 111 patients with a primary adenocarcinoma of the colon or rectum for study. The prevalence of microsatellite instability (MSI) in colorectal cancer (CRC) in this cohort was 9.9%. 95% CI indicates 95% confidence interval; MSS, microsatellite stable CRC.

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Table 1. Characteristics of Individuals of Hispanic Ethnicity Diagnosed With and/or Treated for CRC at Parkland Memorial Hospital, 1997-2007
CharacteristicValue
  1. IQR indicates interquartile range; SEER, Surveillance, Epidemiology, and End Results.

Women, % (no.)41.4(46)
Median age (IQR), y56.7(47.1-63.5)
SEER summary stage, % (no.)  
 In situ1.8(2)
 Localized27.9(31)
 Regional44.1(49)
 Distant23.4(26)
 Unknown2.7(3)
Alive at last follow-up, % (no.)53.2(59)
Median follow-up (IQR), mo30.6(8.1-67.9)
 Among individuals alive at last follow-up53.8(30.2-78.2)
 Among individuals who had died at last follow-up9.5(4.5-28.7)

The prevalence of MSI in the study cohort was 9.9% (n = 11 subjects; 95% confidence interval [95% CI], 4.2%-15.6%) (Fig. 1). The top and bottom panels in Figure 2 depict examples of subjects with abnormal expression of MMR proteins. The prevalence of the abnormal expression of at least 1 MMR protein among all 111 individuals in the cohort was 12.6% (n = 14 individuals; 95% CI, 7.3%-21.8%). All individuals with MSI CRC were found to have abnormal MMR protein expression by immunohistochemistry (IHC), whereas 3.5% of individuals with MSS CRC had abnormal IHC findings (Table 2). Fifteen individuals had incomplete analysis for all 4 MMR proteins because of technical limitations. Histology suggestive of MSI was present in 36.9% of the study cohort (n = 41 subjects; 95% CI, 27.8%-46.1%), and 5 of the 11 MSI CRC cases had histology suspicious for MSI. MSI CRC was associated with age <50 years and right-sided tumor location within the colon, but not female gender or MSI-type histology, although point estimates for odds ratios were consistent with an association with these factors as well (Table 3). Survival appeared to be more favorable among individuals with MSI, although this finding did not achieve statistical significance (P = .11, log-rank test for equality of survivor functions) (Fig. 3).

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Figure 2. Mismatch repair (MMR) protein expression as shown by immunohistochemistry (IHC) for 2 subjects. Top panels depict a subject with abnormal expression of mutL homolog (MLH) 1 and postmeiotic segregation (PMS) 2 proteins and normal expression of mutS homolog (MSH) 2 and MSH6 proteins. Bottom panels depict a subject with normal expression of MLH1 and postmeiotic segregation (PMS) 2 proteins and abnormal expression of MSH2 and MSH6 proteins.

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Table 2. Summary of Molecular Analyses for MSI and Abnormal MMR Protein Expression Among Hispanic Individuals With CRC Diagnosed and/or Treated at Parkland Memorial Hospital 1997-2007a
Analysis ResultMSIMSSTotal
  • MSI indicates microsatellite instability; MMR, mismatch repair; CRC, colorectal cancer; MSS, microsatellite stability; IHC, immunohistochemistry.

  • a

    A total of 15 patients were missing complete data for expression of all 4 MMR proteins.

  • b

    Fisher exact test: P < .001 for MSI vs MSS.

Normal IHC for MMR08282
Abnormal IHC for MMR11314
Total118596
Proportion with abnormal IHCb100%3.5% 
Table 3. Association Between Clinical and Pathological Characteristics and MSI CRC Among Hispanic Individualsa
CharacteristicMSI (%)MSS (%)ORP
  • MSI indicates microsatellite instability; CRC, colorectal cancer; MSS, microsatellite stability; OR, odds ratio.

  • a

    The Fisher exact test was performed for all comparisons.

  • b

    Right-sided was defined as proximal to the descending colon.

  • c

    Based on histological type, degree of differentiation, tumor-infiltrating lymphocytes, or Crohn-like lymphocytic reaction.12

Gender    
 Male8 (72.7)57 (57.0) 
 Female3 (27.3)43 (43.0)0.50 (0.08-2.24).36
Age, y    
 <507 (63.6)29 (29.0) 
 ≥504 (36.4)71 (71.0)0.23 (0.04-1.01).04
CRC locationb    
 Left-sided CRC4 (36.4)76 (76.0) 
 Right-sided CRC7 (63.6)24 (24.0)5.54 (1.26-27.6).01
MSI-type histologyc    
 Not present6 (54.5)64 (64.0) 
 Present5 (45.5)36 (36.0)1.48 (0.33-6.27).53
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Figure 3. Survival by microsatellite instability (MSI) status is shown. Survival was determined by annual review of the medical records and contacting of patients (or families) by the Parkland Memorial Hospital Cancer Registry staff. A nonsignificant trend toward favorable survival among individuals with MSI colorectal cancer (CRC) compared with those with microsatellite stable (MSS) CRC was observed (P = .11, log-rank test for equality of survivor functions). Tick marks indicate subject death.

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A summary of clinical and molecular characteristics in specific subjects with MSI is shown in Table 4. Seven of the 11 subjects were aged <50 years at the time of diagnosis, 7 had abnormal expression of MSH2 and/or MSH6, and 4 of the 11 specific individuals were aged <50 years with abnormal expression of MSH2 and/or MSH6. Two individuals had synchronous CRC, although 1 of these individuals was aged 81 years. Characteristics of the 3 subjects with normal MSI testing and abnormal MMR protein expression are summarized in Table 5. A detailed review suggested that MSI testing may have been falsely negative because of the presence of a very small tumor in 1 case; no clear reason for false-negative MSI testing (or false-positive IHC) could be found for the other 2 cases.

Table 4. Summary of Clinical and Molecular Characteristics of Individuals of Hispanic Ethnicity with MSI CRC (n = 11)
Age, YearsSexProximal TumorAbnormal ExpressionSuspicious for Lynch Syndrome?
MLH1MSH2MSH6PMS2
  • MSI indicates microsatellite unstable; CRC, colorectal cancer; Proximal Tumor, proximal to descending colon; MLH, mutL homolog; MSH, mutS homolog; PMS, postmeiotic segregation.

  • a

    Age <50 years.

  • b

    Abnormal expression of MSH2 and/or MSH6.

  • c

    Synchronous CRC.

44ManNoYesNoNoYesYesa
47ManNoNoNoYesNoYesab
67ManYesNoYesYesNoYesb
59WomanNoNoNoYesNoYesb
33ManNoYesNoNoYesYesa
45ManYesYesNoNoYesYesa
43ManYesNoYesYesNoYesab
81ManYesYesNoNoYesNoc
38ManYesNoYesYesNoYesabc
59WomanYesNoYesYesNoYesb
36WomanYesNoYesYesNoYesab
Table 5. Summary of Clinical and Molecular Characteristics of Individuals of Hispanic Ethnicity With Abnormal Expression of DNA MMR Proteins but MSS CRC (n = 3)
Age, YearsSexProximal TumorAbnormal ExpressionSuspicious for Lynch Syndrome?
MLH1MSH2MSH6PMS2
  • MMR indicates mismatch repair; MSS, microsatellite stable; CRC, colorectal cancer; Proximal Tumor, proximal to descending colon; MLH, mutL homolog; MSH, mutS homolog; PMS, postmeiotic segregation.

  • a

    Abnormal expression of MSH2 and MSH6.

61ManNoNoYesYesNoYesa
72WomanYesYesNoNoYesNo
78ManNoYesNoNoYesNo

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

The results of the current study demonstrate that the prevalence of MSI among individuals of Hispanic origin with CRC diagnosed at a large, urban county hospital in the United States is approximately 10%. Data from a comparable study from Puerto Rico are consistent with these findings. De Jesus-Monge et al evaluated the prevalence of abnormal IHC results for the MMR proteins MLH1 and MSH2 among 164 individuals in Puerto Rico.14 The prevalence of the abnormal expression of either MLH1 or MSH2 was 4.3%, but IHC for PMS2 and MSH6 was not performed, and MSI testing was restricted to those subjects with abnormal IHC findings, perhaps leading to an underestimation of CRC attributable to MMR protein dysfunction. The single patient with abnormal IHC results for MLH1 had MSI but normal testing for a BRAF V600E mutation. Consistent with the results of the current study, the pattern of molecular abnormalities suggested that the prevalence of sporadic MSI among Hispanics was low, and that the abnormalities observed were suspicious for underlying Lynch syndrome. Similar to our study, germline testing for confirmation was precluded by the retrospective nature of the study. When considering other studies, the estimated prevalence of MSI CRC found in the current study is similar to the prevalence of 7% to 13% reported in population-based studies from Italy, Spain, and other parts of the United States,1-3, 15, 16 but lower than the prevalence of 20% reported in a previous large US study,17 suggesting that our reported prevalence is similar to that of non-Hispanic populations. It is interesting to note that 10 of 11 subjects with MSI had clinical and/or molecular characteristics that raised suspicion for Lynch syndrome, suggesting that sporadic MSI may be uncommon among Hispanics. The 1 exception was an individual considered most likely to have sporadic MSI secondary to hypermethylation associated with age and type of MMR abnormality, because he was aged 81 years at the time of diagnosis with abnormal MLH1 and PMS2 expression.18 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.

The findings of the current study may have implications for clinical care and future research. The adaptation of universal screening for MSI and Lynch syndrome for all individuals with CRC is currently a matter of debate on a national level.19, 20 However, on a local level, if the prevalence of MSI CRC is indeed 10%, then universal screening may be worthwhile because the identification of individuals with MSI may result in more optimized surgical care, planning of post resection surveillance, and family risk counseling. Ultimately, this may help reduce disparities between Hispanic and white individuals with regard to CRC survival.21, 22 Indeed, although survival was not found to be statistically significantly different between Hispanic individuals with MSI CRC and those with MSS CRC in the current study, the curves are clearly divergent and approach statistical significance (Fig. 3). We postulate that with a larger sample size, the favorable survival observed for individuals with MSI CRC compared with those with MSS CRC in other studies may have been observed, extending the potential significance of MSI testing for the 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, the findings of the current study may reflect a 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 States.25-27 Further study of these factors and others is warranted, particularly if the prevalence of sporadic MSI is low.

We recognize several potential limitations to the findings and conclusions of the current study. First, because of the retrospective nature of this 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. Therefore, we can only speculate as to whether the MSI cases identified were a result of hereditary or acquired genetic changes. It is well known that although the Bethesda criteria and the presence of abnormal MMR expression are associated with an increased likelihood of Lynch syndrome, the specificity of these characteristics is suboptimal and thus insufficient to make definitive conclusions regarding the presence/absence of Lynch syndrome among MSI cases in the current study.16 Second, neither the country of origin nor birth generation relative to immigration to the United States were available. It has been observed that the incidence of CRC is highly modified by the degree of industrialization and country of origin, presumably because of country-specific differences in lifestyle and environmental risk factors.28 If risk for MSI CRC differs by country of origin based on diet, lifestyle, or hereditary risk, it is possible that the current study findings are not generalizable to all individuals of Hispanic origin living in the United States. Third, Parkland Memorial Hospital serves a disproportionate number of uninsured patients in the Dallas area, perhaps resulting in selection bias toward a younger population with CRC. Sporadic MSI is generally associated with an age at presentation >65 years, when the likelihood of access to insurance is higher in the United States, whereas Lynch syndrome-related MSI CRC is more common among younger individuals who may be more likely to be uninsured and present to Parkland Memorial Hospital if they reside in Dallas County.29 This may have resulted in an underestimation of the prevalence of sporadic MSI (and perhaps overall MSI), and an overestimation of the prevalence of suspected hereditary MSI CRC. Fourth, the identification of individuals of Hispanic ethnicity was based on a 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 with non-Hispanic white and African-American individuals were not performed; therefore, prevalence relative to these groups could not be assessed.

The strengths of the current 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, the 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 toward selection from the potential study pool.

In conclusion, the prevalence of MSI CRC among Hispanic individuals may be similar to that of other races and ethnicities, but clinical and molecular characteristics, including age at diagnosis and type of abnormal MMR protein expression, suggest that sporadic MSI may be less common in individuals of Hispanic ethnicity, and that much of the MSI observed in this instance 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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

We thank Darnetta Miles and the staff at the Parkland Memorial Hospital Clinical Pathology Service as well as the staff at the Parkland Memorial Hospital Cancer Registry for assistance with obtaining study data and materials.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Supported by an American Cancer Society Institutional Research Grant to the University of Texas Southwestern Medical Center (ACS-IRG-02-196), as well as National Institutes of Health grant 1 KL2 RR024983-01 (“North and Central Texas Clinical and Translational Science Initiative”) (Milton Packer, MD, Principal Investigator) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or NIH. Information regarding the NCRR is available at http://www.ncrr.nih.gov/. Information regarding Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp. Additional support was provided by NIH grant R01 CA72851-15 (“Familial and Early Onset Colorectal Cancer”) (C. Richard Boland, MD, Principal Investigator), and NIH grant R01 CA129286 (Ajay Goel, PhD, Principal Investigator).

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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