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. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies.

The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis

Background Measures of socioeconomic disadvantage may enable improved targeting of programs to prevent rehospitalizations, but obtaining such information directly from patients can be difficult. Measures of US neighborhood socioeconomic disadvantage are more readily available, although rarely employed clinically. Objective To evaluate the association between neighborhood socioeconomic disadvantage at the census block-group level, as measured by Singh’s validated Area Deprivation Index (ADI), and 30-day rehospitalization. Design Retrospective cohort study Setting United States Patients Random 5% national sample of fee-for-service Medicare patients discharged with congestive heart failure, pneumonia or myocardial infarction, 2004–2009 (N = 255,744) Measurements 30-day rehospitalizations. Medicare data were linked to 2000 Census data to construct an ADI for each patient’s census block-group, which were then sorted into percentiles by increasing ADI. Relationships between neighborhood ADI grouping and rehospitalization were evaluated using multivariate logistic regression models, controlling for patient sociodemographics, comorbidities/severity, and index hospital characteristics. Results The 30-day rehospitalization rate did not vary significantly across the least disadvantaged 85% of neighborhoods, which had an average rehospitalization rate=21%. However, within the most disadvantaged 15% of neighborhoods, rehospitalization rates rose from 22% to 27% with worsening ADI. This relationship persisted after full adjustment, with the most disadvantaged neighborhoods having a rehospitalization risk (adjusted risk ratio = 1.09, confidence interval 1.05–1.12) similar to that of chronic pulmonary disease (1.06, 1.04–1.08) and greater than that of diabetes (0.95, 0.94–0.97). Limitations No direct markers of care quality, access Conclusions Residence within a disadvantaged US neighborhood is a rehospitalization predictor of magnitude similar to chronic pulmonary disease. Measures of neighborhood disadvantage, like the ADI, could potentially be used to inform policy and post-hospital care. Primary Funding Source National Institute on Aging

SUMMARY MicroRNAs are well-suited to regulate tumor metastasis due to their capacity to coordinately repress numerous target genes, thereby potentially enabling their intervention at multiple steps of the invasion-metastasis cascade. We identify a microRNA exemplifying these attributes, miR-31, whose expression correlates inversely with metastasis in human breast cancer patients. Overexpression of miR-31 in otherwise-aggressive breast tumor cells suppresses metastasis. We deploy a stable microRNA sponge strategy to stably inhibit miR-31 in vivo; this allows otherwise-non-aggressive breast cancer cells to metastasize. These phenotypes do not involve confounding influences on primary tumor development and are specifically attributable to miR-31-mediated inhibition of several steps of metastasis, including local invasion, extravasation or initial survival at a distant site, and metastatic colonization. Such pleiotropy is achieved via coordinate repression of a cohort of metastasis-promoting genes, including RhoA. Indeed, RhoA re-expression partially reverses miR-31-imposed metastasis-suppression. These findings indicate that miR-31 uses multiple mechanisms to oppose metastasis.

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecological system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

Transitional care (TC) has received widespread attention from researchers, health system leaders, clinicians, and policy makers as they attempt to improve patients’ health outcomes and reduce preventable hospital readmissions. Yet little is known about the key elements of effective TC and how they relate to patients’ and caregivers’ needs and experiences. To address this gap, the Patient-Centered Outcomes Research Institute (PCORI) funded a national study, Project ACHIEVE. A primary aim of the study is the identification of TC components that yield desired patient and caregiver outcomes. Project ACHIEVE established a multi-stakeholder workgroup to recommend essential TC components for vulnerable Medicare beneficiaries. Guided by a review of published evidence, the workgroup identified and defined a preliminary set of components, then analyzed how well the set aligned with “real-world” patients’ and caregivers’ experiences. Through this process, the workgroup identified eight TC components: Patient Engagement, Caregiver Engagement, Complexity/Medication Management, Patient Education, Caregiver Education, Patient and Caregiver Well-Being, Care Continuity, and Accountability. While the degree of attention given to each component will vary based on the specific needs of patients and caregivers, workgroup members agree that health systems need to address all components to ensure optimal TC for all Medicare beneficiaries.

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