Search

Jorge Reis-Filho and colleagues identify recurrent mutations in PRKD1 in 73% of polymorphous low-grade adenocarcinoma, a malignant tumor of the minor salivary glands. The mutations cause activation of the PRKD1 serine-threonine kinase.

Mucosal melanomas are not thought to be UV radiation (UVR)-driven, yet some present UVR-related mutations. Here the authors show that some mucosal melanomas, especially conjunctival, present mutations characteristic of UVR exposure, yet share structural variants typical of other mucosal melanomas.

DNA circulating in the plasma of cancer patients carries features of the primary tumour, however such DNA is found in low levels in brain cancer patients. Here, the authors show that circulating tumour DNA can be detected in the cerebral spinal fluid of cancer patients and that this better recapitulates the primary tumour compared to DNA from the plasma.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

The authors develop multimodal machine learning models to infer metastatic recurrence risk for early-stage, hormone receptor-positive breast cancer from H&E images using >6000 cases across three centers, outperforming a nomogram and unimodal methods.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Microarray-based gene-expression profiling has advanced the breast cancer field. However, definitive answers to many of the questions for the successful implementation of personalized medicine remain elusive. The authors discuss the hurdles in the development and validation of molecular classification systems, and the challenges ahead for development of the next generation of molecular predictors.

DNA double-stranded breaks threaten genome stability. Here, the authors show that transcript RNA serves as a repair template in human cells and identify Polζ as a key factor in RNA-templated DSB repair. This process can lead to intron deletion, resulting in a mutational signature in cancer genomes.

Phenotypic variation between tumour types is likely to reflect the nature of the cell of origin and the genes involved in pathogenesis. Compared with most sporadic breast cancers, those arising in carriers of BRCA1 mutations usually have distinctive pathological characteristics. A new study suggests that a role for BRCA1 in the determination of stem-cell fate may explain this phenomenon.

The diagnostic utility of tumor size in breast cancer is dependent on multiple factors. In this Perspective, Foulkes and coauthors recommend that tumor size should not be automatically considered in treatment decisions for all breast cancer subtypes. The authors discuss how the correlation between size and survival is disrupted in triple-negative and basal-like breast cancers and propose two specific mechanisms that might be responsible for this disrupted relationship.

Analysis of a large cohort of metastatic breast cancer samples shows that APOBEC mutational signatures are enriched in post-treatment samples. APOBEC activity was also associated with mutations known to drive drug resistance.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Microarray studies have been used to unravel the molecular characteristics of breast cancer and a molecular taxonomy has been proposed. The authors of this Review discuss the origins of the diversity of breast cancer and, based on the study of histological special types of breast cancer, propose an approach for the identification of novel therapeutic targets.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Little is known about the genetics of sclerosing stromal tumor of the ovary, a rare type of sex cord-stromal tumor. Here, the authors use sequencing strategies to show that in a cohort of 26 tumor samples 65% carry a FHL2-GLI2 fusion gene and demonstrate in vitro that the fusion gene has oncogenic properties.

An analysis of three multi-cancer cohorts shows that the detection of ctDNA using liquid biopsies has the potential to improve the risk prediction of cancer-associated venous thromboembolism.

Publication bias and hidden multiple hypotheses testing distort the assessment of the true value of biomarkers. The authors of this article propose that a registry should be created for biomarker studies initially focused on studies that use specimens from randomized trials, as a means to alleviate the limitations associated with both publication bias and multiple hypotheses testing.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Analyses of in vivo models, cell lines and patient-derived samples show that apolipoprotein B mRNA-editing catalytic subunit 3B (APOBEC3B) not only restrains lung tumor initiation but also that its upregulation is associated with resistance to targeted therapies. This study highlights the complex and context-dependent role of APOBEC3B in lung cancer.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

This report identifies oncogenic fusions in individuals with breast cancer involving the genes encoding NOTCH and MAST, recurring in approximately 5–7% of studied cases. The fusions show growth-promoting properties that suggest that they may represent targetable events in a subset of people with breast cancer.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Collisions of transcription and replication machineries on the same DNA strand threaten genomic stability. Here, the authors show that RAD52 prevents these collisions by regulating R-loop formation and resolution. RAD52 deficiency leads to increased R-loops, exacerbated collisions, DNA damage, and higher mutational burden in tumors.

A study generates a clinicogenomics dataset resource, MSK-CHORD, that combines natural language processing-derived clinical annotations with patient medical data from various sources to improve models of cancer outcome.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Circulating blood biomarkers are promising non-invasive real-time surrogates for tumour tissue-based biomarkers, and in breast cancer they have been used as tools for diagnosis, prognostication, prediction, monitoring of therapeutic response, and resistance. This Review outlines the techniques, challenges and possibilities of this promising area.

The genomic landscape of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC) remains to be explored. Here, the authors analyse a cohort of 233 patients with BM including 47 primary tumour, 42 extracranial metastatic matched samples and reveal distinct mutational patterns.

Shah and colleagues develop a multimodal data integration framework that interprets genomic, digital histopathology, radiomics and clinical data using machine learning to improve diagnosis of patients with high-grade ovarian serous carcinoma.

Immune response during breast cancer progression remains to be explored. Here, the characterisation of sequential and parallel multiregion samples of an index patient and a cohort of metastatic triple-negative breast cancers reveals convergent immune evasion mechanisms and an increase in tumor genomic heterogeneity.