PARTHA MAJUMDER is the founder and Distinguished Professor of the National Institute of Biomedical Genomics, and concurrently a Professor of the Indian Statistical Institute, Kolkata, India. His scientific contributions to human and population genetics span a vast range; from structure and evolution of human populations to genomics of diseases and development of statistical methods for genomic analyses. He is a Sir J.C. Bose National Fellow. He is an elected Fellow of all the three science academies of India, of The World Academy of Sciences and the International Statistical Institute. He is a Council Member of the Human Genome Organisation. He is the Indian National Co-ordinator on the International Cancer Genome Consortium. He has served on the Board of Directors of the International Genetic Epidemiology Society (IGES), and was the founding Chair of its Ethics Committee. He has worked for the International Bioethics Committee of UNESCO. He is a recipient of many awards and medals, including the TWAS Biology Prize, G.D. Birla Award for Scientific Research, Ranbaxy Research Award in Applied Medical Sciences, and the New Millennium Science Medal, Government of India.
Genomics of Lymph Node Metastasis in Oral Squamous Cell Carcinoma
Nidhan K. Biswas, Arindam Maitra, Rajiv Sarin, Subrata Das, Chitrarpita Das,
Partha P. Majumder and the ICGC-India Project Team
National Institute of Biomedical Genomics
Oral squamous cell carcinoma (OSCC) is a major killer in the lesser developed countries. Metastases to regional lymph nodes (N-stage) is the strongest prognostic factor in OSCC, survival of LN+ patients is halved compared to LN- patients. The clinico-radiological evaluation of neck nodes (cN stage) in OSCC is associated with high false positive and false negative rates when compared to the gold standard pathological nodal status of the neck dissection (pN stage). Therefore, identifying genomic correlates of pN stage is useful for prognostication in OSCC.
To reduce the possibility of falsely identifying genomic alterations to be associated with metastasis, patients with highly contrasting pathological nodal stages were compared – LN+ (pN2b,c or N3 with pT1-4 primary) versus LN- (pN0 with pT4 primary). Each patient had undergone comprehensive histopathological staging, curative resection, post-operative radiotherapy+chemotherapy and follow-up. We analyzed exome sequencing and CNV array data of blood and tumor DNA in contrasting patient-subgroups – LN+ patients (n=35) and LN- patients with late stage disease (n=37). We used highly stringent methods of analysis of exome and genome-wide data to identify rare germline, somatic variants, CNV significantly mutated genes and pathways.
Our study revealed that lymph node metastasis in oral cancer is driven by: (a) specific hotspot somatic mutations in TP53 and CASP8 genes; (b) rare non-silent germline mutations in BRCA2 and FAT1 genes; (c) six significantly mutated pathways including a DNA repair pathway, and (d) recurrent deletion of homologous recombination associated DNA repair genes. While disease free survival of LN+ patients with rare germline missense mutations in BRCA2 is shorter than other patients, LN+ patients with NHEJ pathway mutations has better disease free survival.
The results from this study provides new insight into the process of lymph node metastasis from OSCC and the variants in the genes can serve as good prognostic markers for early prediction of lymph node metastasis after adequate validation.