RET Alterations Differentiate Molecular Profile of Medullary Thyroid Cancer.

PURPOSE: Medullary thyroid cancer (MTC) is a rare cancer originating from parafollicular C cells of the thyroid gland. Therapeutically relevant alterations in MTC are predominantly reported in RET oncogene, and lower-frequency alterations are reported in KRAS and BRAF. Nevertheless, there is an unmet need existing to analyze the MTC in the Indian cohort by using in-depth sequencing techniques that go beyond the identification of known therapeutic biomarkers. MATERIALS AND METHODS: Here, we characterize MTC using integrative whole-exome and whole-transcriptome sequencing of 32 MTC tissue samples. We performed clinically relevant variant analysis, molecular pathway analysis, tumor immune-microenvironment analysis, and structural characterization of RET novel mutation. RESULTS: Mutational landscape analysis shows expected RET mutations in 50% of the cases. Furthermore, we observed mutations in known cancer genes like KRAS, HRAS, SF3B1, and BRAF to be altered only in the RET-negative cohort. Pathway analysis showed differential enrichment of mutations in transcriptional deregulation genes in the RET-negative cohort. Furthermore, we observed novel RET kinase domain mutation Y900S showing affinity to RET inhibitors accessed via molecular docking and molecular dynamics simulation. CONCLUSION: Altogether, this study provides a detailed genomic characterization of patients with MTC of Indian origin, highlighting the possible utility of targeted therapies in this disease.

Understanding the Impact of Population and Cancer Type on Tumor Mutation Burden Scores: A Comprehensive Whole-Exome Study in Cancer Patients From India.

PURPOSE: The purpose of this study was to understand the impact of population diversity and geographic variation on tumor mutation burden (TMB) scores across cancers and its implication on stratification of patients for immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: This retrospective study used whole-exome sequencing (WES) to profile 1,233 Indian patients with cancer across 30 different cancer types and to estimate their TMB scores. A WES-based pipeline was adopted, along with an indigenously developed strategy for arriving at true somatic mutations. A robust unsupervised machine learning approach was used to understand the distribution of TMB scores across different populations and within the population. RESULTS: The results of the study showed a biphasic distribution of TMB scores in most cancers, with different threshold scores across cancer types. Patients with cancer in India had higher TMB scores compared with the Caucasian patients. We also observed that the TMB score value at 90th percentile (predicting high efficacy to ICI) was high in four different cancer types (sarcoma, ovary, head and neck, and breast) in the Indian cohort as compared with The Cancer Genome Atlas or public cohort. However, in lung and colorectal cancers, the TMB score distribution was similar between the two population cohorts. CONCLUSION: The findings of this study indicate that it is crucial to benchmark both cancer-specific and population-specific TMB distributions to establish a TMB threshold for each cancer in various populations. Additional prospective studies on much larger population across different cancers are warranted to validate this observation to become the standard of care.

Real-World Evidence of EGFR Targeted Therapy in NSCLC- A Brief Report of Decade Long Single Center Experience.

The significance of EGFR targeted therapy in the lung adenocarcinoma is paramount. Several controlled clinical trials have reported considerable survival of EGFR mutation positive patients on receiving the EGFR tyrosine kinase inhibitor (TKI). However, the real-world evidence of benefits of EGFR TKI would be further useful to understand how the designated therapeutic regimen benefits the patients. In this study, we report a decade long real-world evidence of EGFR molecular testing in lung cancer at Tata Memorial Hospital (Mumbai, India). Laboratory and hospital records containing basic demographic details, clinical characteristics, treatment regimen, survival outcome were collected retrospectively. Statistical association and survival analysis were performed using the R programming. The cohort includes 9,053 lung cancer patients tested for EGFR mutations during 2011 to 2019. Baseline T790M and compound mutations were the only mutations observed co-occurring while all other EGFR mutations were mutually exclusive. Furthermore, the baseline T790M were also observed to be associated with TTF1 positivity, smoking and local metastasis. Overall survival of the patients harboring co-occurring compound mutations was significantly lesser than the other EGFR positive patients. Overall, our study suggests that EGFR TKI may provide real-world benefit to the lung cancer patients harboring mutually exclusive EGFR mutations. On the other hand, further systematic study is essential to develop better therapeutic regimen for co-occurring baseline EGFR T790M and other compound mutations.