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Ayse Ayhan, Elisabetta Kuhn, Ren-Chin Wu, Hiroshi Ogawa, Asli Bahadirli-Talbott, Tsui-Lien Mao, Haruhiko Sugimura, Ie-Ming Shih, Tian-Li Wang
Ovarian clear cell carcinoma is a unique type of ovarian cancer, often derived from endometriosis, and advanced-stage disease has a dismal prognosis primarily due to the resistance to conventional chemotherapy. Previous studies have shown frequent somatic mutations in ARID1A, PIK3CA, hTERT promoter, and amplification of ZNF217; however, the molecular alterations that are associated with its aggressiveness remain largely unknown. This study examined and compared cyclin E1 expression in endometriosis-related ovarian tumors, with the aim of determining the relationship between hTERT mutations and ARID1A expression and evaluating the effects of these molecular alterations on patient survival...
October 21, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Piera Rizzolo, Anna Sara Navazio, Valentina Silvestri, Virginia Valentini, Veronica Zelli, Ines Zanna, Giovanna Masala, Simonetta Bianchi, Marco Scarnò, Stefania Tommasi, Domenico Palli, Laura Ottini
Male breast cancer (MBC) is a rare disease. Due to its rarity, MBC research and clinical approach are mostly based upon data derived from its largely known female counterpart. We aimed at investigating whether MBC cases harbor somatic alterations of genes known as prognostic biomarkers and molecular therapeutic targets in female breast cancer.We examined 103 MBC cases, all characterized for germ-line BRCA1/2 mutations, for somatic alterations in PIK3CA, EGFR, ESR1 and CCND1 genes.Pathogenic mutations of PIK3CA were detected in 2% of MBCs...
September 27, 2016: Oncotarget
Susan Heavey, Sinead Cuffe, Stephen Finn, Vincent Young, Ronan Ryan, Siobhan Nicholson, Niamh Leonard, Niall McVeigh, Martin Barr, Kenneth O'Byrne, Kathy Gately
Clinical PI3K inhibition has been somewhat disappointing, due to both inadequate patient stratification and compensatory cell signalling through bypass mechanisms. As such, investigation of PI3K-MEK co-targeted inhibition has been recommended. With high mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung cancer (NSCLC) is an important setting to investigate the effectiveness of this approach.Here, 174 NSCLC tumours were screened for 150 mutations by Fluidigm technology, with 15 patients being profiled for phosphoprotein expression...
October 19, 2016: Oncotarget
Sarah Hrebien, Ben O'Leary, Matthew Beaney, Gaia Schiavon, Charlotte Fribbens, Amarjit Bhambra, Richard Johnson, Isaac Garcia-Murillas, Nicholas Turner
Circulating tumor DNA (ctDNA) analysis has the potential to allow non-invasive analysis of tumor mutations in advanced cancer. In this study we assessed the reproducibility of digital PCR (dPCR) assays of circulating tumor DNA in a cohort of patients with advanced breast cancer and assessed delayed plasma processing using cell free DNA preservative tubes. We recruited a cohort of 96 paired samples from 71 women with advanced breast cancer who had paired blood samples processed either immediately or delayed in preservative tubes with processing 48-72 hours after collection...
2016: PloS One
Valentina Kovaleva, Anna-Lena Geissler, Lisa Lutz, Ralph Fritsch, Frank Makowiec, Sebastian Wiesemann, Ulrich T Hopt, Bernward Passlick, Martin Werner, Silke Lassmann
BACKGROUND: Targeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases. METHODS: Case-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer Panel(TM), MiSeq sequencing and data analyses (Illumina)...
October 18, 2016: Molecular Cancer
Siavash Rahimi, Iolia Akaev, Costa Repanos, Peter A Brennan, Jean Daniel Dubois
Primary lingual intestinal-type adenocarcinomas are extremely rare with only a few cases described. A case with immunohistochemical expression of Androgen Receptor (AR) which was treated solely by chemo-radiotherapy is reported herein. A 54-year-old male was referred with symptoms of fullness in his tongue. Clinical examination showed an asymmetry of the tongue with a hard mass palpable within the middle of the tongue. Biopsy showed intestinal-type adenocarcinoma. The tumour showed positive staining with cytokeratin 7, cytokeratin 20, CDX2, AR, β-catenin and was mismatch repair proteins (MMR) proficient...
October 17, 2016: Head and Neck Pathology
Samuel B Pattle, Natasa Utjesanovic, Athena Togo, Lucy Wells, Brendan Conn, Hannah Monaghan, Elizabeth Junor, Ingolfur Johannessen, Kate Cuschieri, Simon Talbot
Squamous cell carcinomas of the hypopharynx (HPSCC) and oropharynx (OPSCC) have markedly different patient outcomes. Differences in HPV prevalence between these two patient groups may account for some of this difference, but other molecular markers of prognosis or pathological phenotype have not been established. Copy number gain of oncogenes is a well-established molecular change contributing to HNSCC development. Quantitative PCR was used to explore copy number gains of specific genes (3q - PIK3CA, TP63; 11q13...
October 17, 2016: Genes, Chromosomes & Cancer
Joshua J Meeks, Benedito A Carneiro, Sachin G Pai, Daniel T Oberlin, Alfred Rademaker, Kyle Fedorchak, Sohail Balasubramanian, Julia Elvin, Nike Beaubier, Francis J Giles
The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted selective next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. DNA was extracted from paraffin-embedded sections from 25 HR-NMIBCs (22 with T1HG; 3 with TaHG with or without carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) ("progressors")...
October 14, 2016: Oncotarget
Jia-Jie Hao, De-Chen Lin, Huy Q Dinh, Anand Mayakonda, Yan-Yi Jiang, Chen Chang, Ye Jiang, Chen-Chen Lu, Zhi-Zhou Shi, Xin Xu, Yu Zhang, Yan Cai, Jin-Wu Wang, Qi-Min Zhan, Wen-Qiang Wei, Benjamin P Berman, Ming-Rong Wang, H Phillip Koeffler
Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others...
October 17, 2016: Nature Genetics
Yutong He, Xinyuan Zhang, Liqun Wang, Ziqiang Tian, Qingyi Liu, Jifang Yao, Yueping Liu, Chuanbao Li, Li Min, Baoen Shan
Non-small cell lung cancer (NSCLC) is a major public health problem worldwide and leads to a high mortality. NSCLC is always diagnosed in late stages because of its unapparent symptoms. However, cell-free DNA (cfDNA) may serve as a new potential biomarker to detect early stage of non‑small cell lung cancer. Here we recruited 10 non-small cell lung cancer patients to obtain fresh tumor tissue, peripheral blood lymphocytes (PBLs), and plasma. CfDNAs from 13 elderly people and 7 middle-age smokers were also extracted as controls...
October 12, 2016: International Journal of Oncology
Keisuke Goto, Daichi Maeda, Yukitsugu Kudo-Asabe, Takashi Hibiya, Akimasa Hayashi, Masashi Fukayama, Kenichi Ohashi, Akiteru Goto
AIMS: Hidradenoma papilliferum (HP) is a benign vulvar neoplasm that arises from anogenital mammary-like glands, and its morphology is similar to mammary intraductal papilloma. The aim of this study was to investigate oncogenic mutations involved in the tumourigenesis of HP. We focused specifically on PIK3CA and AKT1 mutations, which are both reported to be detected in 33% of mammary intraductal papillomas. METHODS: In total, seven HP cases were analysed. Clinicopathological analyses and immunohistochemistry for oestrogen receptor, p63, smooth muscle actin (SMA), p53 and β-catenin were performed...
October 14, 2016: Journal of Clinical Pathology
Youn Jin Choi, Je-Keun Rhee, Soo Young Hur, Min Sung Kim, Sung Hak Lee, Yeun-Jun Chung, Tae-Min Kim, Sug Hyung Lee
Intra-individual tumoural heterogeneity (ITH) is a hallmark of solid tumours and impedes accurate genomic diagnosis and selection of proper therapy. The purpose of this study was to identify ITH of ovarian high-grade serous carcinomas (OSCs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling, and DNA methylation profiling of four OSC genomes using multiregional biopsy from 13 intra-ovarian lesions, 12 extra-ovarian tumour lesions (omentum/peritoneum), and ascitic cells...
October 14, 2016: Journal of Pathology
Kyuichi Kadota, Camelia S Sima, Maria E Arcila, Cyrus Hedvat, Mark G Kris, David R Jones, Prasad S Adusumilli, William D Travis
The potential clinical impact of KRAS and epidermal growth factor receptor (EGFR) mutations has been investigated in lung adenocarcinomas; however, their prognostic value remains controversial. In our study, we sought to investigate the prognostic significance of driver mutations using a large cohort of early-stage lung adenocarcinomas. We reviewed patients with pathologic early-stage, lymph node-negative, solitary lung adenocarcinoma who had undergone surgical resection (1995 to 2005; stage I/II=463/19). Tumors were classified according to the IASLC/ATS/ERS classification and genotyped by Sequenom MassARRAY system and polymerase chain reaction-based assays...
October 12, 2016: American Journal of Surgical Pathology
Kaye Showler, Mayumi Nishimura, Kazuhiro Daino, Tatsuhiko Imaoka, Yukiko Nishimura, Takamitsu Morioka, Benjamin J Blyth, Toshiaki Kokubo, Masaru Takabatake, Maki Fukuda, Hitomi Moriyama, Shizuko Kakinuma, Masahiro Fukushi, Yoshiya Shimada
The PI3K/AKT pathway is one of the most important signaling networks in human breast cancer, and since it was potentially implicated in our preliminary investigations of radiation-induced rat mammary carcinomas, our aim here was to verify its role. We included mammary carcinomas induced by the chemical carcinogen 1-methyl-1-nitrosourea to determine whether any changes were radiation-specific. Most carcinomas from both groups showed activation of the PI3K/AKT pathway, but phosphorylation of AKT1 was often heterogeneous and only present in a minority of carcinoma cells...
October 13, 2016: Journal of Radiation Research
Ruoxu Dou, Reiko Nishihara, Yin Cao, Tsuyoshi Hamada, Kosuke Mima, Atsuhiro Masuda, Yohei Masugi, Yan Shi, Mancang Gu, Wanwan Li, Annacarolina da Silva, Katsuhiko Nosho, Xuehong Zhang, Jeffrey A Meyerhardt, Edward L Giovannucci, Andrew T Chan, Charles S Fuchs, Zhi Rong Qian, Shuji Ogino
Experimental evidence suggests that the let-7 family of noncoding RNAs suppresses adaptive immune responses, contributing to immune evasion by the tumor. We hypothesized that the amount of let-7a and let-7b expression in colorectal carcinoma might be associated with limited T-lymphocyte infiltrates in the tumor microenvironment and worse clinical outcome. Utilizing the molecular pathological epidemiology resources of 795 rectal and colon cancers in two U.S.-nationwide prospective cohort studies, we measured tumor-associated let-7a and let-7b expression levels by quantitative reverse-transcription PCR, and CD3(+), CD8(+), CD45RO (PTPRC)(+), and FOXP3(+) cell densities by tumor tissue microarray immunohistochemistry and computer-assisted image analysis...
October 13, 2016: Cancer Immunology Research
Grazia Palomba, Valentina Doneddu, Antonio Cossu, Panagiotis Paliogiannis, Antonella Manca, Milena Casula, Maria Colombino, Annamaria Lanzillo, Efisio Defraia, Antonio Pazzola, Giovanni Sanna, Carlo Putzu, Salvatore Ortu, Mario Scartozzi, Maria Teresa Ionta, Giovanni Baldino, Giuseppina Sarobba, Francesca Capelli, Tito Sedda, Luciano Virdis, Michela Barca, Giulia Gramignano, Mario Budroni, Francesco Tanda, Giuseppe Palmieri
BACKGROUND: Activation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments. The aim of this study was to evaluate the prognostic value of KRAS, BRAF, NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population. METHODS: A total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma (CRC) and presenting with metastatic disease were included into the study...
October 13, 2016: Journal of Translational Medicine
Timothy L Frankel, Efsevia Vakiani, Hari Nathan, Ronald P DeMatteo, T Peter Kingham, Peter J Allen, William R Jarnagin, Nancy E Kemeny, David B Solit, Michael I D'Angelica
BACKGROUND: In the past 3 decades, a better understanding of gene mutations and their role in carcinogenesis has led to improvement in our ability to treat patients with metastatic disease. The objective of the current study was to determine whether the location of a driver mutation within an affected gene impacts the biology of metastatic colorectal cancer. METHODS: DNA was collected from 165 randomly selected specimens of patients who underwent margin-negative resection of colorectal liver metastases with curative intent...
October 13, 2016: Cancer
Shang-Gin Wu, Yih-Leong Chang, Chong-Jen Yu, Pan-Chyr Yang, Jin-Yuan Shih
To understand the impact of PIK3CA mutations on clinical characteristics and treatment response to epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) of lung adenocarcinoma, we examined PIK3CA and EGFR mutations in lung adenocarcinoma patients, and analyzed their clinical outcomes. Surgically excised tumor, bronchoscopy biopsy/brushing specimens and pleural effusions were prospectively collected from 1029 patients. PIK3CA and EGFR mutations were analyzed by RT-PCR and direct sequencing. In EGFR TKI-nave specimens, PIK3CA mutation rate was 1...
October 13, 2016: Scientific Reports
Ping Zhan, Xiao Chen, Xiao-Yuan Wu, Zhi-Bo Hou, Qian Qian, Yu Zhang, Jue Zou, Yuan-Qing Zhang, Ming-Yue Wan, Jian-Dong Wang, Li-Ke Yu, Hai-Yan Xie
INTRODUCTION: For thymic carcinoma (TC), which is a rare epithelial neoplasm of the thymus gland, median survival with current treatments is only 2 years. OBJECTIVES: Mutations in the epidermal growth factor receptor (EGFR) gene or its downstream effectors may cause constitutive activation that leads to cell proliferation and metastases. Thus, molecular profiling is essential for selecting TC patients who may respond to anti-EGFR therapies. METHODS: Genomic DNA was extracted from 61 histological samples of TCs...
October 12, 2016: Clinical Respiratory Journal
Evert van den Broek, Oscar Krijgsman, Daoud Sie, Marianne Tijssen, Sandra Mongera, Mark A van de Wiel, Eric J. Belt, Sjoerd H den Uil, Herman Bril, Hein B A C Stockmann, Bauke Ylstra, Beatriz Carvalho, Gerrit A Meijer, Remond J A Fijneman
Tumor profiling of DNA alterations, i.e. gene point mutations, somatic copy number aberrations (CNAs) and structural variants (SVs), improves insight into the molecular pathology of cancer and clinical outcome. Here, associations between genomic aberrations and disease recurrence in stage II and III colon cancers were investigated. A series of 114 stage II and III microsatellite stable colon cancer samples were analyzed by high-resolution array-comparative genomic hybridization (array-CGH) to detect CNAs and CNA-associated chromosomal breakpoints (SVs)...
October 6, 2016: Oncotarget
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