Stone, A. | bioRxiv Science

bioRxiv2018

MicroRNA-196a is regulated by ER and is a prognostic biomarker in ER+ Breast Cancer

MicroRNAs are potent post-transcriptional regulators involved in all hallmarks of cancer. Mir-196a is transcribed from two loci and has been implicated in a wide range of developmental and pathogenic processes, with targets including Hox, Fox, Cdk inhibitors and annexins. Genetic variants and altered expression of miR196a are associated with risk and progression of multiple cancers including breast cancer, however little is known about the regulation of the genes encoding this miRNA, nor the impact of variants therein. Here we demonstrate that MIR196A displays complex and dynamic expression patterns, in part controlled by long range transcriptional regulation between promoter and enhancer elements bound by ER. Expression of this miRNA is significantly increased in models of hormone receptor positive disease resistance. The expression of MIR196A also proves to be a robust prognostic factor for patients with advanced and post-menopausal ER+ disease. This work sheds light on the normal and abnormal regulation of MIR196A and provides a novel stratification method for therapeutically resistant breast cancer.

cancer biology↗

bioRxiv2018

The Medical Genome Reference Bank: a whole-genome data resource of 4,000 healthy elderly individuals. Rationale and cohort design

Allele frequency data from human reference populations is of increasing value for filtering and assignment of pathogenicity to genetic variants. Aged and healthy populations are more likely to be selectively depleted of pathogenic alleles, and therefore particularly suitable as a reference populations for the major diseases of clinical and public health importance. However, reference studies of the healthy elderly have remained under-represented in human genetics. We have developed the Medical Genome Reference Bank (MGRB), a large-scale comprehensive whole-genome dataset of confirmed healthy elderly individuals, to provide a publicly accessible resource for health-related research, and for clinical genetics. It also represents a useful resource for studying the genetics of healthy aging. The MGRB comprises 4,000 healthy, older individuals with no reported history of cancer, cardiovascular disease or dementia, recruited from two Australian community-based cohorts. DNA derived from blood samples will be subject to whole genome sequencing. The MGRB will measure genome-wide genetic variation in 4,000 individuals, mostly of European decent, aged 60-95 years (mean age [≥] 75 years). The MGRB has committed to a policy of data sharing, employing a hierarchical data management system to maintain participant privacy and confidentiality, whilst maximizing research and clinical usage of the database. The MGRB will represent a dataset of international significance, broadly accessible to the clinical and genetic research community.

genomics↗