paywalled: Evolutionary Pathways in BRCAl-Associated Breast Tumors

Evolutionary Pathways in BRCAl-Associated Breast Tumors

Abstract

BRCAl-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.

SIGNIFICANCE: Defining the temporal order of tumor-driving somatic events is critical for early detection, risk stratification, and the design of chemopreventive therapies. Our combined experimental and computational approach reveal that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors.  

Cancer Discov; 2(6); 1–9. ©2012 AACR.

open access: Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations (technical)

Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations - UKPMC Article - UK PubMed Central

Abstract

Utilizing the concept of synthetic lethality has provided new opportunities for the development of targeted therapies, by allowing the targeting of loss of function genetic aberrations. In cancer cells with BRCA1 or BRCA2 loss of function, which harbor deficiency of DNA repair by homologous recombination, inhibition of PARP1 enzymatic activity leads to an accumulation of single strand breaks that are converted to double strand breaks but cannot be repaired by homologous recombination. Inhibition of PARP has therefore been advanced as a novel targeted therapy for cancers harboring BRCA1/2 mutations. Preclinical and preliminary clinical evidence, however, suggests a potentially broader scope for PARP inhibitors. Loss of function of various proteins involved in double strand break repair other than BRCA1/2 has been suggested to be synthetically lethal with PARP inhibition. Inactivation of these genes has been reported in a subset of human cancers and might therefore constitute predictive biomarkers for PARP inhibition. Here we discuss the evidence that the clinical use of PARP inhibition may be broader than targeting of cancers in BRCA1/2 germ-line mutation carriers.

Key words: homologous recombination, PARP inhibitor, BRCA1, BRCA2, PTEN, PALB2, EMSY, double strand break repair

Prognostic value of microsatellite instability (MSI) and PTEN expression in women with endometrial cancer: results from studies of the NCIC Clinical Trials Group (NCIC CTG)

Abstract

AIM: The impact of PTEN status and microsatellite instability (MSI) on the prognosis of women with endometrial cancer is controversial. The aim of this study was to investigate MSI and PTEN expression in two patient populations using data from NCIC CTG studies.
METHODS: Archival paraffin embedded tumour from women with endometrial cancer enrolled in NCIC CTG studies: EN5 (stage I/II) and IND 126, 148 and 160 (advanced/recurrent disease) were examined for MSI using BAT25/26 and for PTEN expression using immunohistochemistry. PTEN and MSI status were correlated with clinicopathologic variables and survival using data from NCIC CTG trial databases.
RESULTS: PTEN and MSI results were available from 128 and 163 patients, respectively. MSI+ tumours were more common in women enrolled in EN5 compared to the IND studies (p=0.01). PTEN negative tumours were associated with improved survival in both univariate (hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.32-0.94; p=0.03) and multivariate (adjusted HR 0.54, 95% CI 0.30-0.96; p=0.03) analyses in women enrolled in IND studies. Microsatellite stable tumours were associated with an improved prognosis in univariate (HR 0.18, 95% CI 0.06-0.51; p<0.0001)>
CONCLUSIONS: PTEN negative tumours in women with advanced disease are associated with improved survival. MSI+ tumours are more common in early stage disease and in this group of women are associated with a worse prognosis

Mutations in gene protecting body leads to development of cancer

Note: the PTEN mutation has and is being widely studied in ovarian cancer

"The study examined mutations in a gene called PTEN. People who inherit a mutated copy of this gene have Cowden syndrome, a condition that carries a high risk of cancer in a number of organs, including the breast, thyroid and ovary. In addition, PTEN is frequently mutated in normal body cells leading to prostate, lung and pancreatic cancers."