LRP1B Deletion in High-Grade Serous Ovarian Cancers Is Associated with Acquired Chemotherapy Resistance to Liposomal Doxorubicin

High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients. Cancer Res; 72(16); 4060-73. ?2012 AACR.     

Efficient molecular subtype classification of high‐grade serous ovarian cancer

High‐grade serous carcinomas (HGSCs) account for approximately 70% of all epithelial ovarian cancers diagnosed. Using microarray gene expression profiling, we previously identified four molecular subtypes of HGSC: C1 (mesenchymal), C2 (immunoreactive), C4 (differentiated), and C5 (proliferative), which correlate with patient survival and have distinct biological features. Here, we describe molecular classification of HGSC based on a limited number of genes to allow cost‐effective and high‐throughput subtype analysis. We determined a minimal signature for accurate classification, including 39 differentially expressed and nine control genes from microarray experiments. Taqman‐based (low‐density arrays and Fluidigm), fluorescent oligonucleotides (Nanostring), and targeted RNA sequencing (Illumina) assays were then compared for their ability to correctly classify fresh and formalin‐fixed, paraffin‐embedded samples. All platforms achieved > 90% classification accuracy with RNA from fresh frozen samples. The Illumina and Nanostring assays were superior with fixed material. We found that the C1, C2, and C4 molecular subtypes were largely consistent across multiple surgical deposits from individual chemo‐naive patients. In contrast, we observed substantial subtype heterogeneity in patients whose primary ovarian sample was classified as C5. The development of an efficient molecular classifier of HGSC should enable further biological characterization of molecular subtypes and the development of targeted clinical trials. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Extensive amalgam tattoo on the alveolar-gingival mucosa

Amalgam tattoos are common exogenous pigmented lesions of the oral mucosa occurring mainly by inadvertent placement of amalgam particles into soft tissues. The diagnosis of amalgam tattoo is simple, usually based on clinical findings associated with presence or history of amalgam fillings removal. Intraoral X-rays may be helpful in detecting amalgam-related radiopacity. In cases where amalgam tattoo cannot be differentiated from other causes of oral pigmentation, a biopsy should be performed. This article deals with an extensive amalgam tattoo lesion which required a biopsy for a definitive diagnosis.     

Lip biopsy in connective tissue diseases. A review and study of seventy cases.

The labial salivary glands from seventy patients with systemic lupus erythematosus (twenty cases), systemic progressive sclerosis (twenty-two cases), rheumatoid arthritis (twenty-three cases), and Sj?gren's syndrome (five cases) and from fifty subjects without connective tissue diseases were studied by means of light and fluorescence microscopy. The availability of the lip biopsy as a diagnostic tool is stressed, but a differential diagnosis between the different connective tissue diseases was not achieved. Yet some of the latter disclosed peculiar lesions. The role of the inflammatory and degenerative components, as well as the pathogenesis of the lesions, is discussed.     

Bye-bye chiro-inositol - myo-inositol: true progress in the treatment of polycystic ovary syndrome and ovulation induction

Polycystic ovary syndrome (PCOS) is a multifactorial syndrome affecting 10% of women in reproductive age. Insulin sensitizer agents are the best therapeutic option for PCOS patients; among which there is Inositol. Inositol is a polyalcohol existing as nine different stereoisomers, two of which have been shown to be insulin mediators: myo-inositol (MI) and D-chiro-inositol (DCI). So far only MI have been show to be present in the follicular fluid and in a direct comparison between MI and DCI only MI was able to improve oocyte and embryo quality. Therefore, Could we say "bye-bye D-chiro-Inositol" in the practice of clinical gynecology and reproductive medicine?     

Molecular correlates of platinum response in human high‐grade serous ovarian cancer patient‐derived xenografts

Introduction

Improvement in the ability to target underlying drivers and vulnerabilities of high‐grade serous ovarian cancer (HG‐SOC) requires the development of molecularly annotated pre‐clinical models reflective of clinical responses.

Methods

We generated patient‐derived xenografts (PDXs) from consecutive, chemotherapy‐naïve, human HG‐SOC by transplanting fresh human HG‐SOC fragments into subcutaneous and intra‐ovarian bursal sites of NOD/SCID IL2Rγnull recipient mice, completed molecular annotation and assessed platinum sensitivity.

Results

The success rate of xenografting was 83%. Of ten HG‐SOC PDXs, all contained mutations in TP53, two were mutated for BRCA1, three for BRCA2, and in two, BRCA1 was methylated. In vivo cisplatin response, determined as platinum sensitive (progression‐free interval ≥100 d, n = 4), resistant (progression‐free interval <100 d, n = 3) or refractory (n = 3), was largely consistent with patient outcome. Three of four platinum sensitive HG‐SOC PDXs contained DNA repair gene mutations, and the fourth was methylated for BRCA1. In contrast, all three platinum refractory PDXs overexpressed dominant oncogenes (CCNE1, LIN28B and/or BCL2).

Conclusions

Because PDX platinum response reflected clinical outcome, these annotated PDXs will provide a unique model system for preclinical testing of novel therapies for HG‐SOC.