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BACKGROUND: B lymphocytes have multifaceted functions in the tumour microenvironment, and their prognostic role in human cancers is controversial. Here we aimed to identify tumour microenvironmental factors that influence the prognostic effects of B cells. METHODS: We conducted a gene expression analysis of 3585 patients for whom the clinical outcome information was available. We further investigated the clinical relevance for predicting immunotherapy response. RESULTS: We identified a novel B cell-related gene (BCR) signature consisting of nine cytokine signalling genes whose high expression could diminish the beneficial impact of B cells on patient prognosis. In triple-negative breast cancer, higher B cell abundance was associated with favourable survival only when the BCR signature was low (HR = 0.68, p = 0.0046). By contrast, B cell abundance had no impact on prognosis when the BCR signature was high (HR = 0.93, p = 0.80). This pattern was consistently observed across multiple cancer types including lung, colorectal, and melanoma. Further, the BCR signature predicted response to immune checkpoint blockade in metastatic melanoma and compared favourably with the established markers. CONCLUSIONS: The prognostic impact of tumour-infiltrating B cells depends on the status of cytokine signalling genes, which together could predict response to cancer immunotherapy.

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. Significance: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880

BackgroundPan-cancer genomic analyses based on the magnitude of pathway activity are currently lacking. Focusing on the cell cycle, we examined the DNA mutations and chromosome arm-level aneuploidy within tumours with low, intermediate and high cell cycle activity.Patients and methodsMatching mRNA, gene mutational status, chromosomal arm-level aberrations and clinico-pathological data was assembled from pan-cancer studies of 9,515 patients with 32 different cancers. Cell cycle activity was estimated from mRNA data using the cell cycle score (CCS) signature. Barplots were used to visualise mutation and chromosomal aberration frequency within CCS subgroups. Kaplan-Meier and multivariable Cox-regression analyses were used to determine survival differences between CCS subgroups.ResultsCell cycle activity varied broadly across and within all cancers. TP53 and PIK3CA mutations were common in all CCS subgroups but with increasing frequency as cell cycle activity levels increased (P < 0.001). Mutations in BRAF and gains in 16p were less frequent CCS high tumours (P < 0.001). In Kaplan-Meier analysis, patients whose tumours were CCS Low had a longer PFI relative to intermediate or high (P < 0.001) and this significance remained in multivariable analysis (CCS intermediate: HR = 1.37; 95% CI 1.17 – 1.60, CCS high: 1.54; 1.29 – 1.84, CCS Low = Ref).ConclusionsCell cycle activity varies across and within cancers and whilst similar DNA alterations can be found at all activity levels, some notable exceptions exist. These data also demonstrate that independent prognostic information can be derived on a pan-cancer level from a simple measure of cell cycle activity.

Genomic alterations resulting in loss of control over the cell cycle is a fundamental hallmark of human malignancies. Whilst pan-cancer studies have broadly assessed tumour genomics and their impact on oncogenic pathways, analyses taking the baseline signalling levels in normal tissue into account are lacking. To this end, we aimed to reclassify the cell cycle activity of tumours in terms of their tissue of origin and determine if any common DNA mutations, chromosome arm-level changes or signalling pathways contribute to an increase in baseline corrected cell cycle activity. Combining normal tissue and pan-cancer data from over 13,000 samples we demonstrate that tumours of gynaecological origin show the highest levels of corrected cell cycle activity, partially owing to hormonal signalling and gene expression changes. We also show that normal and tumour tissues can be separated into groups (quadrants) of low/high cell cycle activity and propose the hypothesis of an upper limit on these activity levels in tumours. Published version This work was supported by the Iris, Stig och Gerry Castenbäcks Stiftelse for cancer research (N.P.T.); the King Gustaf V Jubilee Foundation (N.P.T.); the Stockholm Cancer Society (Cancerföreningen i Stockholm to L.S.L.); the Swedish Cancer Society (Cancerfonden, N.P.T. grant number: 200802; L.S.L. grant number: 190140); the Swedish Research Council (Vetenskapsrådet, grant number 2020-02466 to L.S.L); the Swedish Research Council for Health, Working life and Welfare, (FORTE, grant number 2019-00477 to L.S.L.); ALF medicine (grant number LS2018-1157 to L.S.L.) and the Gösta Milton Donation Fund (Stiftelsen Gösta Miltons donationsfond, to L.S.L. Open access funding provided by Karolinska Institute.

Purpose: Gene signatures and Ki67 stratify the same breast tumor into opposing good/poor prognosis groups in approximately 20% of patients. Given this discrepancy, we hypothesized that the combination of a clinically relevant signature and IHC markers may provide more prognostic information than either classifier alone. Experimental Design: We assessed Ki67 alone or combined with ER, PR and HER2 (forming IHC subtypes), and the research versions of the Genomic Grade Index, 70-gene, cell-cycle score, recurrence score (RS), and PAM50 signatures on matching TMA/whole tumor sections and microarray data in two Swedish breast cancer cohorts of 379 and 209 patients, with median follow-up of 12.4 and 12.5 years, respectively. First, we fit Cox proportional hazards models and used the change in likelihood ratio (Δ LR) to determine the additional prognostic information provided by signatures beyond that of (i) Ki67 and (ii) IHC subtypes. Second and uniquely, we then assessed whether signatures could compete well with pathology-based IHC classifiers by calculating the additional prognostic information of Ki67/IHC subtypes beyond signatures. Results: In cohort 1, only RS and PAM50 provided additional prognostic information beyond Ki67 and IHC subtypes (Δ LR-χ2 Ki67: RS = 12.8, PAM50 = 20.7, IHC subtypes: RS = 12.9, PAM50 = 11.7). Conversely, IHC subtypes added prognostic information beyond all signatures except PAM50. Similar results were observed in cohort 2. Conclusions: RS and PAM50 provided more prognostic information than the IHC subtypes in all breast cancer patients; however, the IHC subtypes did not add any prognostic information to PAM50. Clin Cancer Res; 23(24); 7512–20. ©2017 AACR.

Purpose: Transcriptional pathway activity and the molecular subtypes of breast cancer metastases have been shown to significantly influence patient postrelapse survival. Here, we further determine the relevance of clinically employed gene signatures in the advanced breast cancer (ABC) setting. Experimental Design: Sufficient RNA for expression profiling was obtained from distant metastatic or inoperable loco-regional relapse tissue by fine-needle aspiration from 109 patients of the Swedish TEX clinical trial. Gene signatures (GGI, 70 gene, recurrence score, cell-cycle score, risk of recurrence score, and PAM50) were applied to all metastases, and their relationship to long- (5-year) and short-term (1.5-year) postrelapse survival at all and locoregional lymph nodes (n = 40) versus other metastatic sites (n = 69) combined was assessed using Kaplan–Meier and/or multivariate Cox regression analyses. Results: The majority of metastases were classified into intermediate or high-risk groups by all signatures, and a significant association was found between metastatic signature subgroups and primary tumor estrogen receptor status and histologic grade (P < 0.05). When considering all sites of metastasis, only PAM50 was statistically significant in Kaplan–Meier analysis (Log-rank P = 0.008 and 0.008 for long- and short-term postrelapse breast cancer–specific survival, respectively). This significance remained in both uni- and multivariate models when restricting analyses to lymph node metastases only, and a similar trend was observed in other metastatic sites combined, but did not reach formal significance. Conclusions: Our findings are the first to demonstrate that the PAM50 signature can provide prognostic information from the lymph node metastases of ABC patients. Clin Cancer Res; 23(23); 7225–31. ©2017 AACR.