AUTHOR=Wu Xiaoxuan , Song Peng , Guo Lei , Ying Jianming , Li Wenbin 

TITLE=Mutant-Allele Tumor Heterogeneity, a Favorable Biomarker to Assess Intra-Tumor Heterogeneity, in Advanced Lung Adenocarcinoma

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.888951

DOI=10.3389/fonc.2022.888951

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Intra-tumor heterogeneity (ITH) plays a vital role in drug resistance and recurrence of lung cancer. We used a mutant-allele tumor heterogeneity (MATH) algorithm to assess ITH and investigated its association with clinical and molecular features in advanced lung adenocarcinoma.</p></sec><sec><title>Methods</title><p>Tissues from 63 patients with advanced lung adenocarcinoma were analyzed by next-generation sequencing (NGS) using a panel targeting 520 cancer-relevant genes. We calculated the MATH values from NGS data and further investigated their correlation with clinical and molecular characteristics.</p></sec><sec><title>Results</title><p>Among the 63 patients with advanced lung adenocarcinoma, the median value of MATH was 33.06. Patients with <italic>EGFR</italic> mutation had higher level of MATH score than those with wild-type <italic>EGFR</italic> status (<italic>P</italic> = 0.008). Patients with stage IV disease showed a trend to have a higher MATH score than those with stage III (<italic>P</italic> = 0.052). MATH was higher in patients with disruptive <italic>TP53</italic> mutations than in those with non-disruptive mutations (<italic>P</italic> = 0.036) or wild-type sequence (<italic>P</italic> = 0.023), but did not differ between tumors with non-disruptive mutations and wild-type <italic>TP53</italic> (<italic>P</italic> = 0.867). High MATH is associated with mutations in mismatch repair (MMR) pathway (<italic>P</italic> = 0.026) and base excision repair (BER) pathway (<italic>P</italic> = 0.008). In addition, MATH was found to have a positive correlation with tumor mutational burden (TMB) (Spearman ρ = 0.354; <italic>P</italic> = 0.004). In 26 patients harboring EGFR mutation treated with first generation EGFR TKI as single-agent therapy, the objective response rate was higher in the Low-MATH group than in the High-MATH group (75% vs. 21%; <italic>P</italic> = 0.016) and Low-MATH group showed a significantly longer progression-free survival than High-MATH group (median PFS: 13.7 months vs. 10.1 months; <italic>P</italic> = 0.024).</p></sec><sec><title>Conclusions</title><p>For patients with advanced lung adenocarcinoma, MATH may serve as a clinically practical biomarker to assess intratumor heterogeneity.</p></sec>