Tumor Mutation Burden May be a Prognostic Biomarker of Long-Term Survival in Resected Small-Cell Lung Cancer

Abstract

BackgroundSmall cell lung cancer (SCLC) has a poor prognosis. The majority of SCLC patients do not survive within a few months of diagnosis, however, a sub-group of patients have a long-term survival. Individual differences in prognosis remain elusive. We present the first comprehensive comparative genomic profiling and tumor mutation burden (TMB) analyses of SCLC on patients with long-term survival (LTS) and short-term survival (STS) after surgery.MethodsThe present study included 52 patients with SCLC who underwent surgery in Zhejiang Cancer Hospital from April 2008 to December 2017. A total of 6 LTS patients (≥4 years) with stage IIB or IIIA SCLC and 5 STS patients (<2 years) with stage IA or IB SCLC were included. The latter subjects were used as control subjects. All subjects underwent resection without neoadjuvant therapy. We assessed their genomic profile and calculated TMB using next-generation sequencing (NGS). Moreover, we assessed the correlation between TMB and prognosis. Subsequently, we analyzed and compared the molecular characteristics of LTS and STS.ResultsThe data indicated that the LTS harbored high TMB. The median TMB for LTS was approximately 16.4 Mutations/Mb, while STS harbored low TMB which was approximately 8.5 Mutations/Mb. A differential trend on the median TMB was revealed between LTS and STS (p = 0.08). Moreover, we discovered that TMB exhibited significant effects on the survival of the patients (p=0.007). In the LTS group, the median number was 10 (range: 6-13) in mutated genes per sample and the samples harbored collectively 60 gene mutations in the following 28 genes: TP53 (n=6), RB1 (n=4), FAT3 (n=4), KMT2D (n=3), NOTCH1 (n=3), FAM135B (n=3), LRP1B (n=3), CDKN2C (n=3), H3F3A (n=3) . In the mutated genes per sample of STS, the median number was 7 (range: 3-8) and 30 mutations were found in the 17 genes as followed: TP53 (n=5), RB1 (n=4), KMT2D (n=2), NOTCH1 (n=2), FAT4 (n=2), MUC16 (n=2), PTEN (n=2), FAM135B (n=1), LRP1B (n=1), KMT2C (n=1). Gene alteration represented the survival difference between the two groups. The FAT3 gene was only noted in LTS and the P-value was 0.06 as determined by the Fisher’s exact test. Interestingly, the FAT3 gene could impact the patients’ survival (p=0.11) though no significant difference were noted.ConclusionsHigh nonsynonymous TMB was associated with improved prognosis on patients with resected SCLC. The FAT3 gene may impact disease prognosis. The data may provide valuable information of differences between individuals in terms of prognosis and guide treatment. Studies involving larger groups are required to confirm these findings.