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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 3  |  Page : 656-660

Microsatellite instability in colon cancer: A single center experience from North India


1 Department of Radiotherapy, Maulana Azad Medical College, Lok Nayak Hospital, New Delhi, India
2 Department of Pathology, Maulana Azad Medical College, GB Pant Hospital, New Delhi, India

Date of Submission22-Mar-2021
Date of Acceptance22-May-2021
Date of Web Publication28-Jan-2022

Correspondence Address:
Narayan Adhikari
Room No 403, House Number 1199K, Sector 38, Gurugram - 122 001, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_423_21

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 > Abstract 


Background: Due to the defects of mismatch repair (MMR) genes MLH1, PMS2, MSH2, and MSH6, the mutations which occur in microsatellite region are not repaired during deoxyribonucleic acid synthesis, leading to microsatellite instability (MSI). MSI is one of the major molecular changes that occur in colorectal carcinoma (CRC). Studies have shown that MMR deficient CRC has different clinicopathological characteristics and a better stage adjusted survival when compared to microsatellite stable tumors.
Materials and Methods: We have retrospectively analyzed the cases of colon cancers treated in our institute for 3 years from 2017 to 2019. Most of the patients underwent surgery and received adjuvant chemotherapy. MSI testing was done in surgical specimen with immunohistochemistry. The clinical details of the patients were tabulated in Microsoft Excel, and statistical analysis was done using IBM SPSS Statistics for Windows, version 21 (IBM Corp., Armonk, NY, USA).
Results: A total of 52 patients who were treated in our institution from 2017 to 2019 were analyzed. The mean age was 46.8 ± 13.5 (19–72) years. The male-to-female ratio was 8:5. No significant association in patient demographics and clinicopathological parameters was observed between MSI stable and unstable disease. However, lymphovascular invasion showed a significantly higher trend in MSI unstable patients (P = 0.052). The median progression-free survival (PFS) of the entire cohort was 27.8 months (95% confidence interval = 22.7–32.9) and the median overall survival (OS) is not reached. The median PFS is 21.3 months in MSI stable patients whereas it is not reached in MSI unstable patients (P = 0.049). The median OS is 27.1 months in MSI stable patients, but it is not reached in MSI unstable patients and the difference shows a trend towards statistical significance (P = 0.061).
Conclusion: MSI unstable tumors were found to have higher PFS and higher OS in our study. It needs prospective validation in larger studies in Indian scenario.

Keywords: Colorectal cancer, microsatellite instability, mismatch repair


How to cite this article:
Arora S, Adhikari N, Rathi AK, Singh K, Sakhuja P. Microsatellite instability in colon cancer: A single center experience from North India. J Can Res Ther 2022;18:656-60

How to cite this URL:
Arora S, Adhikari N, Rathi AK, Singh K, Sakhuja P. Microsatellite instability in colon cancer: A single center experience from North India. J Can Res Ther [serial online] 2022 [cited 2022 Aug 10];18:656-60. Available from: https://www.cancerjournal.net/text.asp?2022/18/3/656/336697




 > Introduction Top


Microsatellites are short tandem repeats of deoxyribonucleic acid (DNA) sequences made by repeating motifs of 2–10 nucleotides. Due to the defects of mismatch repair (MMR) genes MLH1, PMS2, MSH2, and MSH6, the mutations that occur in microsatellite region are not repaired during DNA synthesis which leads to microsatellite instability (MSI). It is one of the major pathways of colorectal carcinogenesis. MSI can be distinguished into three types: high MSI (MSI-H), low MSI (MSI-L), and microsatellite stability (MSS). Currently, clinical research classifies MSI-L and MSS as one kind. In general, MMR deficient tumors (dMMR) is biologically same as MSI-H. Around 10%–20% of colorectal cancer are MMR deficient varying according to the stages.[1] It can be either due to sporadic hypermethylation of the MLH1 promoter or due to germline mutations in MMR genes known as lynch syndrome or hereditary nonpolyposis colorectal cancer. Studies have shown that MMR deficient tumors have a better stage adjusted survival when compared to microsatellite stable tumors.[2] The recent treatment guidelines are also modified according to the MSI.

The objective of this study was to analyze the clinicopathological features and treatment outcomes in colon cancer patients according to the MSI.


 > Materials And Methods Top


All cases of carcinoma colon enrolled between 2017 and 2019 were retrieved from our data base. The data were retrospectively analyzed for patient characteristics and clinical information including tumor location and tumor-node-metastasis (TNM) staging. Information regarding histopathological assessment of the surgical specimen for tumor differentiation, mucin secretion, and presence/absence of perineural and lymphovascular invasion (LVI) was obtained. Microsatellite status was identified by immunohistochemistry. All patients received 5-fluorouracil (5-FU)/Capecitabine and Oxaliplatin-based adjuvant chemotherapy. Patients were regularly followed up with clinical examination, imaging, and serum carcinoembryonic antigen levels to detect recurrence.

In our study, the association of MSI status with clinicopathological characteristics and treatment outcome was analyzed. The clinical details of 52 eligible patients were tabulated in Microsoft Excel and statistical analysis was done using IBM SPSS Statistics for Windows, version 21 (IBM Corp., Armonk, NY, USA). The baseline characteristics between MSI stable and unstable patients were compared using Chi-square test or Fisher's exact test wherever applicable. The survival was analyzed using Kaplan–Meier product limit method and compared between MSI stable and unstable group with log rank test.


 > Results Top


Colon cancer was diagnosed in 52 patients during the 3-year study period. The mean age of the patients was 46.8 ± 13.5 (19–72) years. The male-to-female ratio was 8:5. The patient characteristics are listed in [Table 1].
Table 1: Patient characteristics

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Among 52 patients, six patients had metastatic disease at presentation and did not undergo curative surgery. According to the body mass index (BMI), 34.6% of patients were thin and same number of patients were healthy (34.6%). Few (7.7%) were overweight and 3.8% were obese. Most patients (30.8%) presented in Stage IIIB, followed by IIA (21.2%) and IIIC (17.3%). Among all the patients, 31% of patients were chronic smokers and 21.2% had history of alcoholism. More than half of patients reviewed were nonvegetarians (53.8%). Majority had right-sided tumors (53.8%). Histopathologically, around 69% of tumors had moderate differentiation. MSI status was available in 42 patients, out of which, 27 patients, i.e. 51.9% were MSI stable.

Patient and disease characteristics are compared according to the MSI status in [Table 2]. No significant differences were observed in patient's characteristics like age, gender, BMI, addiction and diet between MSI stable and unstable disease. Similarly, there is no statistical significant difference between disease characteristics like T and N stage, stage group, location, differentiation, mucin secretion, and perineural invasion (PNI) status between two groups. However, there is trend toward higher LVI positivity in MSI unstable patients when compared with MSI stable patients (P = 0.052).
Table 2: Comparison of patient and tumor characteristics according to microsatellite instability status

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The median progression-free survival (PFS) of the entire cohort was 27.8 months (95% confidence interval [CI] =22.7–32.9) [Figure 1] and the median overall survival (OS) is not reached [Figure 2]. Four-year OS is 50.9%. When analyzed according to MSI status, the median PFS is 21.3 months in MSI stable patients whereas it is not reached in MSI unstable patients [Figure 3]. The 3-year PFS in MSI stable patients is 25.8% versus 84.6% in MSI unstable patients. The difference is significant statistically (hazard ratio [HR] = 0.23, 95% CI = 0.09–0.64, P = 0.049) favoring MSI unstable group. Similarly, the median OS is 27.1 months in MSI stable patients but it is not reached in MSI unstable patients [Figure 4]. The 3-year OS is 32.8% versus 92.3% in MSI stable and unstable patients, respectively. The difference in OS shows a trend toward statistical significance (HR = 0.18, 95% CI = 0.05–0.59, P = 0.061) favoring MSI unstable group. In multivariate analysis, none of the factors were independently associated with overall as well as PFS.
Figure 1: Progression-free survival in entire cohort

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Figure 2: Overall survival in the entire cohort

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Figure 3: Comparison of progression-free survival according to microsatellite instability status

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Figure 4: Comparison of overall survival according to microsatellite instability status

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 > Discussion Top


Detection of MMR gene deletion indirectly reflects the status of MSI. It provides important prognostic and predictive information in patients of colon cancer in addition to its utility in Lynch syndrome screening. It is widely recognized that dMMR is associated with both a good prognosis and a lack of benefit from fluorouracil treatment in early stage colon cancer (particularly Stage II).[3] Various studies have shown different clinicopathological characteristics of dMMR tumors when compared with MSS tumors. Studies on molecular aspects of colorectal carcinoma (CRC) are limited in the Indian population. We compared the clinicopathological characteristics and treatment outcomes in patients of colon cancer treated between 2017 and 2019 in our institute according to their MMR status.

Out of 52 patients, MSI status was available in 42 patients. Fifteen of them exhibited MSI-H status and rest 27 were microsatellite stable. No significant difference between two groups was observed according to the patient characteristics, i.e., age, gender, BMI, addiction and diet (vegetarian vs. nonvegetarian). Analysis of data for clinicopathological features between the two groups did not reveal any significant association.

The only factor that showed trend toward significance in our study was LVI status which was higher in MSI-H tumors (P = 0.052). In the study by Gryfe et al., it was observed that, regardless of the depth of tumor invasion, colorectal cancers with high-frequency MSI (MSI-H) had a decreased likelihood of metastasizing to regional lymph nodes (odd's ratio [OR] = 0.33; 95% CI = 0.21–0.53; P < 0.001) or distant organs (OR = 0.49; 95% CI = 0.27–0.89; P = 0.02).[4] Greenson et al. analyzed that right-sided location (P = 0.032), well or poor differentiation (P = 0.037), and mucinous differentiation (P = 0.039) were independent predictors of MSI.[5] Similarly in the study by Ward et al., MSI-H tumors were significantly more likely to be of high histopathological grade, harbor increased numbers of intraepithelial lymphocytes with a mucinous phenotype. They were also more likely to be located on right side and showed female preponderance.[6] In the study by Samowitz et al., significant relationships were seen between MSI and proximal tumor location, female gender, young and old age at diagnosis, poor histological differentiation and early tumor stage.[7] Nazemalhosseini Mojarad et al. found that MSI-H tumors were predominantly located in the colon versus rectum (P = 0.03), associated with poorer differentiation (P = 0.003), and had TNM Stage II/III of tumors (P = 0.02).[8] MSI-high phenotype is characterized by clinical and pathologic features distinct from those observed in microsatellite stable colorectal cancers such as right-sided colon location, early stage at diagnosis, poor differentiation, mucinous histology, and prominent lymphocytic infiltration in most of the studies.[9] However, we did not find such a correlation in our study which can be because of the smaller sample size.

In the metastatic setting, MSI-H colorectal cancer is more frequently diagnosed in women and the elderly, and it often presents with synchronous metastases involving the lymph nodes and peritoneum rather than liver.[1] Recent studies have highlighted distinct patterns characterizing sporadic and inherited cases of MSI-H metastatic colorectal cancers, suggesting a substantial heterogeneity among these tumors based on MSI etiology.[10]

In our study, the median PFS is 21.3 months in MSI stable patients, whereas it is not reached in MSI unstable patients. The 3-year PFS in MSI stable patients is 25.8% versus 84.6% in MSI unstable patients (P = 0.049). Similarly, the median OS is 27.1 months in MSI stable patients versus not reached in MSI unstable patients. The 3-year OS is 32.8%–92.3% in MSI stable and MSI-H groups respectively (P = 0.061). The PFS is significantly higher in MSI-H patients and shows a trend toward significantly higher OS as well. All our patients were treated with 5-FU/Capecitabine and oxaliplatin-based adjuvant chemotherapy. A large analysis of data from 17 different trials in the Adjuvant Colon Cancer End Points database investigated how MSI status affected outcome in patients with Stage II or III CRC undergoing surgery alone or surgery followed by 5-FU – based adjuvant treatment. The results showed that outcomes with surgery alone were better for the patients with MSI-H tumors than for those with MSS tumors (HR for OS in Stage II disease, 0.27; P = 0.01).[11] Our data show concordance with findings of this analysis.

A retrospective subgroup analysis of the adjuvant QUASAR study (Quick and Simple and Reliable) confirmed the positive prognostic value of MSI status in early-stage CRC; the recurrence rate for MMR deficient tumors was half that for MMR-proficient tumors.[12] However, the significance of MSI-H status in combination with various risk factors in high-risk Stage II CRC, i.e., Stage II CRC presenting with a T4 primary tumor, LVI, PNI, bowel obstruction or perforation, inadequate lymph node sampling (<12 resected nodes), or close/undetermined/positive margins, particularly in the presence of multiple risk factors, has not been extensively investigated and remains unclear. In a meta-analysis to explore the prognostic implication of MSI-H tumors in advanced carcinoma colon, it was seen that, for Stage III CRCs, pooled HR for OS was 0.96 (95% CI: 0.75–0.123) in the randomized control trial (RCT) subgroup and 0.89 (95% CI: 0.62–1.28) in the non-RCT subgroup. For disease-free survival (DFS), the HR for the RCT group was 0.83 (95% CI: 0.65–1.07), similar to the non-RCT subgroup (0.83, 95% CI: 0.65–1.07). All these results showed that MSI-H has no beneficial effects in Stage III CRC. For Stage IV CRC, the HR for OS in the RCT subgroup was 1.23 (95% CI: 0.92–1.64). For non-RCT study, the combined HR for OS and DFS was 1.10 (95% CI: 0.77–1.51) and 0.72 (95% CI: 0.53–0.98) respectively, suggesting the beneficial effect for DFS and nonbeneficial effect for OS.[13] Our study included patients from all the stages and the positive prognostic effect of MSI on survival was observed.

Our study has inherent limitation of low sample size. Conclusions are restricted due to relatively small cohort size. Further large prospective study with longer follow-up is required to assess the prognostic and predictive significance of MSI in colon cancers.


 > Conclusion Top


MSI in colon cancer has increased interest in cancer research. It has shown to carry prognostic and predictive significance in colorectal cancers in Western studies. In our study, we have found that MSI unstable tumors have higher PFS and show a trend toward higher OS. It requires a validation from the prospective study with larger sample size and follow-up in Indian scenario.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Battaglin F, Naseem M, Lenz HJ, Salem ME. Microsatellite instability in colorectal cancer: Overview of its clinical significance and novel perspectives. Clin Adv Hematol Oncol 2018;16:735-45.  Back to cited text no. 1
    
2.
Dienstmann R, Mason MJ, Sinicrope FA, Phipps AI, Tejpar S, Nesbakken A, et al. Prediction of overall survival in stage II and III colon cancer beyond TNM system: A retrospective, pooled biomarker study. Ann Oncol 2017;28:1023-31.  Back to cited text no. 2
    
3.
Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010;28:3219-26.  Back to cited text no. 3
    
4.
Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000;342:69-77.  Back to cited text no. 4
    
5.
Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Miselevich I, Resnick MB, et al. Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol 2003;27:563-70.  Back to cited text no. 5
    
6.
Ward R, Meagher A, Tomlinson I, O'Connor T, Norrie M, Wu R, et al. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 2001;48:821-9.  Back to cited text no. 6
    
7.
Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M, et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 2001;10:917-23.  Back to cited text no. 7
    
8.
Nazemalhosseini Mojarad E, Kashfi SM, Mirtalebi H, Taleghani MY, Azimzadeh P, Savabkar S, et al. Low Level of Microsatellite Instability Correlates with Poor Clinical Prognosis in Stage II Colorectal Cancer Patients. J Oncol 2016;2016:2196703.  Back to cited text no. 8
    
9.
Raut CP, Pawlik TM, Rodriguez-Bigas MA. Clinicopathologic features in colorectal cancer patients with microsatellite instability. Mutat Res 2004;568:275-82.  Back to cited text no. 9
    
10.
Cohen R, Buhard O, Cervera P, Hain E, Dumont S, Bardier A, et al. Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency. Eur J Cancer 2017;86:266-74.  Back to cited text no. 10
    
11.
Sargent DJ, Shi Q, Yothers G, Tejpar S, Bertagnolli MM, Thibodeau SN, et al. Prognostic impact of deficient mismatch repair (dMMR) in 7,803 stage II/III colon cancer (CC) patients (pts): A pooled individual pt data analysis of 17 adjuvant trials in the ACCENT database. J Clin Oncol 2014;32 Suppl 15:3507-7.  Back to cited text no. 11
    
12.
Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 2011;29:1261-70.  Back to cited text no. 12
    
13.
Wang B, Li F, Zhou X, Ma Y, Fu W. Is microsatellite instability-high really a favorable prognostic factor for advanced colorectal cancer? A meta-analysis. World J Surg Oncol 2019;17:169.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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