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A study on the frequency and clinicopathological correlates of mismatch repair-deficient colorectal cancer


 Department of Medical Oncology, Father Muller Medical College and Hospital, Mangalore, Karnataka, India

Correspondence Address:
Nishitha Shetty,
Department of Medical Oncology, Father Muller Medical College and Hospital, Father Muller Road, Kankanady, Mangalore - 575 002, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_526_18

 > Abstract 


Introduction: Microsatellite instability is an important pathway of tumorigenesis in colorectal cancer, and there is a need to understand its genetic and phenotypic profile. This study aimed to study the occurrence of deficient mismatch repair (dMMR) in an Indian cohort of patients and document the corresponding clinicopathological correlates.
Materials and Methods: This is a retrospective study of patients admitted between January 2016 and December 2017. dMMR data from immunohistochemistry reports were correlated with histopathological data and demographic details. The data were then analyzed in terms of means and percentages.
Results: About 29% of cases were found to be dMMR and 66.7% of dMMR tumors occurred in males. About 44.4% of dMMR tumors occurred in the ascending colon. MSH2 loss was seen in 44.4% of cases while MLH1 loss was seen in 33.3%, and there were two cases with loss of PMS1.
Conclusions: dMMR tumors in our study were more common in males, presented earlier, were bulky, were less likely to show lymphovascular or perineural invasion, had lower preoperative carcinoembryonic antigen levels, and yielded high number of lymph nodes. Expected differences in age, stage, and grade were not observed. Compared to other studies, a higher proportion of cases in our study had MSH2 and PMS2 loss.

Keywords: Colorectal cancer, comparison, histopathology, microsatellite instability, mismatch repair profile



How to cite this URL:
Rai PR, Shetty N, Rai PR, Shet D, Shetty A. A study on the frequency and clinicopathological correlates of mismatch repair-deficient colorectal cancer. J Can Res Ther [Epub ahead of print] [cited 2019 Nov 21]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=269747




 > Introduction Top


Colorectal cancer is one of the most common cancers globally, being the third most common malignancy in men (10% of all cancers) and the second most common malignancy among women (9.2% of all cancers).[1] The global burden is expected to increase by 60% by 2030 with the incidence increasing in countries as they develop and people adopt more Western lifestyles. The incidence of colorectal cancers varies widely with a 10-fold variation across the world.[2] In India, the incidence of colorectal cancer has consistently been low with its incidence being among the lowest in the world.[3] Alarmingly, multiple studies have shown that diet and environment have more to do with this fact than hereditary predisposition alone.[4],[5] The prevalence of colorectal cancer is on the rise, and the health-care system needs to adapt.[6] Screening colonoscopy is still not being widely advised although it has a proven role in cancer detection.[7] Colorectal cancers detected by screening have better outcomes as it is believed that most carcinomas develop in preexisting adenomas. Although this linear model has been challenged,[8] the fact remains that most of these malignancies arise from two broad pathways: chromosomal instability (CIN) and microsatellite instability (MSI). While CIN affects the APC-Wnt/β catenin pathway and is the underlying mechanism of most malignancies (85% of all cases), MSI is responsible for about 15%–20% of colorectal malignancies.[9],[10] Microsatellite instability has been detected in 15% of spontaneous Colorectal cancer cases. However, in patients with Colorectal cancer secondary to Hereditary Non-Polyposis Colorectal Cancer (HNPCC), microsatellite instability has been detected in 90% of cases.[11]

Microsatellites are repeating tandem base pair sequences that are 1–6 base pairs long which are vulnerable to DNA slippage errors as they are scattered throughout the genome with this risk increasing with sequence length.[12] The most frequent errors associated with MSI include base–base mismatches and insertion–deletion loops which in turn causes frameshift mutations and protein truncation.[13],[14] Certain regions of the genome such as the Type II receptor of transforming growth factor beta 1, insulin-like growth factor-II receptor, and the antiapoptotic BAX are prone to accumulate these errors resulting in neoplastic proliferation.[15],[16],[17] These errors may escape the proofreading activity of DNA polymerase. The MMR proteins form complexes with each other, which then slides along the DNA strand to identify errors which have escaped the proofreading activity of DNA polymerase. Defects in MLH1/MSH2 are associated with loss of expression of PMS2/MSH6 but not vice versa as they are able to form complexes with other minor MMR proteins. It is believed that most cases of loss of expression of MLH1 are a result of epigenetic silencing, due to somatic hypermethylation, which is more common in the elderly while germline inactivation is more common in the young and is responsible for the remaining fraction of cases.[18] MSH2, PMS2, and MSH6 loss are generally due to the germline inactivation. Germline deletion of a part of the epithelial cell adhesion molecule (EPCAM) is associated with methylation of MSH2 which may result in Lynch syndrome.[19]

Microsatellite instability is an early event in tumorigenesis and as a result these tumours tend to be homogenous in terms of gene expression. As a clinical correlate they have certain specific features that set them apart from tumours caused by CIN. Tumours that are a result of microsatellite instability tend to occur in younger patients, are generally located more proximally, they are usually bulky, poorly differentiated, mucin producing, present at a later stage, have intense lymphocytic infiltration, rarely metastasize and remarkably have a better prognosis.[20],[21],[22],[23],[24],[25],[26] Studies on the prevalence of MSI in the Indian populace are lacking, and there is a need to study their specific clinicopathological correlates. A study by Dubey A, Vishwanath S, showed that the incidence of MSI was 22.2% among stage II colorectal cancer. They were found to be more likely to be right sided, occurred in younger individuals with a positive family history and the biopsy usually detected a mucinous adenocarcinoma with a prominent lymphocytic infiltration.[27]

This study aimed to study the proportion of MMR-deficient colorectal cancer cases in an Indian cohort as well as to study their pathological characteristics.


 > Materials and Methods Top


Patient selection

This is a time-bound, retrospective study of patients admitted in a tertiary medical center between January 2016 and December 2017 with Stage I to Stage III colorectal cancer who underwent surgery with curative intent and in whom MMR status was analyzed on the postsurgery tissue blocks. Patients in our center with colorectal cancer are treated as per the National Comprehensive Cancer Network guidelines. MMR testing is done for all patients with Stage I to Stage III colorectal cancer so as to take a call on adjuvant chemotherapy or in those with a strong family history of HNPCC-related malignancies. MMR status testing is done at an independent laboratory using immunohistochemistry (IHC). All demographic details of patients with colorectal cancer who were subjected to MMR status testing were collected. Details of the biopsy report were also collected from the computerized hospital record system.

Definitions

Case

Any patient with biopsy-proven colorectal cancer who meets the inclusion criteria will be considered to be a case. For the purposes of this study, only Stage I to Stage III colorectal cancers were considered.

MMR status was assigned on the basis of IHC testing as below:

  • Deficient MMR (dMMR): Cases showing complete absence of detectable nuclear staining with one or more of the IHC markers tested. Adjacent non-neoplastic* tissue was used as an internal positive control. This group includes those that are classified as MSI-H by polymerase chain reaction (PCR) analysis
  • Proficient MMR (pMMR): No loss of expression detected by immunohistochemistry. Includes cases that are classified as MSI-L and MSS by PCR analysis.


Elevated carcinoembryonic antigen (CEA): Defined as values above 5 ng/ml. Patients were labeled to have synchronous cancer if the second tumor was detected at preoperative screening, at the time of resection of primary, or within 6 months of detection of the primary tumor.

Tumor size was defined as the largest diameter measured along the longitudinal axis.

Tumor location was grouped under the following headings: (1) ascending colon which includes the appendix, cecum, ascending colon, and hepatic flexure, (2) transverse colon between the hepatic flexure and the splenic flexure, (3) descending colon, (4) sigmoid colon, and (5) rectum.

Immunohistochemistry staining

The postsurgery tissue blocks were first fixed in 10% neutral-buffered formalin for 1–2 days. Subsequently, they were subjected to routine dehydration, embedded in paraffin, and routine IHC procedures such as dewaxing, antigen repair, staining, and dehydration and were mounted. Primary antibodies used were anti-MLH1, anti-PSM2, anti-MSH2, and anti-MSH6. Adjacent nonneoplastic tissue was used as an internal positive control. Samples were declared to be negative if they showed complete absence of nuclear staining for that particular antibody. If the sections demonstrated biologically unlikely staining patterns, i.e., MSH2/PMS2, PMS2/MSH6, and MLH1/MSH2, IHC was repeated.

Statistical analysis

All the data were entered and analyzed using Microsoft Excel 2016. Data were analyzed using mean and percentages.


 > Results Top


A total of 31 cases were included in our study. Two cases were excluded as they were diagnosed with Stage IV Colorectal cancer. None of the cases in the study had been diagnosed with HNPCC-related tumors before the presentation. One case in the pMMR group was diagnosed with familial adenomatous polyposis while another case in the pMMR group was diagnosed with T1a clear cell carcinoma of the kidney. In our study, 29% of cases showed dMMR status and 70.96% of tumors were pMMR. There was a definite male preponderance with 66.7% of dMMR tumors detected in males. There was no difference in the mean age of patients with dMMR or pMMR. In general, dMMR tumor harboring patients presented earlier, with mean time to presentation, from symptom onset being 1.8 months. Most dMMR tumors, i.e., 44.4% were proximal to the splenic flexure. None of the dMMR tumors were mucin producing and only one was found to have signet ring cells. The small sample size might have interfered with these findings. As seen in [Table 1], at the time of resection and biopsy, fewer dMMR tumors showed lymphovascular or perineural invasion. Tumor size was also found to be larger at presentation in dMMR tumors with mean size at presentation being 6.3 cm compared to pMMR tumors which had a mean size of 5.3 cm. None of the dMMR tumors were found to have synchronous colorectal cancers. Two of the 22 pMMR cases were found to have synchronous cancers – one of whom had been diagnosed to have familial adenomatous polyposis. As demonstrated by [Table 1], there was no appreciable difference in tumor grade or stage between dMMR and pMMR tumors, possibly due to the small size of the cohort. The mean number lymph nodes harvested in biopsy specimens was 17 in pMMR while it was 19 in dMMR tumors. On evaluating MMR status and preoperative CEA, the proportion of cases with elevated CEA and mean level between the two groups differed. The IHC data was then correlated with CEA levels. The proportion of cases with an elevated CEA as well as the mean level of CEA differed between the two groups. While 45.5% of pMMR tumors had elevated CEA, 22.2% of dMMR tumors had an elevated CEA. In our study, 3 out of the 7 cases of dMMR were due to MLH1/PMS2 loss. Four cases of dMMR were caused by defects in MSH2/MSH6. Two cases were negative for PMS2 on staining, suggesting a germline inactivation of PMS2. The patterns of loss in dMMR cases have been represented in [Table 2].
Table 1: Comparison* of parameters among patients with pMMR and dMMR tumors

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Table 2: Patterns of loss in dMMR cases (n=9) and the likely etiology

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 > Discussion Top


MSI is an important pathway of tumorigenesis as elaborated above. This study hopes to highlight its particular clinicopathological correlates and the specific immunohistochemical patterns in this particular cohort.

In our study, 29% of cases showed dMMR status which is similar to data obtained by Dubey et al. Similar to the study by Dubey et al., there seemed to be a male preponderance. However, other studies elsewhere in the world have shown that dMMR tumors are more common in women.[27],[28],[29],[30] Whether this was an isolated finding due to the small size of the cohorts or whether this truly reflects an inversion in the sex preponderance will need further evaluation. The mean age at diagnosis of dMMR colorectal cancer (CRC) was similar in the two age groups. This study also correlated the MMR status with time to presentation, and this was found to be shorter in dMMR tumors possibly due to the fact that these tumors generally have a larger tumor mass. Although tumors in the right colon are generally detected late, this predisposition for the right colon was only slight in our study, which might explain why they presented earlier. dMMR tumors were slightly more common in the right colon, were less likely to demonstrate perineural or lymphovascular invasion, and were generally bulky. These data are similar to other studies. However, the expected differences in stage and grade were not observed. dMMR tumors were not found to be mucin producing or of medullary type or more likely to harbor signet ring cells. The small size of the cohort coupled with differences in the location of the tumors may have contributed to this finding. Although studies have shown that dMMR tumors are more likely to show synchronous cancers, this was not seen in our study.[31],[32] dMMR tumors were also found to correlate with lower preoperative CEA levels. CEA has a proven role in prognostication of colorectal cancers with lower levels correlating with better outcomes.[33]

It has been suggested that the number of lymph nodes harvested at resection is not a good predictor of prognosis as dMMR tumors are associated with a more aggressive immune response, thereby yielding more lymph nodes despite having a better prognosis. It is believed that dMMR tumors are more likely to elicit a stronger immune response as they are more antigenic. The higher lymph node yield in these cases may represent reactive lymph node changes rather than invasion by tumor cells.[34]

The incidence of MSI decreases with stage of tumor being the highest in Stage II CRC.[35] Comparable results were obtained in our study. MSI in our study was caused by primary MLH1 defects in 33.3% of cases. MLH-1 loss on IHC can result due to promoter methylation, which is more common and occurs in sporadic dMMR CRC. However, germline inactivation must be ruled out by MSI testing. It has been reported that around 71% of cases of sporadic CRC with MLH1 defects arise due to the promoter methylation.[36] Sporadic cases with MLH1 promoter methylation and cases due to the germline inactivation differ in age at presentation and gender predisposition but have similar clinicopathological parameters.[37]

MSH2 mutation occurred in 44.4% of cases, and these are likely to be due to germline inactivation. This percentage is higher than figures obtained by other studies. This difference may have been the result of a higher proportion of cases in our study harboring a germline deletion of MSH2 or an EPCAM deletion. Further, the small sample size in our study might have skewed the results.

Two cases of dMMR were caused by PMS2 mutation which is likely to be due to the germline inactivation. It has been shown that tumors with PMS2 loss are likely to present at an early age due to accelerated tumorigenesis. They have also been shown to occur in fewer female patients, are significantly less likely to be right sided, and have a tendency to be more aggressive.[38] In our study, one case of dMMR with PMS2 loss was detected in a patient who was 19 years old. Both cases with PMS2 loss occurred distal to the splenic flexure. Studies with a larger sample size are needed to correlate the precise behavior with patterns of MSI.

MSI is a mechanism underlying a sizeable proportion of colorectal tumors. Understanding the specific genetic profile and natural history of this subset of CRC will go a long way in furthering treatment of colorectal cancers. In addition, there is a need to analyze data on microsatellite instability in terms of the likely etiology. Hereditary cases are usually a result of germline inactivation, while sporadic cases are often a result of epigenetic silencing. As the mechanisms of loss of expression are different, their responsiveness to therapy may differ. Doing so may also help resolve the contradictory reports on the effectiveness of 5-FU-based therapy in MSI CRC. There is also a need to study the MMR panel in consort with other mutations such as APC, BRAF, KRAS, p53, and PTEN. This approach may help us see the big picture and radically change our approach to this malignancy. The identification of a heterogeneous group of Lynch-like syndromes with no DNA MMR but with reduced MMR protein expression by IHC highlights the fact that as yet unknown mechanisms may be involved in MSI-H phenotype.[39],[40] The development of Poly (ADP-ribose) polymerase inhibitors to be used in patients with MRE11A mutation and the development of anti-PD-1-directed immunotherapy underscores the importance of gaining insight into the pathogenesis of MSI CRC.[41]

The limitations of the study are as follows: as the sample size was small, the data were not subjected to tests for statistical significance as it was believed to be underpowered for the same, with the results unlikely to be representative of the general population. Although IHC is very sensitive and specific for the detection of MSI, it does come with certain drawbacks.[42] The IHC staining pattern may not be uniform throughout the tumor, IHC will be negative for MSH2 staining in the presence of EPCAM deletion, and certain frameshift mutations are associated with truncated protein production with retained antigenicity. Data on results of testing for BRAF V600E, KRAS, MLH1 methylation, and PCR for MSI were not considered which may hamper the interpretation of the results. Cancers of the colon and the rectum were pooled together although their biological behavior and pathological basis are different. Treatment outcomes were not analyzed.


 > Conclusions Top


In our study, approximately one-third of the tumors were dMMR. They were more likely to be male, located in the right colon, bulky, detected at an earlier stage, and less likely to show perineural and lymphovascular invasion. No appreciable differences in age at diagnosis, stage, or grade between dMMR and pMMR tumors were detected. The specific histopathological correlates in our study differed from others, and the IHC pattern showed that a large proportion had MSH2 inactivation, most likely due to either germline inactivation or EPCAM deletion.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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