These findings indicate that MUC16 mutations may be associated with higher TML, better survival outcomes, and immune response and cell cycle pathways. These findings may be immediately applicable for guiding immunotherapy treatment for patients with GC.

We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutations and the TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC.

Immune checkpoint blockade (ICB) therapy has achieved remarkable clinical benefit in melanoma. However, our understanding of biomarkers that predict response to ICB remained obscure. Here we systematically analyzed the association between somatic mutations profile and clinicopathologic information from 336 melanoma patients treated by ICB (CTLA-4/PD-1). We identified eight new significantly mutated genes including COL5A1, SEMA3E, COL28A1, DGKG, RAPGEF5, GLDN, NCF2 and RCAN2. A mutational signature featured by enrichment of T > C mutations was identified to be associated with immune resistance (logistic regression model, OR, 2.59 [95%CI, 1.07 to 7.00], P = .043). High neoantigen quality was associated with prolonged immunotherapy survival (log-rank test, P = .009). This association remained significant after controlling for age, gender, stage and hypermutation (Cox proportional hazards model, HR, 0.56 [95%CI, 0.38 to 0.82], P = .003). Our findings shed new insights on biomarkers that are useful to predict melanoma patients who may benefit from ICB treatment; however, these biomarkers need to be validated in future studies. ARTICLE HISTORY

Acral melanoma is a dismal subtype of melanoma occurring in glabrous acral skin, and has a higher incidence in East Asians. We perform single-cell RNA sequencing for 63,394 cells obtained from 5 acral and 3 cutaneous melanoma samples to investigate tumor heterogeneity and immune environment. We define 5 orthogonal functional cell clusters that are involved in TGF-beta signaling, Type I interferon, Wnt signaling, Cell cycle, and Cholesterol efflux signaling. Signatures of enriched TGF-beta, Type I interferon, and cholesterol efflux signaling are significantly associated with good prognosis of melanoma. Compared with cutaneous melanoma, acral melanoma samples have significantly severe immunosuppressive state including depletion of cytotoxic CD8+ T cells, enrichment of Treg cells, and exhausted CD8+ T cells. PD1 and TIM-3 have higher expression in the exhaustive CD8+ T cells of acral melanoma. Key findings are verified in two independent validation sets. This study contributes to our better understanding of acral melanoma.

Small cell cervical carcinoma (SCCC) is a rare but aggressive malignancy. Here, we report human papillomavirus features and genomic landscape in SCCC via high-throughput HPV captured sequencing, whole-genome sequencing, whole-transcriptome sequencing, and OncoScan microarrays. HPV18 infections and integrations are commonly detected. Besides MYC family genes (37.9%), we identify SOX (8.4%), NR4A (6.3%), ANKRD (7.4%), and CEA (3.2%) family genes as HPV-integrated hotspots. We construct the genomic local haplotype around HPV-integrated sites, and find tandem duplications and amplified HPV long control regions (LCR). We propose three prominent HPV integration patterns: duplicating oncogenes (MYCN, MYC, and NR4A2), forming fusions (FGFR3–TACC3 and ANKRD12–NDUFV2), and activating genes (MYC) via the cis-regulations of viral LCRs. Moreover, focal CNA amplification peaks harbor canonical cancer genes including the HPV-integrated hotspots within MYC family, SOX2, and others. Our findings may provide potential molecular criteria for the accurate diagnosis and efficacious therapies for this lethal disease.