Search

Germline and somatic interactions define actionable genomic patterns driving acquired therapy resistance in breast cancer.

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.

Artifact mutations from FFPE are a major barrier blocking WGS adoption in clinical oncology. FFPErase, a machine learning framework, eliminates these with high accuracy in multiinstitutional datasets, delivering clinical-grade variant reports.

A combined sequencing technique assesses 18 patients with high-grade serous ovarian cancer over a multi-year period from diagnosis to recurrence and shows drug resistance typically arises from selective expansion of one or a few clones present at diagnosis.

Oral poly(ADP)-ribose polymerase (PARP) inhibitors have been shown to have great promise in the treatment of cancer inBRCA mutation carriers. This case provides evidence that these agents are efficacious in patients with PTEN deficiency but no BRCAmutations, opening up a new patient cohort for this treatment.

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.

A single-cell sequencing study using more than 30,000 tumour genomes from human ovarian cancers shows that whole-genome doubling is an ongoing mutational process that drives tumour evolution and disrupts immunity.

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.

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.

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.

Metaplastic breast carcinoma (MBC) accounts for 0.2–5% of invasive breast cancers. The majority of MBCs have a triple-negative phenotype, are highly heterogeneous and respond poorly to chemotherapy. Understanding their divergent differentiation and identifying the cell of origin might provide some much-needed insight into this disease.

In a phase 2 trial, nivolumab achieved a response rate of 58% in patients with mismatch-repair-deficient gynecological cancers, meeting the primary endpoint, and genomic and immunologic features correlated with response.

Multiple treatment-emergent alterations appear in patients with advanced-stage cancer who were treated with a KRAS inhibitor.

A mathematical framework to estimate the fitness of cancer driver mutations by integrating mutational bias, oncogenicity and immunogenicity finds fundamental trade-offs in cancer evolution.

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.

JaBbA v1 pinpoints the ‘loose ends’ of large (>10-kb) unmapped structural variants in short-read DNA sequencing, suggesting that about 90% of cancer chromosomal alterations outside centromeres are resolvable with short reads and that long reads will primarily improve calling of smaller somatic variants.

When do cancer cells acquire metastatic identity? Recent reports have indicated that the propensity to metastasize might be hardwired early during tumor development. Now it seems that breast cancer cells might acquire a gene signature early in tumorigenesis that predicts the site of metastasis.

Linked-read whole-genome sequencing reveals patterns of structural DNA variants that are specific to homologous recombination deficiency and can be used to distinguish between BRCA1- and BRCA2-deficient phenotypes.

Missegregated chromosomes that are sequestrated in micronuclei are subject to changes in histone modifications leading to abnormalities in chromatin accessibility that remain long after the chromosomes have been reincorporated into the primary nucleus.

Multi-modal analysis of genomically unstable ovarian tumours characterizes the contribution of anatomical sites and mutational processes to evolutionary phenotypic divergence and immune resistance mechanisms.

Single-cell whole-genome sequencing shows that 'foreground' cell-to-cell structural variation and alterations in copy number are associated with genomic diversity and evolution in triple-negative breast and high-grade serous ovarian cancers.

A new high-throughput platform to find rare T cells that can recognize shared cancer neoantigens identifies T cell receptors specific for a conserved, immunogenic and therapeutically actionable epitope in mutant PI3Kα, one of the most common driver oncogenes

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.

Immunogenomic analyses of advanced high-grade serous ovarian cancer samples before and after neoadjuvant chemotherapy show that the tumor–immune microenvironment is intrinsically heterogeneous and that chemotherapy induces local immune activation.

Applying the concept of ecosystem energetics to a grassland biodiversity experiment, the authors show that the storage and flow of energy across the whole trophic network, both above- and belowground, becomes more efficient as plant diversity increases.

Samstein et al. report that mutations in BRCA1 and BRCA2 result in distinct mutational genomic landscapes, effects on the tumor-immune microenvironment and response to immune checkpoint therapy.

Germline mutations in homologous recombination (HR) DNA repair genes are linked to breast and ovarian cancer. Here, the authors show that mutually exclusive bi-allelic inactivation of HR genes are present in other cancer types and associated with genomic features of HR deficiency, expanding the potential use of HR-directed therapies.

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.

A method enabling copy-number analysis of single cells from formalin-fixed paraffin-embedded samples is described, validated and applied to analyze samples of synchronous ductal carcinoma in situ and invasive breast carcinoma.

Granular cell tumors (GCTs) are rare tumors that arise in multiple anatomical locations. Here, the authors investigate the genomics of GCTs, finding inactivating somatic mutations in ATP6AP1 or ATP6AP2 in 72% of the 82 GCTs analyzed. In vitro manipulation of these genes recapitulated GCT phenotypes in cellular models.

Adenomyoepithelioma is a rare tumor of the breast with an unknown genetic basis. Here the authors perform a genomic analysis of adenomyoepitheliomas revealing that their repertoire of somatic mutations vary according to the estrogen receptor (ER) status, and that ER-negative tumors harbor recurrent mutations in HRAS and PI3K pathway genes.