Comprehensive Molecular Genetic and Clinical Profiling in CLL: Role of Del 13q14, 17p13, 11q22, Trisomy 12, TP53, NOTCH1, MYD88, SF3B1, ATM, and IGHV Status - a Real World Data in an Indian Subcontinent
Authors: T Sudhahar , Bains Rupali , Naithani Manisha , Mirza Anissa Atif , Nath Uttam Kumar , Chandra Harish , Bahurupi Yogesh 
Published: December 2024

Study conducted for FISH (del 13q14, 17p13, 11q22, trisomy 12), NGS Analysis (TP53, NOTCH1, MYD88, SF3B1, FBXW7, ATM) and PCR, Sanger Sequencing (IGHV status) determining their prognostic impact and the factors associated with a progressive disease coursein treatment-naïve Chronic Lymphocytic Leukemia (CLL) patients. Clinical staging (Rai III/IV & Binet C), mutated TP53 status and Unmutated IGHV status were taken as potential factors for progressive disease course in these cases.
To investigate the molecular genetic profiling (FISH, IGHV, TP53, NOTCH1, MYD88, SF3B1, FBXW7, ATM abnormalities) and its association with clinical and hematological characteristics in patients of Chronic Lymphocytic Leukemia (CLL). A combined analysis of patient's genetic profile to provide comprehensive prognostication and risk stratification for the treatment approach.
Newly diagnosed 117 (n) CLL cases of all age groups and of both sex. Immunophenotyping and cytomorphology were used in accordance with conventional protocols to diagnose CLL. Baseline clinical parameters, including age, gender, comorbidities, CLL-related symptoms, and physical findings, were documented. Clinical and hematological characteristics, including hemoglobin, total leukocyte count, absolute lymphocyte count, and platelet count, were recorded in the laboratory and used to establish the CLL disease stage. Molecular genetic profile including: FISH (Del 13q14, Del 17p13, Del 11q22, and Trisomy 12), NGS Analysis (TP53, NOTCH1, MYD88, SF3B1, FBXW7, and ATM) and PCR, Sanger Sequencing (IGHV status) was performed.
Median age was 62 years (range: 26-85). Male: Female ratio was 2.3:1. Patients were classified into clinical staging as: Modified Rai (III/IV) 43.6% and Binet C staging 40.2%. FISH profile of 89 patients revealed the following genetic abnormalities: Del (13q) in 64% of patients, trisomy 12 in 26%, Del (11q) in 20%, and Del (17q) in 12.3%. IGHV gene mutation status was assessed in 79 patients showing 44% IGHV Unmutated, 54% IGHV hyper mutated and 2% IGHV indeterminate status. Next Generation Sequencing performed in 71 patients identified the following gene mutations: NOTCH1 (17%), SF3B1 (8.5%) with average 26.3% mutant allele content, TP53 (7%), ATM (5.6%), FBXW7 (4.2%), and MYD88 (3%). Mutated TP53 status, Unmutated IGHV status, presence of Del (17p13), Del(11q22), Trisomy 12, and NOTCH1 mutation were identified as potential predictors of progressive disease course & reduced survival. In correlational analysis, Del 17p13 (r: 0.77) and SF3B1 (r: 0.70) mutation showed strong correlation with TP53-Mutated/IGHV-Unmutated status in these cases.
In our research, assessing IGHV gene mutation status revealed a significant percentage of patients with Unmutated IGHV, which was associated with an aggressive illness course. Next Generation Sequencing (NGS), on the other hand, focuses on CLL's complicated genomic landscape and the implications for tailored treatment options. Correlational study indicated a strong correlation between Del 17p13 and SF3B1 mutation with TP53-mutated/IGHV-Unmutated status, implying that both genetic abnormalities frequently coexist and are associated with more severe disease behavior in CLL.