Profiling genetic mutations in the DNA damage repair genes of oral squamous cell carcinoma patients from Pakistan

Herein, we reported mutations in five DNA Damage Repair (DDR) i.e., TP53, ATR, ATM, CHEK1 and CHEK2 involved in OSCC using NG-WES and their analysis using bioinformatics tools. Out of 42 identified mutations, 16.7% are reported for the 1st time. A total of 28 nonsynonymous SNVs are identified. TP53 harbored the highest number of mutations followed by ATM, ATR, CHEK1 and CHEK2. Nine mutations (TP53p.R43H, TP53p.L125Q, TP53p.R116Q, TP53p.C110Y, TP53p.L62F, ATRp.H120Y, ATMp.P1054R, ATMp.D1853V, ATMp.T2934N) were predicted highly pathogenic. SAAFEQ-SEQ predicted destabilizing effects for all mutations, while ISPRED-SEQ identified 09 IS mutations, 07 on TP53, 01 in ATR and 01 in CHEK1 with no IS mutations predicted for ATM and CHEK2. Among the IS mutations, only SNVs were used in MDS simulations. The gyration radius for all IS SNVs was larger for mutant as compared to the wild type indicating perturbed folding behavior of the mutant proteins. Structural deviations across the carbon back bone were noted by RMSD for mutant and wild type. The TP53 IS mutations include TP53p.R116Q, TP53 p.C110Y, TP53p.R43H, TP53p.E214X, TP53p.R210X, TP53 p.C110Afs*5 and TP53 p,S108Ffs*23 whereas ATR and CHEK1 IS mutations consist of ATRp.M1932T and CHEK1p.E76Kfs*21. ConSurf analysis revealed four SNVs with a high conservation score (9) on TP53 and ATM. TP53p.P33R was predominantly associated with moderately differentiated tumors (84.60%), naswar users (86.60%) and positive family history of cancer (91.60%). The TP53p.P33R, ATRp.M211T and CHEK1p.I437V mutations were found recurrently in 21/27 (77.7%), 20/27 (74.04%), and 27/27 (100%) patients, suggesting its potential biomarker applications in local screening.