Aberrant epigenetic inactivation of RASSF1A and MGMT gene and genetic mutations of KRAS, cKIT and BRAF in Indian testicular germ cell tumours

Testicular germ cell tumor (TGCT) development may involve a series of modification at epigenetic and genetic level which may act synergistically and transform the primordial gonocyte. This study evaluated the frequency and distribution pattern of RASSF1A/MGMT gene methylation and KRAS, BRAF and cKIT gene mutation in Indian TGCT patient, and their correlation with clinicopathological features. Forty-one TGCT tumors were used to investigate hypermethylation of RASSF1A and MGMT gene and mutations of KRAS codon 12/13, BRAF V600E and cKIT exon 17 mutations. RASSF1A and MGMT methylation was noted in 58.5% and 10% of the TGCTs. A higher frequency of RASSF1A methylation was noted in seminomas (71%, 17/24), while MGMT methylation was frequent in mixed tumors (23%, 3/13). Interestingly, 3 of 41 cases showed concurrent methylation of both the genes. The absence of tumor necrosis was significantly associated with increased frequency of MGMT hypermethylation (30% vs. 3%, p = 0.03). KRAS mutation was identified in 17% (7/41), while none showed BRAF and cKIT mutation. KRAS mutations were predominantly found in codon 12 with G12V as the most recurrent mutations. Mixed germ tumors tends to show increased frequency of KRAS mutation (31%, 4/13), followed by pure seminomas (4%, 1/24). Interestingly, KRAS mutation rate was significantly higher in metastatic tumors in comparison to primary tumors (100% vs. 13%, p = 0.02). No other association of RASSF1A/MGMT/KRAS alterations with other clinicopathological features was noted. In conclusion, these data support the notion that the cancer-associated alterations in the RASSF1, MGMT and KRAS gene may significantly contribute to TGCT pathogenesis. (C) 2019 Elsevier Inc. All rights reserved.