Rationale: Microsatellite instability (MSI) or mismatch repair deficiency (MMRd) testing in all colorectal cancer (CRC) patients is recommended by the national agencies of USA, UK, EU and India. However, recent data from European populations indicates high prevalence of MSI/MMRd in non-colonic tumours such as small intestine, endometrium, stomach, oesophagus, liver and pancreas, which together account for approximately 1 in every 6 cancers seen in cancer clinics in India. MSI/ MMRd status is useful in estimating prognosis, stratifying patients to chemotherapy and immunotherapy treatments, surgical interventions and identification of Lynch syndrome (LS), previously known as HNPCC, patients. Despite the apparent usefulness, MSI/ MMRd testing is not carried out routinely in non-colonic tumours and no systematic prevalence data of MSI/ MMRd and Lynch syndrome in these tumours is currently available for patients from India.

Objective: To systematically study MSI/ MMRd status in tumour DNA and germline mutations in mismatch repair (MMR) genes across a unique, large and heterogeneous group of commonly observed non-colorectal gastrointestinal and genitourinary tumours in the Indian population.

Study design: This is an observational study.

Study population: All participants in this study are patients having primary cancers in one of the anatomical sites- small intestine, endometrium, stomach, oesophagus, liver and pancreas. DNA from tumour biopsy sample will be tested for MSI status using PCR based fragment length analysis assay (PCR-FLA) and MMRd status will be assessed using 4 MMR protein based immunohistochemistry (IHC). Patients with MSI/ MMRd status will be tested for germline mutations in mismatch repair (MMR) genes (MSH2, MSH6, MLH1, PMS2 and EPCAM) using whole exome sequencing (WES), as they have a high likelihood of being Lynch syndrome carriers. First degree relatives (with or without prior cancer history) of patients with germline pathogenic/ likely pathogenic variants in MMR genes, will be tested for the variants to identify LS carriers. Detailed food frequency questionnaire (FFQ) developed by the National Cancer Institute will be used to capture dietary and lifestyle data of all LS patients and these patients will be followed up annually for upto 3 years.  

Intervention: Not applicable.

Main study parameters/endpoints: a) Generation of robust estimates of MSI and LS prevalence across commonly observed non-colorectal gastrointestinal and genitourinary tumours in 300 patients in India

b) Calculate annual incidence and cumulative incidence rates of cancer in 3 yearly cohorts together with identification of catalogue of dietary and lifestyle factors that affect penetrance of MMR gene and anatomical site in LS patients.  

c) Develop an interactive tool which would calculate cumulative 10-year cancer risk for LS carriers with or without prior cancer history based on their age, gender, mutated MMR gene, lifestyle/ dietary factors and anatomical site.