No abstract

Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.

Clinical response to immune checkpoint inhibitors (ICIs) varies significantly and the majority of studies into their effectiveness are focused on primary tumours of single histologies. This retrospective study utilises whole genome and transcriptome analysis (WGTA) to examine a pan-cancer cohort of advanced and previously treated patients which are currently underrepresented in the field, yet encompass a large proportion of cancer patients routinely seen in clinics. Our results reveal that tumour mutation burden and immune expression signatures are efficient at stratifying patients in this context, but suggest that PD-L1 testing may not be the most appropriate clinical biomarker for these patients. This study also demonstrates the benefit of measuring multiple markers simultaneously, highlighting the clinical utility of WGTA in selecting patients most likely to benefit from ICIs. Research.

ersistent HPV infection, in episomal or integrated form, is necessary but not sufficient for the development of cervical cancer 1. HPV-16 and HPV-18 are detected in at least 70% of affected individuals 2. HPV-16 (clade A9) is common in both squamous cell carcinomas and adenocarcinomas, while HPV-18 (clade A7) is associated with adenocarcinomas 2 and inferior survival 3-5. Cervical cancer prevention strategies include vaccination and screening for HPV and treatment of high-grade precancer. Although effective 6 , vaccine use remains low in low-and middle-income countries 7 where HIV is prevalent. Resource constraints similarly complicate screening, surgery 8 and radiotherapy 9 , such that a 50% increase in cervical cancer mortality by 2040 is predicted 10. Genomic cervical cancer studies, primarily conducted in non-African individuals 11,12 , identified APOBEC mutational signatures, copy number amplifications of CD274 (PD-L1) and PDCD1LG2 (PD-L2), somatic alterations affecting the PI(3)K-MAPK and TGFβR2 pathways 11,12 and mutations in chromatin modifier genes 11-13. Studies in HPV-infected individuals with head and neck squamous cell carcinomas linked HPV integration to changes in histone modification 14 and DNA methylation 15 , suggesting the potential for similar findings in cervical cancer. As part of the National Cancer Institute's (NCI's) HIV+ Tumor Molecular Characterization Project (HTMCP), we characterized the genomic, transcriptomic and epigenomic landscapes of cervical cancers from Ugandan patients. We identified previously uncharacterized differences in the epigenomes and transcriptomes of cervical tumors from individuals infected by different HPV clades and note that these clades appear relevant to prognosis. Results Patient samples and clinical data. Our cohort of 212 patients with cervical cancer received treatment at the Uganda Cancer Institute in Kampala. Of these, 118 made up our discovery cohort and 89 made up our extension cohort (Supplementary Tables 1 and 2, and Methods). HIV + patients (72/118, 61%) were 10 years younger, on average, than HIV-negative (HIV-) patients (mean, 42.9 versus 52.4 years).

No abstract