The research aimed to investigate whether genomic alterations in SCLC may differentiate LTS and STS who experienced surgical resection for early-stage SCLC. The data demonstrated that high TMB may be a prognostic biomarker of long-term survival in resected SCLC, regardless of the disease stage. A tendency was noted for the FAT3 gene to separate between the LTS and STS groups. Although the present study contains a limited number of samples, our data suggests a discovery that warrants further investigation.
The association between TMB and disease prognosis in lung cancer is still unclear. Whether TMB is a prognostic factor for postoperative non–small-cell lung cancer (NSCLC) is controversial. Devarakonda et al. proved that high nonsynonymous TMB was significantly connected with a favorable prognosis in resected NSCLC . In contrast to this study, Owada-Ozaki et al. demonstrated opposite results suggesting that high TMB could be related to a poor prognostic in lung cancer and in resected NSCLC . However, the former study contained 908 samples, while the latter only 90 samples. As a consequence, the former conclusion seems more convincing. McGranahan et al. observed an association between higher OS and high neo-epitope burden on early-stage lung adenocarcinoma patients . Yu et al. assessed 255 specimens from patients suffering early-stage squamous cell lung cancers (SqCLC) to evaluate the potential role of PD-L1 protein expression and TMB, and the putative identification of an immune gene signature . The authors of that study found that TMB was not associated with OS. SCLC is characterized by high TMB because of its association with smoking. However, whether TMB affects the prognosis of resected SCLC has not been studied. Zhou et al analyzed the correlations between clinical outcomes and genomic alterations in 53 SCLC samples . The authors of this study reported that high TMB (> 21 mutations/Mb) was connected with a favorable prognosis in OS (21.7 vs. 10.4 months, p = .012). In our study, we found that LTS exhibited higher median TMB (16.4 mutations/Mb, ranging from 10.8 to 35.6 compared with 8.5, from 5.2 to 17.9). There was no significant difference in the median TMB between the LTS and STS groups (p = 0.08) (Fig. 2). However, exploratory analyses suggested that TMB may have a significant predictive effect on OS (p = 0.007) (Fig. 3). For patients with high TMB and low TMB, The former group did not reach mOS and the latter one survived 22 months. These findings provide evidence that high TMB exhibits optimal prognostic value.
The genetic mutational landscape of SCLC is complex and heterogeneous. However, the most common genetic alterations include inactivation of the tumor suppressor genes TP53 and RB1 [16, 17]. Hu et al. demonstrated that the most frequently altered genes in small cell lung cancer were as followed: TP53 (93.4%), RB1 (78.7%), LRP1B(18.9%), KMT2D (15.6%), FAT1 (11.5%), KMT2C (11.5%),STK24 (11.5%), FAM135B (10.7%), and NOTCH1 (10.7%) . The results were derived from genomic profiling of 122 Chinese patients. In the study, with the exception of TP53 and RB1, the remaining high frequency mutated genes were those that encoded enzymes involved in histone modification, notably those that participate in the NOTCH and Wnt signaling pathways. With the Fisher’s exact test, we found a significant correlation between LTS and gene mutations on FAT3. The human FAT gene family consists of the FAT1, FAT2, FAT3 and FAT4 genes [18–21]. Hong et al reported the partial coding sequence of FAT3 in 2004, whereas Katoh et al reported the complete coding sequence of FAT3 and FAT4 in 2006. FAT3 is found on chromosome 11q14.3-q21 and has 26 exons encoding a protein of 4,557 amino acids . The FAT1 and FAT3 genes adjoin the MTNR1A and MTNR1B genes, respectively. FAT1 exhibits a higher homology with FAT3, while MTNR1A exhibits a higher homology with MTNR1B. A previous study in mice indicated that FAT3 expression restricted the development of central nervous system (CNS), with highest expression found at the olfactory bulb and retina . These findings led to the hypothesis that murine FAT3 plays significant roles in the development of CNS, possibly in axon organization and interaction [23, 24]. Sadeqzadeh et al reported that on patients suffering breast and ovarian cancer exhibited high frequency FAT3 mutations and FAT3 impacts the development of the central nervous system [22, 25, 26]. Ji-Yeon Kim et al examined 119 patients of breast cancer in an exploratory biomarker study: a total of 40 subjects from that study exhibited an available biomarker. With targeted deep sequencing, FAT3 (48%) was found to be the most frequently mutated gene. However, further survival analysis indicated that FAT3 mutations seemed to be associated with poor prognosis, though the results were statistically insignificant . The information regarding the association between FAT3 and the prognosis in SCLC was lacking in the present study. Interestingly, FAT3 mutation occurred solely in LTS and the P-value from the comparison with the STS group was 0.06 as determined by the Fisher’s exact test. The survival curve analysis (Fig. 3) also showed that FAT3 mutation may be associated with optimal prognosis among SCLC patients, although there was no notable difference between them (p = 0.11) (Fig. 3). This may be the first report regarding the effects of FAT3 mutations on the prognosis of SCLC patients. However, the reports that exist on FAT3 are limited and it remains unknown whether the genetic changes occurring in FAT3 can significantly affect the pathophysiology of the cancer . Further studies that can prove the implication of FAT3 in SCLC would be of significant value.
This study has a few limitations. The sample size was small and this was retrospective study. Surgical specimens were scarce and precious due to the less opportunity for surgery. For this reason, scientific studies about SCLC molecular profiles are hampered by a lack of tissue availability. Moreover, in order to thoroughly ignore the effect of stage on prognosis, we selected two extreme cohorts of LTS with stage IIB-III and STS with stage I as the objects of study. All the patients were followed up for more than 2 years. Therefore, the number of patients who qualified is very small. Despite these limitations, our study offered some new discoveries.