Citations

Abstract Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here, we report wide variation in the expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in the majority of ovarian cancer cell lines (three SDs above the mean of normal ovarian surface epithelial cells) and high-grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5′-TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5′-TC dinucleotide motifs in early-stage high-grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA "repair" enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability. Cancer Res; 73(24); 7222–31. ©2013 AACR.

Abstract The American Joint Committee on Cancer/Union Internationale Contre le Cancer ( AJCC / UICC ) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression‐based stratification. These parameters rely on tumour‐cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named ‘Immunoscore’ has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC / UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC / UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM ‐I ( TNM ‐Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Abstract Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SM for the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials.

Abstract Benign breast disease (BBD) is an established risk factor for breast cancer among Caucasian women but less is known about BBD in African American women. As African American women suffer from disproportionate mortality due to breast cancer, special focus on pathologic characteristics that may influence disease risk is warranted. Benign breast biopsies from African American women were identified by the University Pathology Group (Detroit, MI). African American women of ages 20 to 84 years, who underwent a breast biopsy from 1997 to 2000, were eligible for the study. Subsequent breast cancers were identified through a linkage with the Detroit Surveillance Epidemiology and End Results (SEER) program. The first biopsy was reviewed by the pathologist, and lesions were classified following Dupont and Page criteria along with involution and other histologic features. Logistic regression was used to estimate the risk of developing a subsequent breast cancer with the histologic characteristics of BBD. A total of 1,406 BBD biopsies from African American women were included in this study with a median follow-up of 10.1 years. The majority (68%) showed nonproliferative disease, 29% had proliferative disease without atypia, and 3% had proliferative disease with atypia. Subsequent incident breast cancers occurred in 55 women (3.9%). Women whose biopsies showed proliferative disease with atypia were more than three-fold more likely to develop breast cancer as compared with women who had nonproliferative disease [relative risk (RR) 3.29, 95% confidence interval (CI) 1.21–8.93]. Better characterization of the risk of breast cancer among women with BBD, considering both ethnicity and detailed molecular findings, can lead to better surveillance, earlier diagnosis, and potentially improved survival. Cancer Prev Res; 5(12); 1375–80. ©2012 AACR.

Abstract High throughput sequencing technologies open up a new dimension in cancer genomics by enabling the characterization of cancer genomes at base-pair resolution. To date, the majority of large-scale genomics projects rely on fresh-frozen biospecimens in their studies, which are difficult to obtain and often lack long-term clinical data. Unlike fresh-frozen samples, archived formalin-fixed paraffin-embedded (FFPE) tissues are more readily accessible, and are often associated with known clinical outcomes and more complete clinical annotations. However, sequencing library preparation methods need to be further optimized with regard to applicability to FFPE samples. To test whether next-generation sequencing technologies could overcome previously reported artifacts associated with formalin fixation and report accurate sequencing results, we compared whole-genome and targeted enrichment DNA sequencing data obtained from five FFPE tumor samples for which matching frozen tissues were available. We successfully generated sequencing libraries using 1 µg of genomic DNA as input material and a modified TruSeq™ sample preparation protocol. We designed a custom enrichment pool targeting exons from 215 cancer-related genes and utilized this pool to pull-down and sequence approximately 1.3 Mb region of the genome with an average 400x coverage depth to test if deep sequencing would improve validation of tumor-specific somatic mutations. We used the Illumina sequence analysis pipeline and the Windows-based second generation DNA sequencing software NextGENe® to analyze the data and identify sequence variations that are different from the human reference genome. CNV detection was overall higher among FFPE samples compared with fresh-frozen samples, demonstrating that tissue processing impacts sequencing data quality. We obtained good concordance in variant calls between matched FFPE and fresh-frozen samples. Discordant variant calls were mainly due to low depth of coverage in the regions where variant calls were made. Improvements to DNA sequencing methods for archived samples will significantly enhance cancer research and will result in more reliable prediction of individual cancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3179. doi:1538-7445.AM2012-3179

Abstract Background: Ovarian cancer (OC) is the leading cause of gynecologic cancer death in the United States. Survival in advanced OC is highly variable; some patients are cured of their disease with a combination of surgery and systemic chemotherapy, while the majority of patients develop recurrence and ultimately die of metastatic OC. While markers of poor prognosis within advanced OC exist, they have not translated to changes in therapy or outcomes. Vascular growth factors are important soluble mediators of tumor growth, vasculogenesis and angiogenesis that may be targeted therapeutically. We therefore explored the association between plasma levels of vascular growth factors and clinical outcomes in advanced OC. Methods: We enrolled 200 patients with OC or benign surgical conditions from the Mayo Ovarian SPORE Biospecimens Core. Presurgical plasma samples from patients with advanced OC (AJCC Stage III and IV, n = 100), early stage OC (Stage I and II, n = 50), and benign surgical conditions (n = 50) were assayed for vascular growth factors via multiplex electrochemiluminescence and by ELISA. Differences in plasma levels between benign, early, and advanced OC patient groups were assessed using plate-adjusted linear models. Associations between plasma levels of vascular growth factors and overall survival in advanced OC patients were assessed by Cox proportional hazards models. Results: Both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels were increased in patients with advanced OC (mean ng/mL = 130.8, p = 0.004; mean ng/mL = 20.1, p = 0.025, respectively) compared to patients with early stage (mean ng/mL = 75.1 and 19.0 respectively) and benign conditions (mean ng/mL = 86.8 and 15.0, respectively). An increase in PlGF levels was associated with poor overall survival in patients with advanced OC (HR = 2.52, p = 0.005), while increase in VEGF levels were of borderline significance (HR = 1.21, p = 0.061) Conclusions: Soluble PlGF and VEGF are increased in the setting of advanced OC. Increased plasma PlGF is strongly linked to poor prognosis, while VEGF levels have a borderline association with prognosis. These data provide a rationale for therapeutic targeting of both VEGF and PlGF. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1382. doi:1538-7445.AM2012-1382