Accumulation Of Molecular Alterations Research Articles

EXPRESSION OF P53 IN COLORECTAL CARCINOMAS AND ITS CORRELATION WITH CLINICOPATHOLOGICAL PARAMETERS

Colorectal cancer is one of the most life-threatening gastrointestinal diseases encountered in clinical practice.1 The rectum is one of the most frequently involved sites and accounts for 25% of primary colorectal cancers.2 Accumulation of molecular alterations, including K-ras, P53, Bcl-2 and adenomatous polyposis coli, contribute to colorectal carcinogenesis.3 According to the literature, the deletion of p53 with the overexpression of p53 protein is correlated with a low rate of survival, thus being an independent prognosis factor.17 Summary: Overexpression of p53 protein is associated with high grade of colorectal carcinoma.

Mechanisms of development and progression of pancreatic neoplasms.

Pancreatic ductal adenocarcinoma (PDAC) develops via dysplastic changes in the epithelia graded as low- and high-grade with accumulation of molecular alterations. Constitutive activation of mitogen-activated protein kinase (MAPK) contributed by attenuation of DUSP6 plays a key role in sustaining PDAC. Active MAPK induces various molecules that function as effectors to sustain PDAC. AURKA and SON are downstream effectors that contribute substantially to the proliferation and survival of PDAC cells and are potentially useful as therapeutic targets. Active MAPK also promote microRNAs that modulate the proliferation of PDAC cells and are useful as diagnostic markers. Familial pancreatic cancer kindreds in Japan show various germline mutations supposed to increase a pancreatic cancer risk. Intraductal papillary mucinous neoplasms (IPMNs) consist of dilated ducts lined by papillary neoplastic epithelia of various shapes and varying grades of atypia. Various papillae of IPMNs are classified into four subtypes that are associated with clinicopathological features, including patient prognosis. GNAS is a specific driver gene for the development of IPMN through gain-of-function mutations. Tracing of molecular alterations has elucidated the mechanism of progression of IPMN from dysplasia to carcinoma, as well as one type of papillae. Intraductal tubulopapillary neoplasms belong to a distinct class of pancreatic neoplasms.

APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target.

Background: The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process contributed by the accumulation of molecular alterations. We identified Apelin (APLN) as an outlier gene up-regulated in hepatocellular carcinoma (HCC) through RNA-Seq and microarray analysis. We aimed to investigate its function, mechanism of action and clinical implication in HCC.Methods: Gene expression and clinical implication of APLN were assessed in multiple human HCC cohorts. Ectopic expression and silencing of APLN were performed to determine its function. The therapeutic potential of APLN and its downstream pathway was investigated using in vitro and in vivo models.Results: APLN overexpression was commonly observed in more than 80% of HCCs and independently predicted poorer survival of patients in three independent HCC cohorts. Apelin up-regulation was mediated by active β-catenin, which binds to the APLN promoter to induce transcription. Ectopic APLN expression in HCC cells promoted cell proliferation, accelerated G1/S progression and inhibited apoptosis, whilst APLN knockdown exerted opposite effects in vitro and inhibited HCC xenograft growth in mice. Mechanistically, APLN activated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway via APLN receptor, leading to increased expression of phospho-glycogen synthase kinase 3β (p-GSK3β) and cyclin D1. Pharmacological targeting of APLN by ML221 was safe and effective in inhibiting APLN-PI3K/Akt cascade and HCC growth in vitro and in vivo.Conclusions: Our findings unraveled an oncogenic role of APLN in HCC, and that targeting of APLN might be a promising for HCC treatment. APLN may serve as an independent prognostic factor for HCC patients.

Abstract 5743: Characterization of mitochondrial DNA mutations and tumor evolution in ulcerative colitis-associated colorectal cancer

Abstract The role of mitochondrial DNA (mtDNA) mutations in cancer is highly controversial. While specific mtDNA mutations have been associated with certain cancers, it has been recently reported that mtDNA mutations are negatively selected in most tumors. We aimed to clarify the role of mtDNA mutations in cancer progression by: 1) capitalizing on the multi-step sequence of tumorigenesis in ulcerative colitis (UC), a premalignant disease ideal for the study of tumor progression, and 2) employing a highly accurate, ultra-deep sequencing method to fully characterize the mtDNA mutational profile at different stages of tumor evolution. UC is an inflammatory bowel disease characterized by chronic colonic inflammation that increases the risk of colorectal cancer (CRC). UC CRC evolves through a stepwise process that involves the accumulation of molecular alterations in otherwise histologically normal epithelium, low-grade dysplasia (LGD), high-grade dysplasia (HGD), and cancer. Our lab has previously identified mitochondrial alterations as a facet of dysplastic progression in UC. Here we have worked to fully characterize the spectrum and frequency of mtDNA mutations in UC tumorigenesis by applying a novel, highly sensitive NGS technology, Duplex Sequencing (DS), that can accurately detect mutant allele frequencies (MAF) as low as 0.01%. For two patients that developed cancer, we analyzed 15-20 colon biopsies obtained at colectomy, representing all stages of tumorigenesis. The median duplex sequencing depth was 4,000x, which allowed unprecedented resolution to detect subclonal mutations (MAF 1-99%) and rare mutations (MAF<1%). Several subclonal mutations were present in all biopsies, but with variable MAF, thus enabling construction of phylogenetic trees via PHYLIP analysis. Rare mutations were abundant in all biopsies; on average one in every 10,000 nucleotides sequenced was mutated. Most rare mutations were G to A transitions, indicative of replicative errors, but G to T and C to A transversions, the oxidative damage mutational signature, were prevalent in some biopsies. We conclude, therefore, that most mtDNA mutations are caused by proliferation with a contribution by inflammatory processes, and that this may have greater implications for their role in other cancer types. Citation Format: Kathryn Terese Baker, Daniela Nachmanson, Scott R. Kennedy, Teresa A. Brentnall, Rosa Ana Risques. Characterization of mitochondrial DNA mutations and tumor evolution in ulcerative colitis-associated colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5743. doi:10.1158/1538-7445.AM2017-5743

EGFR Expression and KRAS and BRAF Mutational Status in Intestinal-Type Sinonasal Adenocarcinoma

Accumulation of molecular alterations, including EGFR overexpression and mutations in KRAS and BRAF, contribute to colorectal carcinogenesis. Since intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinus has morphologic and phenotypic features that are usually indistinguishable from colorectal cancer (CRC), it is likely that both tumor types share equivalent genetic alterations. Data from a series of 43 patients treated surgically for ITAC in Montpellier, France between November 1998 and December 2012 were collected. Tumors were characterized for mutations in KRAS and BRAF as well as EGFR overexpression. Kaplan-Meier survival curves were constructed using overall survival as the primary end points. Patient survival was analyzed using the hazards ratio. Twenty seven tumors (63%) showed EGFR positivity and 30% exhibited a high expression level (+2/+3). KRAS mutations were detected in 43% of cases. BRAF mutations were identified in 3.6% of specimens. Patients with age superior to 60 years, metastatic status, and KRAS mutations had significant overall survival values (p = 0.026, p = 0.001 and p = 0.03, respectively). Our results indicate that KRAS mutations and EGFR expression are frequent in ITAC and that KRAS mutations predict good patient prognosis in ITAC. Finally, EGFR directed molecular treatments could be investigated in a subset of patients affected by ITAC.

Chemoprevention of lung cancer: concepts and strategies

Lung cancer develops in a stepwise fashion, with an accumulation of molecular alterations progressing through preinvasive steps to invasive disease. This progression could be arrested or reversed through pharmacologic treatments, which are known as cancer chemoprevention. Preclinical and clinical findings relating to different classes of candidate chemopreventive agents provide support for this strategy as an active and promising approach for controlling this disease.