Distinct mutational backgrounds and clonal architectures implicated prognostic discrepancies in small-cell carcinomas of the esophagus and lung

Abstract

Small-cell carcinoma of the esophagus (SCCE) is a rare and aggressive cancer. Although several consistent genomic changes were observed previously between SCCE and small-cell lung cancer (SCLC), detailed mutational landscapes revealing discrepancies in genetic underpinnings of tumorigenesis between these two cancers are scarce, and little attention has been paid to answer whether these genetic alterations were related to the prognosis. Herein by performing whole-exome sequencing of 48 SCCE and 64 SCLC tumor samples, respectively we have shown that the number of driver mutations in SCCE was significantly lower than in SCLC (p = 0.0042). In SCCE, 46% of recurrent driver mutations were clonal, which occurred at an early stage during tumorigenesis, while 16 driver mutations were found clonal in SCLC. NOTCH1/3, PIK3CA, and ATM were specifically clonal in SCCE, while TP53 was clonal in SCLC. The total number of clonal mutations differed between two cancers and presented lower in SCCE compared to SCLC (p = 0.0036). Moreover, overall survival (OS) was shorter in patients with higher numbers of clonal mutations for both cancers. In summary, SCCE showed distinct mutational background and clonal architecture compared with SCLC. Organ-specific clonal events revealed different molecular mechanisms underlying tumorigenesis, tumor development, patients' prognosis, and possible variations in therapeutic outcomes to candidate treatments.

Fig. 1. Study design and pipeline.

FFPE of patients with SCCE and SCLC was sequenced using WES. Somatic mutations were evaluated with Pure CN.

Fig. 2. Driver mutation spectrum of SCCE and SCLC.

A Driver mutation profiling of SCCE (Top20 was shown); B Driver mutation profiling of SCLC (Top20 was shown); C Comparison of mutation frequency between SCCE and SCLC; D Driver gene NO. was significantly lower in SCCE than that in SCLC.

Fig. 3. Clonal and subclonal driver mutations in SCCE and SCLC.

A Clonal and subclonal driver gene in SCCE (x-axis) and SCLC (y-axis), clonality of genes was identified using PureCN, and presented with different colors; B the total number of clonal mutations differed between two cancers, and presented lower in SCCE, compared with SCLC (median, 7 v.s. 10 mutations, Mann−Whitney test, p = 0.0036).

Fig. 4. Clonal mutation NO. in relation to the outcome of both SCCE and SCLC.

A Kaplan−Meier analysis of overall survival (OS) in SCCE patients with more and less clonal mutation NO. (HR, 0.36; 95% CI, 0.11–1.15; P = 0.08). B Kaplan−Meier analysis of overall survival (OS) in SCLC patients with more and less clonal mutation NO. (HR, 0.39; 95% CI, 0.21–0.72; P = 0.003).

Fig. 5. Driver mutation number in relation to the mortality rate of SCLC.

SCLC patients with more driver mutation number showed a higher 1-year mortality rate (68%) than those with less driver mutation number (38%, Fisher’s exact test, P = 0.0473).