Common Tumor Subtypes Research Articles

Identification of Transcriptional Metabolic Dysregulation in Subtypes of Pituitary Adenoma by Integrated Bioinformatics Analysis.

BackgroundPituitary adenoma (PA) is a prevalent intracranial tumor. Metabolites differ between pituitary tumor and healthy tissues or among different tumor subtypes. However, the transcriptional changes in metabolic enzymes, which are usually seemed as targets for metabolic therapy, remain unidentified.MethodsUsing microarray data for 160 samples from the Gene Expression Omnibus database, across the four most common tumor subtypes, we present the integrated identification of differentially expressed genes (DEGs) between tumors and controls.ResultsSubtype-specific DEGs revealed 1081 prolactin tumor-specific DEGs, 437 nonfunctioning tumor-specific DEGs, and 217 common DEGs among the four subtypes. Functional enrichment showed that a lot of biological functions related to metabolism had changed. Twenty-one prolactin and twenty-three nonfunctioning tumor-specific metabolic-related DEGs are mainly involved in fatty acid and nucleotide metabolism, redox reaction, and gluconeogenesis. Eighteen metabolic-related DEGs enriched in the metabolism of xenobiotics by the cytochrome P450 pathway, sulfur metabolism, retinoid metabolism, and glucose homeostasis were abnormal in all subtypes of PA.ConclusionBased on a comprehensive bioinformatics analysis of the available PA-related transcriptomics data, we identified specific DEGs related to metabolism, and some of them might be new attractive therapeutic targets. Especially, PDK4 and PCK1 might be new attractive biomarkers and therapeutic targets.

PO-343 The microRNA-146b-IRAK1 signalling axis in tumour recurrence of papillary thyroid cancer

IntroductionPapillary thyroid cancer (PTC) is the most common tumour subtype of thyroid cancer. However, not all PTCs are responsive to current surgical and radioiodine treatment. The well-established clinical prognostic factors include tumour size, lymph node/distal metastasis, and extrathyroidal invasion. The RET/PTC-RAS-BRAF linear molecular signalling cascade is known to mediate PTC pathogenesis. However, whether presence of BRAF mutation, the most common genetic alteration in PTC, can affect PTC behaviour and prognosis is controversial. MicroRNAs (miRNAs) have been labelled as promising molecular prognostic markers in several tumour types. However, the underlying mechanism of miR-146b in relation to its oncogenic behaviour in PTC and its putative targets remain to be fully elucidated.Material and methodsWe used genome-wide microarray, computational analysis and 3 UTR reporter gene assays to identify IRAK1 as a miR-146b target gene. In vitro gain/loss-of-function experiments were fur- ther performed to determine the effects of IRAK1 on proliferation, colony formation, and wound- healing in PTC cancer cell lines. Expression levels of miR-146b and IRAK1 of 50 cases of PTC and its adjacent normal thyroid specimens were assessed via quantitative real-time polymerase chain reaction.Results and discussionsMicroarray expression profile revealed that the mRNA level of IRAK1 gene was down- regulated by miR-146b. The 3 UTR of IRAK1 mRNA was found to be a molecular target of miR-146b posttranscriptional repression in BCPAP cells by reporter gene assays. MiR-146b promoted the migration and proliferation of PTC cells by downregulating IRAK1 expression, whereas restoration of IRAK1 expression reversed this effect. In addition, the expression of IRAK1 mRNA was significantly lower in PTC clinical tissue samples than normal adjacent thyroid specimens and showed a strong inverse correlation with the expression of miR-146b in PTC specimens. Our results demonstrated that IRAK1 is a direct target of miR-146b and has functional roles to inhibit various aggressive PTC cell activities.ConclusionIn conjunction with current therapeutic regimens, targeting the miR-146b-IRAK1 axis not only may provide a potential approach for PTC management but also serve as a unique supplemental tool for diagnosis and predicting prognosis for PTC in the near future.

What Factors Are Predictive of Outcome in the Treatment of Soft Tissue Sarcomas of the Foot and Ankle?

Category: Tumor Introduction/Purpose: Soft tissue sarcomas (STS) of the foot and ankle are common, accounting for 10% of sarcomas; however, there exists little published data on the outcome of treatment. Because of the unique anatomy of the foot and ankle, and the fact that benign lesions in this area are 200-fold more common than malignant lesions, these tumors can be frequently misdiagnosed, leading to unplanned excision and poor outcomes. The purpose of this study was to describe outcomes of the surgical treatment of STS of the foot and ankle at our institution, with an analysis on risk factors for local and distant recurrence, as well as overall survival. Methods: We reviewed the records of 62 foot and ankle soft tissue sarcomas treated with definitive surgery at our institution between 1992 and 2013. The cohort consisted of 35 males and 27 females with a mean age at diagnosis of 45 years and a mean follow-up of 7 years. Age, gender, anatomic location, tumor size, subtype, stage, neoadjuvant and adjuvant treatments, previous surgery, surgical procedure, and disease status at latest follow-up was recorded. Results: The most common tumor subtype was synovial sarcoma (n = 16). The overall limb salvage rate was 53%. Local recurrence was observed in 9 patients and distant metastases in 15 patients. Tumor size >=3 cm in maximal dimension was the greatest risk factor in mortality. Post treatment complications occurred in 15 patients. Local recurrence and development of distant disease was relatively common following wide excision of a soft tissue sarcoma of the foot and ankle. Tumors that were >=3 cm in maximal dimension were associated with a worse overall survival and patients with neoadjuvant radiation were at increased risk of complications. Conclusion: The results of our study highlight the aggressive nature of soft tissue sarcomas of the foot and ankle, with smaller tumors than previously reported (<5 cm) behaving like high-grade advanced disease.

Functional Role of Matrix gla Protein in Glioma Cell Migration.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor subtype. Despite that metastasis of GBM beyond the central nervous system (CNS) is rare, its malignancy is attributed to the highly infiltration trait, leading to the difficulty of complete surgical excision. Matrix gla protein (MGP) is a vitamin K-dependent small secretory protein, and functions as a calcification inhibitor. The involvement of MGP function in glioma cell dynamics remains to be clarified. The study showed that a low proliferative rat C6 glioma cell line named as C6-2 exhibited faster migratory and invasive capability compared to that observed in a high tumorigenic rat C6 glioma cell line (called as C6-1). Interestingly, C6-2 cells expressed higher levels of MGP molecules than C6-1 cells did. Lentivirus-mediated short hairpin RNA (shRNA) against MGP gene expression (MGP-KD) in C6-2 cells or lentivirus-mediated overexpression of MGP transcripts in C6-1 cells resulted in the morphological alteration of the two cell lines. Moreover, MGP-KD caused a decline in cell migration and invasion ability of C6-2 cells. In contrast, increased expression of MGP in C6-1 cells promoted their cell migration and invasion. The observations were further verified by the results from the implantation of C6-1 and C6-2 cells into ex vivo brain slice and in vivo rat brain. Thus, our results demonstrate that the manipulation of MGP expression in C6 glioma cells can mediate glioma cell migratory activity. Moreover, our findings indicate the possibility that high proliferative glioma cells expressing a high level of MGP may exist and contribute to tumor infiltration and recurrence.

Dynamic Contrast-enhanced MRI in Renal Tumors: Common Subtype Differentiation using Pharmacokinetics

Preoperative renal tumor subtype differentiation is important for radiology and urology in clinical practice. Pharmacokinetic data (Ktrans & Ve, etc.) derived from dynamic contrast-enhanced MRI (DCE-MRI) have been used to investigate tumor vessel permeability. In this prospective study on DCE-MRI pharmacokinetic studies, we enrolled patients with five common renal tumor subtypes: clear cell renal cell carcinoma (ccRCC; n = 65), papillary renal cell carcinoma (pRCC; n = 12), chromophobic renal cell carcinoma (cRCC; n = 9), uroepithelial carcinoma (UEC; n = 14), and fat-poor angiomyolipoma (fpAML; n = 10). The results show that Ktrans of ccRCC, pRCC, cRCC, UEC and fpAML (0.459 ± 0.190 min−1, 0.206 ± 0.127 min−1, 0.311 ± 0.111 min−1, 0.235 ± 0.116 min−1, 0.511 ± 0.159 min−1, respectively) were different, but Ve was not. Ktrans could distinguish ccRCC from non-ccRCC (pRCC & cRCC) with a sensitivity of 76.9% and a specificity of 71.4%, respectively, as well as to differentiate fpAML from non-ccRCC with a sensitivity of 100% and a specificity of 76.2%, respectively. Our findings suggest that DCE-MRI pharmacokinetics are promising for differential diagnosis of renal tumors, especially for RCC subtype characterization and differentiation between fpAML and non-ccRCC, which may facilitate the treatment of renal tumors.

MicroRNA-146b: A Novel Biomarker and Therapeutic Target for Human Papillary Thyroid Cancer.

Papillary thyroid cancer (PTC) is the most common tumor subtype of thyroid cancer. However, not all PTCs are responsive to current surgical and radioiodine treatment. The well-established clinical prognostic factors include tumor size, lymph node/distal metastasis, and extrathyroidal invasion. The RET/PTC-RAS-BRAF linear molecular signaling cascade is known to mediate PTC pathogenesis. However, whether presence of BRAF mutation, the most common genetic alteration in PTC, can affect PTC behavior and prognosis is controversial. MicroRNAs (miRNAs) have been labeled as promising molecular prognostic markers in several tumor types. Our recent studies demonstrated that microRNA-146b (miR-146b) deregulation is associated with PTC aggressiveness and prognosis. Here we summarize the current knowledge related to the functional roles, regulated target genes, and clinical applications of miR-146b in PTC and discuss how these studies provide insights into the key role of miR-146b as an oncogenic regulator promoting cellular transformation as well as a prognosis marker for tumor recurrence in PTC. In conjunction with the current perspectives on miRNAs in a wide variety of human cancers, this review will hopefully translate these updated findings on miR-146b into more comprehensive diagnostic or prognostic information regarding treatment in PTC patients before surgical intervention and follow up strategies.

Biological and Clinicopathological Characteristics of Breast Cancer at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia

Breast cancer (BC) is one of the most heterogeneous types of cancer and is characterized by several molecular subtypes. Descriptive cross-sectional study was conducted on 137 confirmed BC cases at Tikur Anbessa Specialized Hospital (TASH) in Ethiopia from December 2015 to November 2016 to assess the biological and clinicopathological characteristics of BC in Ethiopian women patients. Socio-demographic characteristics of the study subjects was obtained with pretested structured interview and clinical data was collected from the Hospital records. Surgical specimens were analysed histopathologically with hematoxyline and eosin staining, and Immunohistochemistry analysis was conducted with specific antibodies to ER, PR and HER2. The mean and median age of the study participants were 47 and 46.7, respectively. More than 50% of the patients were categorized in the age group of 15-40. Sixty percent were in the age group of 41-100. Infiltrating ductal carcinoma was the most common type of BC (70%) in this study, followed by lobular carcinoma (8.5%). Almost all of the BC cases under study were at advanced stage of the disease: 48.5% were with stage III and 51% were grade II tumors. Half of the study participants belonged to T2 tumor size (2-5 cm) and 52.3% of the patients had axillary lymph node metastases. Sixty five percent were ER+, 58% were PR+ and 28% were HER2+. Luminal A was the most common tumor subtype (54%), followed by luminal B (22%) and TNBC (18%). Based on crude analysis, patients with family history of BC had a lesser likelihood of being ER+ as compared to those patients with no family history of BC [COR=0.10 (95% CI: 0.028, 0.34)]. None of the other risk factors were correlated with the prevalence of ER+ results. In conclusion, the age distribution of BC cases in this study suggests the need to create awareness and improvement of advanced diagnostic services and make available screening programs for younger people. In a resource poor setting like Ethiopia, the use of anti-estrogens (like tamoxifen) in treatment of BC cases with undetermined receptor status could be helpful as most BC cases are ER+ and hormonal therapy is relatively easily available.

What Factors Influence the Outcome of Surgically Treated Soft Tissue Sarcomas of the Hand and Wrist?

Soft tissue sarcomas (STS) of the hand are exceedingly rare. The aim of this study was to review our institution's experience with STS of the hand to identify factors affecting outcomes and survivorship. We retrospectively reviewed the records of 46 hand STS treated with definitive surgery at our institution between 1992 and 2013. Pertinent demographics as well as information regarding the surgical procedure, and disease status at latest follow-up were reviewed. Mean age at diagnosis was 38 years with a mean follow-up of 5 years. The most common tumor subtypes were epithelioid (n = 10) and synovial sarcoma (n = 8). Sixty-one percent were superficial in location. Thirty-three patients had had a nononcologic resection prior to definitive surgical treatment at our institution. Ultimately, negative margins were obtained in all cases. Local recurrence was observed in 5 patients and distant metastases in 14 patients. Tumor sizes ≥2 cm, American Joint Committee on Cancer (AJCC) grade, and depth of the tumor were found to adversely affect the outcome in terms of disease-free and overall survival. Reexcision of an inadvertently excised tumor at an outside institution did not adversely affect the outcome. The 10-year overall and disease-free survival was 72% and 63%. Local recurrence after a wide excision was observed infrequently; however, distant disease was relatively common. Tumors with a size ≥2 cm were associated with a worse disease-free and overall survival, highlighting the aggressive nature of these tumors.

What Factors Are Predictive of Outcome in the Treatment of Soft Tissue Sarcomas of the Foot and Ankle?

Level IV: Retrospective Case Series.

Abstract LB-178: Genomic profiling of 1239 diverse pediatric cancers identifies novel discoveries across tumors

Abstract Pediatric cancers are rare and diverse entities characterized by low mutational burden. Multiple studies investigating the genomic events driving oncogenesis have identified characteristic diagnostic lesions as well as targets suitable for therapeutic exploitation in common tumor subtypes. Here, we present genomic profiles from 1239 pediatric tumors (ages 0-18) from 51 disease subtypes representing sarcomas (26.6%), other blastomas (22.4%), brain tumors (20.4%), hematological malignancies (19.5%), carcinomas (9.8%), and gonadal tumors (1.4%). This collection represents real-world tumor specimens in which select cancer-associated genes were analyzed for all classes of alterations as part of routine clinical care. Samples were sequenced to a median unique depth of >500x to allow for optimal detection of oncogenic events in low purity specimens. Additionally, 635 samples (51%) were analyzed by targeted RNA-seq for fusions in 265 genes. Alterations with proven clinical actionability in pediatric cancers (BRAF V600E and ALK, NTRK1, and ABL1 fusions) were found in 3.9% of samples from brain, sarcoma, and heme cases. Three novel ALK fusions were identified in a neuroblastoma (BEND5-ALK), a soft tissue sarcoma (IGFBP5-ALK), and an astrocytoma (PPP1CB-ALK). Two novel BRAF fusions were also found in an astrocytoma (BCAS1-BRAF) and a ganglioglioma (TMEM106B-BRAF). In rhabdomyosarcoma, we identified a novel PAX3-GLI2 fusion and confirmed a second occurrence of the rare PAX3-NCOA1 fusion. This large data set also challenged the paradigm of “disease-specific” alterations as previously characterized fusions involving ALK, NTRK1, and PAX3 were observed in novel diseases from which they were originally reported. We investigated variants of unknown significance for potentially novel cancer mutations, and identified four recurrent and likely somatic variants in KMT2C, PRSS1, and CTNNB1 predicted to have functional impact by in silico analyses. Compared to other large published data sets in neuroblastoma, ALL, AML, rhabdomyosarcoma, and medulloblastoma, similar frequencies of clinically significant alterations were observed, thereby validating this dataset as biologically relevant. While many common and diagnostic alterations have been described in pediatric cancers, researchers are becoming increasingly aware of other rarer, yet equally important, clinically relevant genomic alterations. As demonstrated by the identification of novel fusions and mutations, this data set is ripe with discovery potential, and can be used to generate hypotheses, validate rare findings, and investigate the genomic landscape of rare tumors for which only small studies exist. Data from these 1239 tumors will be publicly available to the research community for exploration and incorporation into future experiments that will ultimately improve the treatment and prognosis for children with cancer. Citation Format: Juliann Chmielecki, Mark Bailey, Jie He, Julia Elvin, Jo-Anne Vergilio, Shakti Ramkissoon, James Suh, Garrett M. Frampton, Siraj Ali, Jeffrey Ross, Vincent A. Miller, Philip J. Stephens, Doron Lipson. Genomic profiling of 1239 diverse pediatric cancers identifies novel discoveries across tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-178.

Molecular Signaling in Benign Odontogenic Neoplasia Pathogenesis.

Several molecular pathways have been shown to play critical roles in the pathogenesis of odontogenic tumors. These neoplasms arise from the epithelial or mesenchymal cells of the dental apparatus in the jaw or oral mucosa. Next generation genomic sequencing has identified gene mutations or single nucleotide polymorphisms associated with many of these tumors. In this review, we focus on two of the most common odontogenic tumor subtypes: ameloblastoma and keratocystic odontogenic tumors. We highlight gene expression and protein immunohistological findings and known genetic alterations in the hedgehog, BRAF/Ras/MAPK, epidermal growth factor receptor, Wnt and Akt signaling pathways relevant to these tumors. These various pathways are explored to potentially target odontogenic tumors cells and prevent growth and recurrence of disease. Through an understanding of these signaling pathways and their crosstalk, molecular diagnostics may emerge as well as the ability to exploit identified molecular differences to develop novel molecular therapeutics for the treatment of odontogenic tumors.

Abstract 2227: Effects of cathepsin S in differentiated and stem-like glioblastoma cells

Abstract Background: Glioblastoma (GBM) is the most common and aggressive brain tumour subtype with a poor prognosis of ∼15 months. A GBM stem-like population within the tumour is hypothesised to promote resistance to current treatment and invasion through normal tissue. Cathepsin S (Cat S) is a lysosomal cysteine protease that remains catalytically active at neutral pH and has been shown to play a role in radiation resistance and invasion of cancer cells. It is also an independent predictor of GBM patient survival. Materials and methods: GBM cell lines (U87MG and LN229) with lentiviral shRNA knockdown of Cat S are grown in serum-free medium with growth factors that allow de-differentiation of the cells into a stem-like state. A transwell system is used for quantifying monolayer invasion. Under stem conditions, spheroid structures are formed and their invasion in 3D is analysed with GFP expression. Protein expression determined via Western blot. Radiation response determined via clonogenic survival assay. Proliferation measured using MTT assay. Cat S-like activity measured using fluorogenic peptide substrate cleavage. Results: Radiation induces Cat S protein expression and protease activity in both GBM cell lines at 24 hours. Knockdown of Cat S induces radiation sensitivity in both cell lines when differentiated. In stem-like conditions, this is observed for U87MG but not for LN229 cells. Similarly, Cat S knockdown has no effect on proliferation of cell lines, except LN229 stem-like cells where it is increased. Finally, Cat S knockdown reduces the invasive capacity of both differentiated cell lines and U87MG stem-like cells 3D invasion through both collagen and matrigel, but has no effect on LN229 stem-like cells. Cat S-like activity is reduced in all but stem LN229, despite complete knockdown. Further investigation into differential effects in stem-like cells will examine possible role of autophagy, which is linked to radiation resistance and Cat S inhibition. Conclusion Cat S is a potential drug target in GBM as it reduces invasion and radio-resistance of glioma cell lines. The differential effect seen in stem-like cells suggests that the genetic background of tumours may be an important factor in determining utility of Cat S therapy in targeting the stem-like GBM population thought to be responsible for recurrence. Citation Format: Robyn A. Foster, Shahnaz T. Al Rashid, Roberta E. Burden, Christopher J. Scott, Kevin M. Prise, Thomas J. Flannery. Effects of cathepsin S in differentiated and stem-like glioblastoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2227. doi:10.1158/1538-7445.AM2015-2227

Long-term disease and neurological outcomes in patients with pediatric intramedullary spinal cord tumors.

Radical resection is recommended as the first-line treatment for pediatric intramedullary spinal cord tumors (IMSCTs), but it is associated with morbidity, including risk of neurological decline and development of postoperative spinal deformity. The authors report long-term data on clinical and treatment determinants affecting disease survival and neurological outcomes. Case records for pediatric patients (< 21 years of age at presentation) who underwent surgery for IMSCTs at the authors' institution between January 1975 and January 2010 were analyzed. The patients' demographic and clinical characteristics (including baseline neurological condition), the treatment they received, and their disease course were reviewed. Long-term disease survival and functional outcome measures were analyzed. A total of 55 patients (30 male and 25 female) were identified. The mean duration of follow-up (± SEM) was 11.4 ± 1.3 years (median 9.3 years, range 0.2-37.2 years). Astrocytomas were the most common tumor subtype (29 tumors [53%]). Gross-total resection (GTR) was achieved in 21 (38%) of the 55 patients. At the most recent follow-up, 30 patients (55%) showed neurological improvement, 17 (31%) showed neurological decline, and 8 (15%) remained neurologically stable. Patients presenting with McCormick Grade I were more likely to show functional improvement by final follow-up (p = 0.01) than patients who presented with Grades II-V. Kaplan-Meier actuarial tumor progression-free survival rates at 5, 10, and 20 years were 61%, 54%, and 44%, respectively; the overall survival rates were 85% at 5 years, 74% at 10 years, and 64% at 20 years. On multivariate analysis, GTR (p = 0.04) and tumor histological grade (p = 0.02) were predictive of long-term survival; GTR was also associated with improved 5-year progression-free survival (p = 0.01). The prognosis for pediatric IMSCTs is favorable with sustained functional improvement expected in a significant proportion of patients on long-term follow-up. Long-term survival at 10 years (75%) and 20 years (64%) is associated with aggressive resection. Gross-total resection was also associated with improved 5-year progression-free survival (86%). Hence, the treatment benefits of GTR are sustained on extended follow-up.

Adult brain cancer in the U.S. black population: a Surveillance, Epidemiology, and End Results (SEER) analysis of incidence, survival, and trends.

BackgroundDespite much epidemiological research on brain cancer in the United States, the etiology for the various subtypes remains elusive. The black population in the United States currently experiences lower incidence but higher survival rates when compared to other races. Thus, the aim of this study is to analyze the trends in incidence and survival for the 6 most common primary brain tumors in the black population of the United States.Material/MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was utilized in this study to analyze the incidence and survival rates for the 6 most common brain tumor subtypes. Joinpoint 3.5.2 software was used to analyze trends in the incidence of diagnosis from 1973 to 2008. A Kaplan-Meier curve was generated to analyze mean time to death and survival at 60 months.ResultsJoinpoint analysis revealed that per year the incidence of brain cancer in the U.S. black population increased by 0.11 between 1973 and 1989. After this period, a moderate decrease by 0.06 per annum was observed from 1989 to 2008. Lymphoma was the most common primary tumor subtype for black individuals ages 20–34, and glioblastoma was identified as the most common tumor subtype for black individuals in the age groups of 35–49, 50–64, 65–79, and 80+.ConclusionsThis population-based retrospective study of brain cancer in black adults in the United States revealed significant sex and age differences in the incidence of the 6 most common brain tumor subtypes from 1973 to 2008.

Ovarian Germ Cell Tumor – Histopathological and statistical analysis

Background: Ovarian cancers are common among females. The ovarian tumors are classified according to its histogenesis. In the present study, we analyzed the germ cell ovarian tumors reported in our institute. Materials and Methods: This study was a hospital based retrospective study. All ovarian germ cell tumor reported from Jan 2001 to Feb 2013 were retrieved and analyzed. The specimens were routinely processed and the slides were stained with H&amp;E and special stains wherever required. Results: A total of 340 cases of ovarian tumors were reported and 150 cases (44%) were of germ cell origin. We had 137 cases of benign and 13 cases of malignant germ cell tumors. Most common subtype was mature cystic teratoma comprising 125 cases. Among the malignant cases, the most common was immature teratoma (5 cases). Age range in our series was from 8 to 82 years (mean 28 years). The most common age group affected was 21-30 years. Most of the malignant cases (76.9%) were in less than 30 years. Among the malignant cases majority (84.6%) were more than 10 cm in size. None of the malignant germ cell tumors were bilateral. Conclusion: Among germ cell tumors of ovary, mature cystic teratoma is the most common tumor and malignant subtypes are uncommon. Malignant tumors tend to occur in younger age group. DOI: http://dx.doi.org/10.3126/jpn.v3i6.8990 Journal of Pathology of Nepal (2013) Vol. 3, 441-446

Molecular Pathways: Extracting Medical Knowledge from High-Throughput Genomic Data

High-throughput genomic data that measures RNA expression, DNA copy number, mutation status, and protein levels provide us with insights into the molecular pathway structure of cancer. Genomic lesions (amplifications, deletions, mutations) and epigenetic modifications disrupt biochemical cellular pathways. Although the number of possible lesions is vast, different genomic alterations may result in concordant expression and pathway activities, producing common tumor subtypes that share similar phenotypic outcomes. How can these data be translated into medical knowledge that provides prognostic and predictive information? First-generation mRNA expression signatures such as Genomic Health's Oncotype DX already provide prognostic information, but do not provide therapeutic guidance beyond the current standard of care, which is often inadequate in high-risk patients. Rather than building molecular signatures based on gene expression levels, evidence is growing that signatures based on higher-level quantities such as from genetic pathways may provide important prognostic and diagnostic cues. We provide examples of how activities for molecular entities can be predicted from pathway analysis and how the composite of all such activities, referred to here as the "activitome," helps connect genomic events to clinical factors to predict the drivers of poor outcome.

Melanoma epidemiology, prognosis and trends in Latvia

Melanoma incidence and mortality rates are increasing worldwide within the white population. Clinical and histological factors have been usually used for the prognosis and assessment of the risk for melanoma. The aim of the study was to describe the clinical and histopathological features of the cutaneous melanoma (CM) in the Latvian population, to test the association between melanoma features and patient survival, and to assess the time trends for melanoma incidence. We undertook a descriptive, retrospective analysis of archive data of 984 melanoma patients treated at the largest oncological hospital of Latvia, Riga East University Hospital Latvian Oncology Centre (LOC), between 1998 and 2008. Cox proportional hazards model was used to analyse patient survival and autoregressive models were applied to detect trends in melanoma incidence over time for various categories of melanoma. The study showed a significant ascending trend in melanoma incidence in Latvia during the time period from 1998 to 2008 (ß = 1.83, 95% CI = 1.15-2.91, P = 0.011). Nodular melanoma was the most common tumour subtype with a frequency of 39.2%. Ulceration was present in 45.2% of melanomas. The mean Breslow thickness was 6.0 mm (6.8 mm) and no significant decline in median Breslow thickness was observed during the study period (P = 0.609). A better overall prognosis was detected for females in comparison with males (HR = 1.49; 95% CI = 1.22-1.81; P < 0.001). There is a steady increase in melanoma incidence in Latvia with the majority of melanomas diagnosed at late stages with poor prognosis for survival.

Role of Immunohistochemistry in the Evaluation of Needle Core Biopsies in Adult Renal Cortical Tumors

Multiple therapeutic options for renal tumors that are now available have put pathologists under increasing pressure to render diagnosis on limited material. Results on biopsies by hematoxylin and eosin (H&E) have historically not been encouraging. Currently, multiple immunohistochemical markers with differential expression in these renal tumors are available. We studied the utility of such markers on needle biopsies that were obtained ex vivo. After nephrectomy, two 18-guage cores were obtained and processed routinely. Expressions of carbonic anhydrase (CA) IX, CD117, α-methylacyl-CoA racemase (AMACR), cytokeratin 7 (CK7), and CD10 were evaluated. Results, with or without immunostaining, were compared with the final nephrectomy diagnosis. We studied 145 tumors, including 119 renal cell carcinomas (83 clear cell, 18 papillary, 14 chromophobe, and 4 type unclassified), 11 oncocytomas, and 15 miscellaneous tumors. Adequate evaluable material was present in 123 (85%) cases. In such biopsies, 81% of cases were correctly classified by H&E alone, with correct diagnosis in 90% of cases in the most common tumor subtypes (clear cell, papillary and chromophobe renal cell carcinoma, and oncocytoma). By adding immunostains, the accuracy was 90% overall and 99% among the 4 most common subtypes. The following extent and patterns of immuneexpression were highly useful in the diagnoses: diffuse, membranous CAIX expression in clear cell renal cell carcinoma, diffuse positivity for AMACR in papillary renal cell carcinoma, distinct peripheral cytoplasmic accentuation for CD117 in chromophobe renal cell carcinoma, widespread and intense positivity for CK7 in chromophobe and papillary renal cell carcinoma, and diffuse membranous reactivity in clear cell and patchy/luminal in papillary renal cell carcinoma for CD10. In conclusion, utilizing immunostains improves classification of renal tumors on needle biopsy, which may be of particular help for pathologists with limited experience. Both extent and patterns must be considered for a definitive diagnosis.

Adjuvant Radiotherapy for Pediatric and Young Adult Nonrhabdomyosarcoma Soft-Tissue Sarcoma

To evaluate the prognostic factors, outcomes, and complications in patients aged ≤30 years with resectable nonrhabdomyosarcoma soft-tissue sarcoma treated at the University of Florida with radiotherapy (RT) during a 34-year period. A total of 95 pediatric or young adult patients with nonrhabdomyosarcoma soft-tissue sarcoma were treated with curative intent with surgery and RT at the University of Florida between 1973 and 2007. The most common histologic tumor subtypes were synovial sarcoma in 22 patients, malignant fibrous histiocytoma in 19, and malignant peripheral nerve sheath tumor in 11 patients. The mean age at RT was 22 years (range, 6-30). Of the 95 patients, 73 had high-grade tumors; 45 had undergone preoperative RT and 50 postoperative RT. The prognostic factors for survival, local recurrence, and distant recurrence were analyzed. The median follow-up was 7.2 years (range, 0.4-30.5). The actuarial 5-year local control rate was 88%. A microscopically negative margin was associated with superior local control. Although 83% of local recurrence cases initially developed in the absence of metastases, all patients with local failure ultimately died of their disease. The actuarial estimate of 5-year overall survival and disease-free survival was 65% and 63%, respectively. Of all the deaths, 92% were disease related. An early American Joint Committee on Cancer stage, tumor<8 cm, and the absence of neurovascular invasion were associated with superior disease-free survival. The National Cancer Institute Common Toxicity Criteria, version 3, Grade 3-4 treatment complication rate was 9%. No secondary malignancies were observed. In the present large single-institution study, we found positive margins and locally advanced features to be poor prognostic factors for both local progression and survival. The results from the present study have helped to characterize the therapeutic ratio of RT in pediatric and young adult sarcoma patients and have provided a basis for identifying high-risk patients for whom treatment intensification might be justified.

Applying unmixing to gene expression data for tumor phylogeny inference.

BackgroundWhile in principle a seemingly infinite variety of combinations of mutations could result in tumor development, in practice it appears that most human cancers fall into a relatively small number of "sub-types," each characterized a roughly equivalent sequence of mutations by which it progresses in different patients. There is currently great interest in identifying the common sub-types and applying them to the development of diagnostics or therapeutics. Phylogenetic methods have shown great promise for inferring common patterns of tumor progression, but suffer from limits of the technologies available for assaying differences between and within tumors. One approach to tumor phylogenetics uses differences between single cells within tumors, gaining valuable information about intra-tumor heterogeneity but allowing only a few markers per cell. An alternative approach uses tissue-wide measures of whole tumors to provide a detailed picture of averaged tumor state but at the cost of losing information about intra-tumor heterogeneity.ResultsThe present work applies "unmixing" methods, which separate complex data sets into combinations of simpler components, to attempt to gain advantages of both tissue-wide and single-cell approaches to cancer phylogenetics. We develop an unmixing method to infer recurring cell states from microarray measurements of tumor populations and use the inferred mixtures of states in individual tumors to identify possible evolutionary relationships among tumor cells. Validation on simulated data shows the method can accurately separate small numbers of cell states and infer phylogenetic relationships among them. Application to a lung cancer dataset shows that the method can identify cell states corresponding to common lung tumor types and suggest possible evolutionary relationships among them that show good correspondence with our current understanding of lung tumor development.ConclusionsUnmixing methods provide a way to make use of both intra-tumor heterogeneity and large probe sets for tumor phylogeny inference, establishing a new avenue towards the construction of detailed, accurate portraits of common tumor sub-types and the mechanisms by which they develop. These reconstructions are likely to have future value in discovering and diagnosing novel cancer sub-types and in identifying targets for therapeutic development.