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This publication surveys the profound and far-reaching ramifications that have arisen from the very significant advances in our understanding of the genetic basis of familial breast and ovarian cancer. Written by international experts from Europe and North America, this book provides the busy clinician with a contemporary and wide-ranging guide to the latest developments in the diagnosis, genetics, screening, prevention and management of familial breast cancer. This area has advanced in knowledge so rapidly that this publication provides an unrivalled source of information including sections on ethical and insurance issues and the different cultural differences in breast cancer. The use of recently devised cancer genetics clinics and different referral criteria and patterns to these clinics are detailed. The volume will be of immense value to all clinical geneticists, oncologists, and healthcare professionals involved in screening and counselling programmes.

Pharmacogenetics is becoming increasingly relevant in the diagnosis, treatment, and recovery of cancer patients. A major problem facing oncologists is the outstanding varied efficacy of treatment. Promising advances in pharmacogenetics have allowed the development of effective agents which will enable personalized cancer chemotherapy to become routine for the clinical practice. Written by experts in the field and combining information that is unable to be found in a single source volume, Pharmocogenetics of Breast Cancer: combines a complete overview of pharmacogenetics and how it relates to breast oncology for diagnosis, treatment, and the recovery of patients using an individualized therapy model is the first single source reference demonstrating the application of pharmacogenetics in the care of breast cancer patients enables physicians a coherent interpretation of the emerging science of pharmacogenetics, aiding them to incorporate individual therapies in their own practice gives practical guidance on various forms of specimen collection, tissue selection, and handling procedures

Health & Sickness -- Consumer Health -->. This book by a scientist whose background is in cellular and molecular biology examines the fearsome disease that strikes one in eight women in the United States. Although women are more likely to die of heart disease or of lung cancer, a diagnosis of breast cancer is the medical pronouncement that a woman is most likely to fear. It kills more than 40,000 Americans annually. Why are some women more vulnerable than others? The interplay between genetics and environment is suspected. Thus this book for general readers will help them understand the genetic bases of both sporadic and inherited breast cancers. Although only five to ten percent of breast cancer patients have inherited mutations in these genes, all women need to understand the genetic implications of the disease. In clear, concise language Barbara T. Zimmerman guides the reader through the complexities, discussing in detail the genes that are known to increase susceptibility and the ways they are passed on. Examining the general biology of breast cancer, Zimmerman describes how sporadic and inherited forms of the disease arise and how the location of the tumors can affect the body. She discusses genetic mutations and their roles in the development of tumors and tells how these potentially cancer-inducing genes were discovered. Covered too are the issues of risk, prevention, screening, diagnosis, therapy, and genetic testing and counseling. Zimmerman concludes with a comprehensive analysis of current research and with an emphasis on how a woman's understanding of inherited breast cancer can help doctors seeking to design better methods for prevention and therapy. A useful list of resources for further information about the genetic causes of breast cancer is included. Barbara T. Zimmerman did her graduate work in experimental pathology and her post-doctoral research in the cellular and molecular processes of disease. Widely published, she is the manager of the Denver-based firm Biomedical Communication and Consulting.

BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR–Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, ‘Shieldin’ (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance. Through CRISPR–Cas9 screen, Dev et al. identified that SHLD1/2 inhibition contributes to PARP-inhibitor resistance. Mechanistically, SHLDs promote non-homologous end-joining and antagonize homologous recombination.

Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans -effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets. Quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of genomically annotated human breast cancer samples elucidates functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies potential therapeutic targets. Proteogenomics of breast cancer This large-scale collaborative study describes quantitative-mass spectrometry-based proteomic and phosphoproteomic analyses of 105 breast cancer samples from The Cancer Genome Atlas (TCGA), representing the four principal mRNA-defined breast cancer intrinsic subtypes. The result is a high-quality proteomic resource for human breast cancer investigation, achieved using technologies and analytical approaches that illuminate the connections between genome and proteome. The data narrow candidate nominations for driver genes within large deletions and amplified regions, and identify potential therapeutic targets.

Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Barcoding experiments showed that cell line evolution occurs as a result of positive clonal selection that is highly sensitive to culture conditions. Analyses of single-cell-derived clones demonstrated that continuous instability quickly translates into heterogeneity of the cell line. When the 27 MCF7 strains were tested against 321 anti-cancer compounds, we uncovered considerably different drug responses: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origins and consequences of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research. The extent, origins and consequences of genetic variation within human cell lines are studied, providing a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.

Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2 + macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed ‘ecotypes’, with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer. A multi-omic atlas of breast cancers, integrating single-cell RNA sequencing, spatial transcriptomics and immunophenotyping, identifies nine ecotypes associated with cellular heterogeneity and prognosis.