MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%-7.8%) of healthy individuals carry the SNP285C/309G haplotype. In vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n = 1993) and breast (n = 1973) cancer patients versus healthy controls (n = 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58-0.94) and breast cancer (OR 0.79; CI 0.62-1.00) among SNP309G carriers.

A B S T R A C TBreast cancer is a heterogeneous disease that can be divided in subtypes based on histol-

BackgroundThe course of fatigue in long-term breast cancer survivors (BCSs) is unknown. The current study examined chronic fatigue (CF) cross-sectionally and longitudinally in relapse-free women up to 10 years after multimodal treatment for BC stage II/III. The prevalence of persistent fatigue (PF: having CF at two assessments separated by >2 years) and its predictors were also investigated.MethodsData from questionnaires (including the Fatigue Questionnaire and questions regarding socio-demographics and physical symptoms) were collected twice from 249 BCSs: 2.5–7 years post-BC diagnosis (T1) and 2.5–3 years thereafter (T2). A physical examination including blood sampling was performed at T1.ResultsCF was diagnosed in 33% of the women at T1 and in 39% at T2, including 57 (23%) subjects with PF. Current psychological distress, treatment-area related discomfort and high body mass index (BMI) were associated with CF at T1 and predicted PF. Increased leukocyte count also predicted PF. Treatment for mental problems prior to the BC, increased hsCRP-level and respiratory symptoms were associated with CF at T1 but did not predict PF.ConclusionsWomen may experience fatigue up to 10 years after multimodal BC treatment, with about one third having CF and about one fourth having PF.Implications for cancer survivorsDuring follow-up, BCSs and their doctors should maximize their efforts to reduce psychological distress, overweight and pain within the BC-treated area, all linked to the development of persistent fatigue.

BackgroundDuctal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development.ResultsWe generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma.ConclusionsThis work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0435-x) contains supplementary material, which is available to authorized users.