SUMMARYCDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1-and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators.
Neurofibromatosis Type I (NF1) is caused by variants in neurofibromin (NF1). NF1 predisposes to a variety of benign and malignant tumor types, including breast cancer. Women with NF1 <50 years of age possess an up to five-fold increased risk of developing breast cancer compared with the general population. Impaired emotional functioning is reported as a comorbidity that may influence the participation of NF1 patients in regular clinical surveillance despite their increased risk of breast and other cancers. Despite emphasis on breast cancer surveillance in women with NF1, the uptake and feasibility of high-risk screening programs in this population remains unclear. A retrospective chart review between 2014–2018 of female NF1 patients seen at the Elizabeth Raab Neurofibromatosis Clinic (ERNC) in Ontario was conducted to examine the uptake of high-risk breast cancer screening, radiologic findings, and breast cancer characteristics. 61 women with pathogenic variants in NF1 enrolled in the high-risk Ontario breast screening program (HR-OBSP); 95% completed at least one high-risk breast screening modality, and four were diagnosed with invasive breast cancer. Our findings support the integration of a formal breast screening programs in clinical management of NF1 patients.
The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca++ signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.
IntroductionFollowing a cancer diagnosis, patients and their caregivers face crucial decisions regarding goals of care and treatment, which have consequences that can persist throughout their cancer journey. To foster informed and value-driven treatment choices, evidence-based information on outcomes relevant to patients is needed. Traditionally, clinical studies have largely focused on a few concrete and easily measurable outcomes such as survival, disease progression and immediate treatment toxicities. These outcomes do not capture other important factors that patients consider when making treatment decisions. Patient-centred outcomes (PCOs) reflect the patients’ individual values, preferences, needs and circumstances that are essential to directing meaningful and informed healthcare discussions. Often, however, these outcomes are not included in research protocols in a standardised and practical fashion. This scoping review will summarise the existing literature on PCOs in gastrointestinal (GI) cancer care as well as the tools used to assess these outcomes. A comprehensive list of these PCOs will be generated for future efforts to develop a core outcome set.Methods and analysisThis scoping review will follow Arksey and O’Malley’s expanded framework for scoping reviews. We will systematically search Medline, Embase, CINAHL, Cochrane Library and APA PsycINFO databases for studies examining PCOs in the context of GI cancer. We will include studies published in or after the year 2000 up to the date of the final searches, with no language restrictions. Studies involving adult patients with GI cancers and discussion of any PCOs will be included. Opinion pieces, protocols, case reports and abstracts will be excluded. Two authors will independently perform two rounds of screening to select studies for inclusion. The data from full texts will be extracted, charted and summarised both quantitatively and qualitatively.Ethics and disseminationNo ethics approval is required for this scoping review. Results will be disseminated through scientific publication and presentation at relevant conferences.
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