Faculty Bibliography

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer deaths worldwide. Proper classification and early identification of HCC and precursor lesions is essential to the successful treatment and survival of HCC patients. Recent molecular genetic, pathologic, and clinical data have led to the stratification of hepatic adenomas into three subgroups: those with mutant TCF1/HNF1 alpha gene, those with mutant beta-catenin, and those without mutations in either of these loci. Hepatic adenomas with alpha-catenin mutations have a significantly greater risk for malignant transformation in comparison with the other two subgroups. Telangiectatic focal nodular hyperplasia has now been reclassified as telangiectatic adenoma due to the presence of non-random methylation patterns, consistent with the monoclonal origin which is similar to hepatic adenoma and HCC. HCC precursor lesions demonstrate unique molecular alterations of HSP70, CAP2, glypican 3, and glutamine synthetase that have proven useful in the histologic diagnosis of early HCC. Though specific genetic alterations depend on HCC etiology, the main proteins affected include cell membrane receptors (in particular tyrosine kinase receptors) as well as proteins involved in cell signaling (specifically Wnt/beta-catenin, Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways), cell cycle regulation (i.e. p53, p16/INK4, cyclin/cdk complex), invasiveness (EMT, TGF-beta) and DNA metabolism. Advances in gene expression profiling have provided new insights into the molecular genetics of HCC. HCCs can now be stratified into two clinically relevant groups: Class A, the low survival subclass (overall survival time 30.3+/- 8.02 months), shows strong expression signatures of cell proliferation and antiapoptosis genes (such as PNCA and cell cycle regulators CDK4, CCNB1, CCNA2, and CKS2) as well as genes involving ubiquitination and sumoylation; Class B, the high survival subclass (overall survival time 83.7 +/-10.3 months), does not have the above expression signature. In fact, insights into HCC-specific alterations of signal transduction pathways and protein expression patterns have led to the development of new therapeutic agents with molecular targets such as EGFR, VEGF, or other multi-kinase inhibitors. In the future, these specific molecular alterations in HCC can potentially serve as diagnostic tools, prognostic markers, and/or therapeutic targets with the potential to alter clinical outcomes

Before high-grade papillary serous carcinoma (HG-PSC) becomes invasive, it is believed to be a poorly defined short-lived precursor lesion. A recent characterization of serous tubal intraepithelial carcinoma (STIC) and of the p53 signature suggested that HG-PSC may follow a stepwise progression on cellular and molecular levels. High-mobility group AT-hook 2 (HMGA2), an oncofetal protein, is overexpressed in ovarian cancer. To test whether HMGA2 can be another valuable marker for STIC, we examined HMGA2 expression in 3 groups of patients: (1) 24 patients with STIC and its invasive counterpart, HG-PSC of the fallopian tubes, (2) 24 patients with HG-PSC of the ovaries but without STIC (positive control), and (3) 30 patients with cancer and normal fallopian tubes (negative control). We found that HMGA2 was overexpressed in 75% of patients with STIC, was coexpressed with p53 in more than 50% of patients, and was completely negative in the secretory cells of the 30 patients with normal fallopian tubes. Among 7 patients with cells negative for p53 staining, HMGA2 was positive in 5; among 6 patients whose tumor cells were negative for HMGA2 in STIC, 3 were positive for HMGA2 in the invasive component; about 70% of invasive HG-PSC tumor cells were immunoreactive for both HMGA2 and TP53. In invasive carcinoma, HMGA2 overexpression was correlated with p53 (r=0.45), indicating the role of HMGA2 in p53 mediated tumor progression. Our findings of immunoreactivity for HMGA2 may lead to a novel, useful biomarker to complement p53 in the detection of early-stage serous carcinoma

ABSTRACT: Cancer is a multifaceted disease that results from dysregulated normal cellular signaling networks caused by genetic, genomic and epigenetic alterations at cell or tissue levels. Uncovering the underlying protein signaling network changes, including cell cycle gene networks in cancer, aids in understanding the molecular mechanism of carcinogenesis and identifies the characteristic signaling network signatures unique for different cancers and specific cancer subtypes. The identified signatures can be used for cancer diagnosis, prognosis, and personalized treatment. During the past several decades, the available technology to study signaling networks has significantly evolved to include such platforms as genomic microarray (expression array, SNP array, CGH array, etc.) and proteomic analysis, which globally assesses genetic, epigenetic, and proteomic alterations in cancer. In this review, we compared Pathway Array analysis with other proteomic approaches in analyzing protein network involved in cancer and its utility serving as cancer biomarkers in diagnosis, prognosis and therapeutic target identification. With the advent of bioinformatics, constructing high complexity signaling networks is possible. As the use of signaling network-based cancer diagnosis, prognosis and treatment is anticipated in the near future, medical and scientific communities should be prepared to apply these techniques to further enhance personalized medicine

Overexpression of HMGA2 is common in uterine leiomyomas (ULM). The expression of HMGA2 in its malignant counterpart - uterine leiomyosarcomas (ULMS) remains undetermined. Recently it has been shown that repression of HMGA2 by microRNA let-7s is a critical molecular regulatory mechanism associated with tumour growth in many tumours and cell types, including leiomyomas. To test whether HMGA2 and let-7s play a role in ULMS, we examined the levels of endogenous HMGA2 and let-7 expression and found a significant correlation between these two molecules in a case-matched cohort of human ULMS. We found that overexpression of HMGA2 and let-7-mediated HMGA2 repression is a relevant molecular alteration in ULMS. Disrupting the control of HMGA2 and let-7 pairs promotes ULMS cell growth in vitro

The preponderance of pancreatic tumors is adenocarcinoma of the ductal type; carcinomas with multiple lineage differentiation are extremely rare. We report an unusual case of pancreatic carcinoma with combined acinar and neuroendocrine differentiation and minor ductal component with concurrent acinar-ductal metaplasia (ADM), an early lesion implicated in ductal carcinogenesis. The patient is a 56-year-old man with vague complaints of dull left upper quadrant pain with radiation across the mid-portion of his abdomen. A computer tomography scan revealed an irregular enlargement of the distal 3.2 cm of the pancreatic body. A distal pancreatectomy was then performed. Histologic examination revealed a pancreatic carcinoma with cellular features of eosinophilic granular cytoplasm and salt-pepper nuclei. The acinar differentiation of the carcinoma was confirmed by positivity on periodic acid-Schiff stain resistant to diastase digestion (dPAS), positivity for antitrypsin on immunohistochemistry (IHC), and presence of zymogen granules on electron microscopy (EM). The neuroendocrine differentiation was evident by positive synaptophysin and chromogranin stain on IHC and neuroendocrine granules on EM. The ductal component was only visible by PAS stain and immunostains for CEA and CK19A and accompanied by a number of the acinar-ductal metaplasia lesions adjacent to the main tumor. Thus, the histological, histochemical, immunohistochemical and electron-microscopic evidence all suggested that the pancreatic carcinoma underwent trilineage differentiation

Preneoplastic lesions for renal oncocytosis have not been well defined. We have attempted to identify the putative in-situ or dysplastic change in nephrectomy specimens with oncocytosis. Cases of multiple oncocytoma previously identified in radical nephrectomy specimens (n = 5) were reviewed for early lesions of renal oncocytosis by light microscopic analysis and by immunohistochemical studies for p53, bcl2 and MIB-1. Microscopic analysis showed that the renal cortical regions in all cases contain isolated groups of tubules partially or completely replaced by oncocytic cells with morphologic features resembling tumor cells in oncocytosis. The oncocytic cells within these tubules are increased in number and are arranged either as solid groups or as single layers in cystically dilated tubules, and may assume a hobnail appearance. They can be distinguished from small foci of oncocytosis as they do not form a coalescent group but are separated in part by intervening normal-appearing tubules. Cytologically, the cells have abundant eosinophilic, granular cytoplasm with a low nuclear/cytoplasmic ratio and demonstrate distinct cell borders. A very characteristic feature of these cells is the retraction space ('windows') between the oncocytic cells. Nuclear features of these cells are not distinctive from normal tubules. Immunostaining with Bcl-2, p53 and MIB-1 antibodies also does not differentiate the putative preneoplastic lesions from normal tubules. Thus, recognition of a putative dysplastic lesion for oncocytosis is possible by routine microscopic analysis. Identification of this lesion in a biopsy or partial nephrectomy specimen should raise the possibility of the existence of renal oncocytosis (multifocality), leading to adequate clinical management

OBJECTIVE: To study whether dysregulation of insulin-like growth factors (IGFs) and IGF signaling are common molecular changes in symptomatic leiomyomas (fibroids) and whether IGFs are associated with large fibroids. DESIGN: Examination of IGFs and IGF pathway genes in a large cohort of fibroids at transcriptional and translational levels. Mechanisms leading to alterations of IGFs and related genes were also analyzed. SETTING: University clinical research laboratory. PATIENT(S): Hysterectomies for symptomatic fibroids were collected: 180 cases from paraffin-embedded tissues and 50 cases from fresh-frozen tissues. INTERVENTION(S): Tissue microarray and immunohistochemistry, DNA methylation analysis, reverse-transcriptase polymerase chain reaction, and Western blot. MAIN OUTCOME MEASUREMENT(S): Transcription and translation analyses of IGF-1/2, p-AKT, p-S6K, and TSC1/2 in fibroids and matched myometrium. RESULT(S): Insulin-like growth factors and downstream effectors were dysregulated in approximately one third of fibroids. All except for IGF-2 seemed to be abnormally regulated at translation levels. Up-regulation of IGF-2 messenger RNAs was contributed by all four alternating slicing promoters. There was a positive correlation of IGF-1 and p-AKT over-expression with fibroid size. Insulin-like growth factor 1 but not IGF-2 levels directly correlated with activation of p-AKT and p-S6K. CONCLUSION(S): Altered expressions of IGFs and their related downstream proteins were found in one third of fibroids. Large fibroids show high levels of IGF-1 and p-AKT activity compared with small ones