The demographic and clinical characteristics of the enrolled patients are detailed in Table 1. The median age at diagnosis was 55 years (range: 1–92), including 53.7% male and 16.4% current or former smokers. Smoking status was known for 2,103 patients, including 383 (16.4%) smokers. The distribution of cancer types is illustrated in Fig. 2A. The most common cancer type was colorectal cancer (CRC, n = 681, 29.2%), followed by lung cancer (n = 510, 21.9%), melanoma (n = 232, 10.0%), and gastric cancer (n = 143, 6.3%). Histologically, 1582 (67.8%) of the cases were adenocarcinoma, irrespective of tumor origin (Fig. 2B). The other histopathological types included mesenchymal tumors, squamous cell carcinoma, and adeno-squamous cell carcinoma.
Landscape Of Tmb
In total, 2,332 tumor samples were successfully sequenced using the 295- and 1021- gene panels. The overall median TMB was 6 (range: 2-227) and 7 (range: 2-802) mutations per Mb in the 295- and 1021- gene panels, respectively (P < 0.0001, Supplementary Figure S1, online only). Not surprisingly, sex and smoking status were associated with median TMB (P < 0.0001 for sex and smoking status, Supplementary Figure S2, online only).
Among all cancer types, the median TMB ranged from 3 to 10 with the lowest median of 3 (range: 2–9) noted in salivary gland carcinoma (n = 46) and the highest median of 10 (range: 3–41) noted in esophageal carcinoma (n = 19, Fig. 3A and Supplementary Table S2). Fourteen patients had a median TMB > 100, including eight CRC patients, three endometrial cancer patients and three melanoma patients. The median TMB was 7 (range: 2-802) among CRC patients, and was greater when using the 1021- gene panel (median: 8; range: 2-802) than using the 295- gene panel (median: 7; range: 2-145) (P = 0.0003, Fig. 3B). Among patients with endometrial, gallbladder, liver or gastric cancer, the difference in median TMB was also statistically significant when comparing the 295- and the 1021- Genepanels (P for difference < 0.05, Fig. 3B and Supplementary Table S2, online only). Although similar trend was also noted for lung cancer, the difference was not statistically significant (median: 6; range: 2–37 for the 295- Genepanels and median: 7; range: 2–55 for the 1021- Genepanels (P = 0.3066; Fig. 3B). Comparisons of median TMB values for other cancer types using are shown in Supplementary Table S2 (online only).
The majority of histological subtype was adenocarcinoma (67.8%, 1582/2332). The median of TMB was 6 among patients with adenocarcinoma, and there was statistically significant difference between the two Genepanels (median: 6, range: 2-145; and median: 7, range: 2-802; P for difference < 0.0001, Fig. 3C and D; Supplementary Table S3, online only). The greatest median TMB was observed in neuroendocrine carcinoma patients (median: 8; range: 2–50). The median TMB was 10 in squamous cell carcinoma when using the 1021-Genepanel, which was higher than that of the 295-Genepanels (P = 0.003, Fig. 3C; Supplementary Table S3, online only). Relatively low median TMB values were found among patients with mesenchymal tumors (median: 4; range: 2-227) and blastoma (median: 4; range: 2–12) (Fig. 3C), with no significant difference observed between the two panels (Fig. 3D). Please refer to Supplementary Table S3 for more details.
In lung cancer, the substantial proportion was adenocarcinoma (404/510, 79.2%). The median TMB was higher in squamous cell lung cancer than adenocarcinoma (P = 0.0195, Supplementary Figure S3, online only). In CRC, no difference was found in median TMB between left- and right-sided colon, irrespective of gene panels used (P = 0.0780 and P = 0.5072, Supplementary Figure S4A and B, online only). Median TMB values in specific pathological subtypes of ovarian cancer, gastric cancer and melanoma are summarized in Supplementary Figure S4 (online only).
Variations in TP53 were observed among 1,241 of the 1993 patients analyzed (62.2%; Supplementary Figure S5A, online only). KRAS mutations were observed in 517 of the 1993 patients (26.0%), including 304 patients with CRC (58.8%), indicating mutated KRAS was probably associated with higher TMB. PIK3CA mutations were enriched in 9 out of 14 patients with a median TMB above 100. Other main genes with mutation types and frequencies were summarized in Supplementary Figure S5A, in relation to TMB. More importantly, the variations in ARID1A were most frequent among patients with high TMB (25.3%, 191/754), followed by BRCA2 (21.4%, 161/754) and ATM (19.0%, 143/754) (Supplementary Figure S5B).
Tmb, Hr-ddr Status And Immunotherapy Response
The characteristics of the 222 patients treated with ICIs are described in Table 2, mainly including patients with melanoma (n = 107, 48.2%) and lung cancer (n = 34; 15.3%). The prevalence of HR-DDR mutation was 15.8% (n = 35), and the proportion of DCB was 46.8% (n = 104). We found a higher median TMB among patients with HR-DDR mutation than patients without HR-DDR mutation (P < 0.0001, Fig. 4). Interestingly, patients with HR-DDR mutation and high TMB had a better disease control than patients with low TMB (P = 0.0001, Fig. 4). Specifically, in the HR-DDR mutant subgroup, there were two CRC patients with Lynch syndrome that had a DCB: a median TMB was 79 and 80 Muts/Mb, respectively.
Among the 116 patients who were evaluable for PD-L1 expression (Supplementary Figure S6, online only), 52 patients were defined as PD-L1 expression with ≤ 1% and had a median TMB of 5. The remaining 64 patients were classified as having PD-L1 expression > 1% and had a median TMB of 5. These were no statistically significant correlation between TMB and PD-L1 expression. No clear difference was however detected in ICIs response by PD-L1 expression status, without taking TMB in to account.