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Complete loss of BRCA1 or BRCA2 function is associated with sensitivity to DNA damaging agents. However, not all BRCA1 and BRCA2 germline mutation-associated tumors respond. Herein we report analyses of 160 BRCA1 and BRCA2 germline mutation-associated breast and ovarian tumors. Retention of the normal BRCA1 or BRCA2 allele (absence of locus-specific loss of heterozygosity (LOH)) is observed in 7% of BRCA1 ovarian, 16% of BRCA2 ovarian, 10% of BRCA1 breast, and 46% of BRCA2 breast tumors. These tumors have equivalent homologous recombination deficiency scores to sporadic tumors, significantly lower than scores in tumors with locus-specific LOH (ovarian, P  = 0.0004; breast P  < 0.0001, two-tailed Student’s t -test). Absence of locus-specific LOH is associated with decreased overall survival in ovarian cancer patients treated with platinum chemotherapy ( P  = 0.01, log-rank test). Locus-specific LOH may be a clinically useful biomarker to predict primary resistance to DNA damaging agents in patients with germline BRCA1 and BRCA2 mutations. Most tumours associated with germline BRCA1/BRCA2 loss of function mutations respond to DNA damaging agents, however, some do not. Herein, the authors identify that a subset of breast/ovarian tumors retain a normal allele, which is associated with decreased overall survival after DNA damage-inducing platinum chemotherapy.

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade. Neoadjuvant PD-1 blockade in patients with resectable melanoma followed by adjuvant maintenance results in early immunological effects driving clinical benefit and reveals transcriptional and genomic mechanisms of response.

Background Understanding the genetic causes underlying variability in chromatin accessibility can shed light on the molecular mechanisms through which genetic variants may affect complex traits. Thousands of ATAC-seq samples have been collected that hold information about chromatin accessibility across diverse cell types and contexts, but most of these are not paired with genetic information and come from distinct projects and laboratories. Results We report here joint genotyping, chromatin accessibility peak calling, and discovery of quantitative trait loci which influence chromatin accessibility (caQTLs), demonstrating the capability of performing caQTL analysis on a large scale in a diverse sample set without pre-existing genotype information. Using 10,293 profiling samples representing 1454 unique donor individuals across 653 studies from public databases, we catalog 24,159 caQTLs in total. After joint discovery analysis, we cluster samples based on accessible chromatin profiles to identify context-specific caQTLs. We find that caQTLs are strongly enriched for annotations of gene regulatory elements across diverse cell types and tissues and are often linked with genetic variation associated with changes in expression (eQTLs), indicating that caQTLs can mediate genetic effects on gene expression. We demonstrate sharing of causal variants for chromatin accessibility across human traits, enabling a more complete picture of the genetic mechanisms underlying complex human phenotypes. Conclusions Our work provides a proof of principle for caQTL calling from previously ungenotyped samples and represents one of the largest, most diverse caQTL resources currently available, informing mechanisms of genetic regulation of gene expression and contribution to disease.

Understanding the gene-specific risks for development of breast cancer will lead to improved clinical care for those carrying germline mutations in cancer predisposition genes. We sought to detail the spectrum of mutations and refine risk estimates for known and proposed breast cancer susceptibility genes. Targeted massively-parallel sequencing was performed to identify mutations and copy number variants in 26 known or proposed breast cancer susceptibility genes in 2134 BRCA1/2- negative women with familial breast cancer (proband with breast cancer and a family history of breast or ovarian cancer) from a largely European–Caucasian multi-institutional cohort. Case–control analysis was performed comparing the frequency of internally classified mutations identified in familial breast cancer women to Exome Aggregation Consortium controls. Mutations were identified in 8.2% of familial breast cancer women, including mutations in high-risk (odds ratio > 5) (1.4%) and moderate-risk genes (2 < odds ratio < 5) (2.9%). The remaining familial breast cancer women had mutations in proposed breast cancer genes (1.7%), Lynch syndrome genes (0.5%), and six cases had two mutations (0.3%). Case–control analysis demonstrated associations with familial breast cancer for ATM, PALB2 , and TP53 mutations (odds ratio > 3.0, p  < 10 −4 ), BARD1 mutations (odds ratio = 3.2, p  = 0.012), and CHEK2 truncating mutations (odds ratio  =  1.6, p  = 0.041). Our results demonstrate that approximately 4.7% of BRCA1/2 negative familial breast cancer women have mutations in genes statistically associated with breast cancer. We classified PALB2 and TP53 as high-risk, ATM and BARD1 as moderate risk, and CHEK2 truncating mutations as low risk breast cancer predisposition genes. This study demonstrates that large case–control studies are needed to fully evaluate the breast cancer risks associated with mutations in moderate-risk and proposed susceptibility genes. Familial breast cancer: Pinning down susceptibility genes beyond BRCA Women with the heritable form of breast cancer often harbor mutations in cancer-linked genes other than the usual suspects, BRCA1 and BRCA2 . Slavin, Maxwell, Lilyquist, Joseph, and colleagues from major national and international cancer centers studied 2134 women with familial breast cancer who tested negative for BRCA1/2 gene mutations. The researchers sequenced 26 known or proposed breast cancer susceptibility genes and found mutations in approximately 1 in every 12 of the study subjects. They then further broke down the susceptibility genes into those that confer high-, moderate- or low-risk—although not all the proposed breast cancer genes reached statistical significance and, as such, their clinical importance remains unclear. The results support adding some of the high- and moderate-risk genes to multi-panel diagnostic tests that aim to determine the likelihood of a women developing heritable breast cancer.

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (T ex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating T ex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade. The clinical benefit of anti-PD-1 antibody treatment is dependent on the extent to which exhausted CD8 T cells are reinvigorated in relation to the tumour burden of the patient. Blood biomarkers of blockade therapy response Only a small proportion of patients with advanced melanoma currently experience a long-term clinical benefit from therapeutic PD-1 blockade. Until now, blood-based profiling has not been widely explored as a means to understand the mechanisms of PD-1 blockade. In this study, Alexander Huang et al . analyse CD8 T cells in the blood and show that the clinical benefit of PD-1 blockade depends on the extent to which it reinvigorates exhausted CD8 T cells in relation to the pre-treatment tumour burden. Identifying the ratio of tumour burden to CD8 T-cell reinvigoration may help to predict how well a patient will respond to PD-1-blocking therapy.

The vast majority of trait-associated loci discovered through genome-wide association studies (GWAS) are non-coding, yet most lack statistical alignment with any discovered expression quantitative trait loci (eQTLs). In particular, eQTLs are depleted at gene-distal regions and at \"functionally important\" genes - those with strong selective constraint and complex regulatory landscapes - likely due to selective depletion of high-effect variants. Here, we investigate the role of variants with weaker effects on expression transmitted through distal regulatory elements, which are detectable as chromatin accessibility QTLs (caQTLs). We aggregated caQTL data from ten studies derived across different tissues, cell-types and lines, representing 104,024 lead caQTLs across 3,457 samples. We found that, across a range of gene properties, caQTLs are discovered at functionally important genes more often than eQTLs. These observations are consistent with a model in which many eQTLs and GWAS hits are mediated through genetic effects on regulatory elements, which may have weak or context-dependent effects on gene expression. Our results suggest that caQTL discovery is more sensitive than eQTL discovery in capturing the molecular consequences of GWAS hits, and can provide complimentary information to eQTLs by implicating functional mechanisms of additional disease-associated loci.

A correction to this article has been published and is linked from the HTML version of this article.

Non-coding variants discovered by genome-wide association studies (GWAS) are enriched in regulatory elements harboring transcription factor (TF) binding motifs, strongly suggesting a connection between disease association and the disruption of cis-regulatory sequences. Occupancy of a TF inside a region of open chromatin can be detected in ATAC-seq where bound TFs block the transposase Tn5, leaving a pattern of relatively depleted Tn5 insertions known as a \"footprint\". Here, we sought to identify variants associated with TF-binding, or \"footprint quantitative trait loci\" (fpQTLs) in ATAC-seq data generated from 170 human liver samples. We used computational tools to scan the ATAC-seq reads to quantify TF binding likelihood as \"footprint scores\" at variants derived from whole genome sequencing generated in the same samples. We tested for association between genotype and footprint score and observed 693 fpQTLs associated with footprint-inferred TF binding (FDR < 5%). Given that Tn5 insertion sites are measured with base-pair resolution, we show that fpQTLs can aid GWAS and QTL fine-mapping by precisely pinpointing TF activity within broad trait-associated loci where the underlying causal variant is unknown. Liver fpQTLs were strongly enriched across ChIP-seq peaks, liver expression QTLs (eQTLs), and liver-related GWAS loci, and their inferred effect on TF binding was concordant with their effect on underlying sequence motifs in 80% of cases. We conclude that fpQTLs can reveal causal GWAS variants, define the role of TF binding site disruption in disease and provide functional insights into non-coding variants, ultimately informing novel treatments for common diseases.

Understanding the genetic causes for variability in chromatin accessibility can shed light on the molecular mechanisms through which genetic variants may affect complex traits. Thousands of ATAC-seq samples have been collected that hold information about chromatin accessibility across diverse cell types and contexts, but most of these are not paired with genetic information and come from diverse distinct projects and laboratories. We report here joint genotyping, chromatin accessibility peak calling, and discovery of quantitative trait loci which influence chromatin accessibility (caQTLs), demonstrating the capability of performing caQTL analysis on a large scale in a diverse sample set without pre-existing genotype information. Using 10,293 profiling samples representing 1,454 unique donor individuals across 653 studies from public databases, we catalog 23,381 caQTLs in total. After joint discovery analysis, we cluster samples based on accessible chromatin profiles to identify context-specific caQTLs. We find that caQTLs are strongly enriched for annotations of gene regulatory elements across diverse cell types and tissues and are often strongly linked with genetic variation associated with changes in expression (eQTLs), indicating that caQTLs can mediate genetic effects on gene expression. We demonstrate sharing of causal variants for chromatin accessibility and diverse complex human traits, enabling a more complete picture of the genetic mechanisms underlying complex human phenotypes. Our work provides a proof of principle for caQTL calling from previously ungenotyped samples, and represents one of the largest, most diverse caQTL resources currently available, informing mechanisms of genetic regulation of gene expression and contribution to disease.

[This corrects the article DOI: 10.1038/s41523-017-0024-8.].