The development and progression of invasive breast cancer is characterized by alterations to the genome and epigenome. However, the relationship between breast tumor characteristics, disease subtypes, and patient outcomes with the cumulative burden of these molecular alterations are not well characterized. We determined the average departure of tumor DNA methylation from adjacent normal breast DNA methylation using Illumina 450K methylation data from 700 invasive breast tumors and 90 adjacent normal breast tissues in The Cancer Genome Atlas. From this we generated a novel summary measure of altered DNA methylation, the DNA methylation dysregulation index (MDI), and examined the relation of MDI with tumor characteristics and summary measures that quantify cumulative burden of genetic mutation and copy number alterations. Our analysis revealed that MDI was significantly associated with tumor stage (P = 0.017). Across invasive breast tumor subtypes we observed significant differences in genome-wide DNA MDIs (P = 4.9E–09) and in a fraction of the genome with copy number alterations (FGA) (P = 4.6E–03). Results from a linear regression adjusted for subject age, tumor stage, and estimated tumor purity indicated a positive significant association of MDI with both MCB and FGA (P = 0.036 and P < 2.2E–16). A recursively partitioned mixture model of all 3 somatic alteration burden measures resulted in classes of tumors whose epigenetic and genetic burden profile were associated with the PAM50 subtype and mutations in TP53, PIK3CA, and CDH1. Together, our work presents a novel framework for characterizing the epigenetic burden and adds to the understanding of the aggregate impact of epigenetic and genetic alterations in breast cancer.

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Summary.-Serum concentrations of oestradiol-173 were measured daily throughout one menstrual cycle in 32 normal women, 31 women with benign disease of the breast and 10 with cancer of the breast. The concentrations were found to differ significantly from normal in women with cysts and to a lesser extent in those with cancer of the breast. In 25 normal post-menopausal and in 27 post-menopausal women with cancer repeated assays disclosed consistently low levels of oestradiol-17/f.

comparable age, while finding no difference in plasma levels of androstenedione or testosterone.The present study was undertaken to measure by radioimmunoassay oestradiol-17/ in the serum of male breast-cancer patients to determine whether there was an excess of this oestrogen over normal controls of comparable age; also, to determine whether such an excess was elicited from the testis by an abnormal stimulation by LH and FSH, or whether the excess of oestrogen was transformed from a high level of its precursor, testosterone.During this study, 3 of the patients had biopsy specimens taken from skin metastases, and the tissue was then assayed for receptor sites for oestradiol-173 and progesterone. Leclereq et al. (1976) reported 6 out of 7 primary tumours in men with positive oestrogen-receptor activity, and one out of 3 patients with metastatic disease had receptor sites in tissue biopsy material.The investigations were performed on 10 men aged between 30 and 75 years with histologically proven carcinoma. Blood samples were taken before the start of primary treatment.Control studies were carried out on 31 men with a mean age of 61-9 years (range 37-89) who were free from any evidence of disease or history of chronic illness, and none of whom were taking any drugs, including hormones.Blood was collected in plain tubes,