Results from London Regional Clinical Genetics services over a 5-year period on germline TP53 testing in women diagnosed with breast cancer at <30 years.

BACKGROUND: The most common cancer diagnosed in germline TP53 pathogenic variant (PV) carriers is premenopausal breast cancer. An increased rate of breast tumour HER2 positivity has been reported in this group. Screening for breast/other cancers is recommended in PV carriers. OBJECTIVES: 1. To assess the frequency of germline TP53 PVs reported diagnostically in women with breast cancer at <30 years of age.2. To evaluate the impact of personal/family history and HER2 status on the likelihood of germline TP53 pathogenic/likely pathogenic variant (PV/LPV) identification. METHODS: Genetic test results from patients undergoing diagnostic germline TP53 tests between 2012 and 2017 in the four London Regional Clinical Genetics Services were reviewed. Clinical/pathology data and family history were extracted from genetics files for women diagnosed with breast cancer at <30 years. RESULTS: The overall germline TP53 PV/LPV variant detection rate was 9/270=3.3% in all women diagnosed with breast cancer at <30 years and 2/171=1.2% in those with no second/subsequent cancer diagnosis or family history of TP53-spectrum cancers. Breast cancers were significantly more likely to be HER2-positive in TP53 PV/LPV carriers than in non-carriers (p=0.00006). CONCLUSIONS: Germline TP53 PVs/LPVs are uncommon among women diagnosed with breast cancer aged <30 years without other relevant personal or family cancer history but have an important clinical impact when identified.

Panomics: New Databases for Advancing Cardiology.

The multifactorial nature of cardiology makes it challenging to separate noisy signals from confounders and real markers or drivers of disease. Panomics, the combination of various omic methods, provides the deepest insights into the underlying biological mechanisms to develop tools for personalized medicine under a systems biology approach. Questions remain about current findings and anticipated developments of omics. Here, we search for omic databases, investigate the types of data they provide, and give some examples of panomic applications in health care. We identified 104 omic databases, of which 72 met the inclusion criteria: genomic and clinical measurements on a subset of the database population plus one or more omic datasets. Of those, 65 were methylomic, 59 transcriptomic, 41 proteomic, 42 metabolomic, and 22 microbiomic databases. Larger database sample sizes and longer follow-up are often better suited for panomic analyses due to statistical power calculations. They are often more complete, which is important when dealing with large biological variability. Thus, the UK BioBank rises as the most comprehensive panomic resource, at present, but certain study designs may benefit from other databases.

Identification of rare and common regulatory variants in pluripotent cells using population-scale transcriptomics.

Induced pluripotent stem cells (iPSCs) are an established cellular system to study the impact of genetic variants in derived cell types and developmental contexts. However, in their pluripotent state, the disease impact of genetic variants is less well known. Here, we integrate data from 1,367 human iPSC lines to comprehensively map common and rare regulatory variants in human pluripotent cells. Using this population-scale resource, we report hundreds of new colocalization events for human traits specific to iPSCs, and find increased power to identify rare regulatory variants compared with somatic tissues. Finally, we demonstrate how iPSCs enable the identification of causal genes for rare diseases.