Geographic and age-related variations in mutational processes in colorectal cancer.

Colorectal cancer incidence rates vary geographically and have changed over time. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, has doubled in many countries. The reasons for this increase are unknown.

The Complexity of Tobacco Smoke-Induced Mutagenesis in Head and Neck Cancer.

Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). Here, we further explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported.

Geographic variation of mutagenic exposures in kidney cancer genomes.

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations.

COSMIC: a curated database of somatic variants and clinical data for cancer.

The Catalogue Of Somatic Mutations In Cancer (COSMIC), https://cancer.sanger.ac.

Uptake of invitations to a lung health check offering low-dose CT lung cancer screening among an ethnically and socioeconomically diverse population at risk of lung cancer in the UK (SUMMIT): a prospective, longitudinal cohort study.

Background: Lung cancer screening with low-dose CT reduces lung cancer mortality, but screening requires equitable uptake from candidates at high risk of lung cancer across ethnic and socioeconomic groups that are under-represented in clinical studies. We aimed to assess the uptake of invitations to a lung health check offering low-dose CT lung cancer screening in an ethnically and socioeconomically diverse cohort at high risk of lung cancer.

Methods: In this multicentre, prospective, longitudinal cohort study (SUMMIT), individuals aged 55-77 years with a history of smoking in the past 20 years were identified via National Health Service England primary care records at practices in northeast and north-central London, UK, using electronic searches.

Uncovering novel mutational signatures by extraction with SigProfilerExtractor.

Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures.

Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence.

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates.

Convergent somatic mutations in metabolism genes in chronic liver disease.

The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease than in normal liver, which enables positive selection to shape the genomic landscape. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease.

Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis.

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced.

Author Correction: Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. '. The Article has not been corrected.

Classification and Personalized Prognosis in Myeloproliferative Neoplasms.

Background: Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment.

Methods: We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations and copy-number changes.

Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups.

In multiple myeloma, next-generation sequencing (NGS) has expanded our knowledge of genomic lesions, and highlighted a dynamic and heterogeneous composition of the tumor. Here we used NGS to characterize the genomic landscape of 418 multiple myeloma cases at diagnosis and correlate this with prognosis and classification. Translocations and copy number abnormalities (CNAs) had a preponderant contribution over gene mutations in defining the genotype and prognosis of each case.

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations.

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening.

The driver landscape of sporadic chordoma.

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases.

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases.

ascatNgs: Identifying Somatically Acquired Copy-Number Alterations from Whole-Genome Sequencing Data.

We have developed ascatNgs to aid researchers in carrying out Allele-Specific Copy number Analysis of Tumours (ASCAT). ASCAT is capable of detecting DNA copy number changes affecting a tumor genome when comparing to a matched normal sample. Additionally, the algorithm estimates the amount of tumor DNA in the sample, known as Aberrant Cell Fraction (ACF).

cgpCaVEManWrapper: Simple Execution of CaVEMan in Order to Detect Somatic Single Nucleotide Variants in NGS Data.

CaVEMan is an expectation maximization-based somatic substitution-detection algorithm that is written in C. The algorithm analyzes sequence data from a test sample, such as a tumor relative to a reference normal sample from the same patient and the reference genome. It performs a comparative analysis of the tumor and normal sample to derive a probabilistic estimate for putative somatic substitutions.

Genomic Classification and Prognosis in Acute Myeloid Leukemia.

Background: Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice.

Methods: We enrolled a total of 1540 patients in three prospective trials of intensive therapy.

Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations.

VAGrENT: Variation Annotation Generator.

VAGrENT is a tool that provides biological context and effect prediction for genomic sequence variants. It annotates single base substitutions and small insertions and deletions by comparing them to reference information within or close to genes or other transcribed elements. This information provides the critical insight required to inform the biological or clinical significance of variant data generated from sequencing studies.

cgpPindel: Identifying Somatically Acquired Insertion and Deletion Events from Paired End Sequencing.

cgpPindel is a modified version of Pindel that is optimized for detecting somatic insertions and deletions (indels) in cancer genomes and other samples compared to a reference control. Post-hoc filters remove false positive calls, resulting in a high-quality dataset for downstream analysis. This unit provides concise instructions for both a simple 'one-shot' execution of cgpPindel and a more detailed approach suitable for large-scale compute farms.

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing.

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods.