All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

/pdf/signatures-of-mutational-processes-in-human-cancer-j3duru54oq.pdf

Signatures of mutational processes in human cancer

CA : A Cancer Journal for Clinicians

The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.

/pdf/mutational-landscape-and-significance-across-12-major-cancer-118o8k5wzj.pdf

Mutational landscape and significance across 12 major cancer types

UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses.

https://thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)00561-4.pdf

Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial

845 irreversible electroporation: non-thermal and thermal capabilities for kidney ablation in a porcine model

1717 bilharzial related bladder cancer: pathological characteristics and value of cyclooxygenase-2 expression

4530 Background: A subset (10-20%) of clear cell renal cell carcinoma (ccRCC) tumors evades the immune system through expression of programmed death ligand 1 (PDL1), and these tumors are associated...

Association of loss of BAP1 expression in cell renal cell carcinomas with PDL1 expression.

1400 expression of cell cycle-related molecular markers in patients treated with radical cystectomy for squamous cell carcinoma of the bladder

Background: Nivolumab was the first immune checkpoint inhibitor to gain FDA approval for use in the treatment of renal cell carcinoma (RCC), however only a quarter of patients respond to nivolumab monotherapy (Nivo). More recently, the combination of ipilimumab and nivolumab (Ipi/Nivo) gained approval as first-line therapy in RCC with better outcomes than previously described with Nivo. Whether Ipi/Nivo can rescue RCC patients who progress on Nivo is an important question that remains unanswered. We sought to evaluate the oncologic benefit of treating metastatic RCC patients with Ipi/Nivo following progression on Nivo at our institution. Methods: A systematic medical record search was conducted to identify patients with RCC who had been treated with Ipi/Nivo following progression on Nivo from 2013 to Jan 31, 2018. Clinical benefit after starting Ipi/Nivo was measured by time to next therapy (TNT), overall survival (OS), and objective responses defined by RECIST v1.1. Kaplan Meier methods were used to analyze event-free survival. Results: 90 RCC patients were treated with Nivo from 2013 until Jan 31st, 2018. 17 (19%) of these patients received Ipilimumab following progression. Baseline characteristics of this subgroup were similar to the entire cohort. 13 (76.5%) had intermediate or poor risk disease by the Heng prognostic risk score. 6 (35.3%) patients had one prior line of therapy and 11 (64.7%) had two or more prior lines of therapy. The median duration of nivolumab monotherapy was 11.9 (95% CI; 4.4 - 13.0) months. Following the addition of ipilimumab at progression, the median TNT was 3.9 (95% CI; 3.3 to 7.0) months and the median OS was 20.3 (95% CI; 12.1 - 22.1) months. There were no objective responses to Ipi/Nivo following Nivo alone. Stable disease was the best overall response in 5 (29%) patients, and the remainder demonstrated progressive disease. One patient had stable disease lasting 11 months. Immune related adverse events were observed in 8 (47%) of patients resulting in cessation of therapy for 1 patient. Discussion: In this analysis, Ipi/Nivo did not confer substantial treatment benefit to patients who had already progressed on Nivo alone. The were no objective responses, and most patients were started on the next line of therapy at their first set of imaging studies. These patients still demonstrated approximately a 2-year OS suggesting that alternative agents, such as TKIs, remain effective treatments in this population. Prospective evaluation is warranted to further evaluate the utility of Ipi/Nivo following progression on Nivo alone. Citation Format: Roy M. Elias, Nirmish Singla, Isaac A. Bowman, Payal Kapur, Raquibul Hannan, Hans Hammers, James Brugarolas. Outcomes of combined ipilimumab and nivolumab therapy following progression on nivolumab monotherapy in renal cell carcinoma: A retrospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4106.

Abstract 4106: Outcomes of combined ipilimumab and nivolumab therapy following progression on nivolumab monotherapy in renal cell carcinoma: A retrospective cohort study

Payal Kapur

Papers

845 irreversible electroporation: non-thermal and thermal capabilities for kidney ablation in a porcine model

1717 bilharzial related bladder cancer: pathological characteristics and value of cyclooxygenase-2 expression

Association of loss of BAP1 expression in cell renal cell carcinomas with PDL1 expression.

1400 expression of cell cycle-related molecular markers in patients treated with radical cystectomy for squamous cell carcinoma of the bladder

Abstract 4106: Outcomes of combined ipilimumab and nivolumab therapy following progression on nivolumab monotherapy in renal cell carcinoma: A retrospective cohort study