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

Pathologic quiz case: a woman with right facial nerve paralysis. Endolymphatic sac tumor associated with von Hippel-Lindau disease.

Over the past couple of decades, with discovery of novel targeted therapies, and expansion of our understanding of the molecular biology of rectal cancer, there has been an emergence of a wide variety of therapeutic options designed to facilitate a personalized approach for the treatment of this malignancy. A plethora of new prognostic and predictive single genes and proteins are being discovered that may reflect susceptibility and/or resistance to therapy. Pathologic complete response rates occur in 10-16% of patients and have been shown to correlate with both disease-free and overall survival. However, the response to neoadjuvant therapy remains variable and unpredictable. In this review, some of these novel markers are discussed for their potential use as pharmacogenetic predictors for specific therapy, drug toxicity, and disease outcome.

Predictive biomarkers for response to therapy in advanced colorectal/rectal adenocarcinoma.

Cell competition, a fitness sensing process is essential for tissue homeostasis. Employing cancer metastatic latency models, we show that cell competition results in displacement of latent metastatic (Lat-M) cells from the primary tumor. Lat-M cells resist anoikis and survive as residual metastatic disease. Remodelled extracellular matrix facilitates Lat-M cell displacement and survival in circulation. Disrupting cell competition dynamics by depleting SPARC reduced displacement from orthotopic tumors and attenuated metastases. In contrast, depletion of SPARC post-extravasation in lung resident Lat-M cells increased metastatic outgrowth. Furthermore, multi-regional transcriptomic analyses of matched primary tumors and metachronous metastases from kidney cancer patients identified tumor subclones with latent metastatic traits. Kidney cancer enriched for these latent metastatic traits had rapid onset of metachronous metastases and significantly reduced disease-free survival. Thus, an unexpected consequence of cell competition is displacement of cells with latent metastatic potential, thereby shaping metastatic latency and relapse.

Cell Competition Shapes Metastatic Latency and Relapse.

Pathologic Quiz Case A Woman With Right Facial Nerve Paralysis

493 Background: Epithelial to mesenchymal transition (EMT) is thought to play a crucial role in cancer progression and development of metastasis. Thus, we evaluated dysregulation of beta-catenin as...

Payal Kapur

Papers

Pathologic quiz case: a woman with right facial nerve paralysis. Endolymphatic sac tumor associated with von Hippel-Lindau disease.

Predictive biomarkers for response to therapy in advanced colorectal/rectal adenocarcinoma.

Cell Competition Shapes Metastatic Latency and Relapse.

Pathologic Quiz Case A Woman With Right Facial Nerve Paralysis

Dysregulation of the beta-catenin complex as an independent predictor of oncological outcomes in patients with ccRCC.