Molecular Genetics of Pancreatic Neoplasms and Their Morphologic Correlates

Reid, Michelle D.; Saka, Burcu; Balcı, Serdar; Goldblum, Andrew; Adsay, Volkan

doi:10.1309/ajcp0fkdp7envkev

Cited by 73 publications

(24 citation statements)

References 90 publications

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“…GNAQ p.T96S mutation has been reported in skin and prostate cancers [27, 28]. GNAS mutation identified in this study was the hotspot mutation p.R201C that is common in low-grade appendiceal mucinous neoplasm and pancreatic intraductal papillary mucinous neoplasm [29, 30]. Nonsense mutation of ARID2 p.R1273X in our study has been reported in esophageal and head/neck cancers [31, 32].…”

Section: Resultssupporting

confidence: 62%

Whole-exome sequencing identified mutational profiles of high-grade colon adenomas

et al. 2016

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Although gene-to-gene analyses identified genetic alterations such as APC, KRAS and TP53 mutations in colon adenomas, it is largely unknown whether there are any others in them. Mutational profiling of high-grade colon adenoma (HGCA) that just precedes colon carcinoma might identify not only novel adenoma-specific genes but also critical genes for its progression to carcinoma. For this, we performed whole-exome sequencing (WES) of 12 HGCAs and identified 11 non-hypermutated and one hypermutated (POLE-mutated) cases. We identified 22 genes including APC, KRAS, TP53, GNAS, NRAS, SMAD4, ARID2, and PIK3CA with non-silent mutations in the cancer Census Genes. Bi-allelic and mono-allelic APC alterations were found in nine and one HGCAs, respectively, while the other two harbored wild-type APC. Five HGCAs harbored either mono-allelic (four HGCAs) or bi-allelic (one HGCA) SMAD4 mutation or 18q loss that had been known as early carcinoma-specific changes. We identified MTOR, ACVR1B, GNAQ, ATM, CNOT1, EP300, ARID2, RET and MAP2K4 mutations for the first time in colon adenomas. Our WES data is largely matched with the earlier ‘adenoma-carcinoma model’ (APC, KRAS, NRAS and GNAS mutations), but there are newly identified SMAD4, MTOR, ACVR1B, GNAQ, ATM, CNOT1, EP300, ARID2, RET and MAP2K4 mutations in this study. Our findings provide resource for understanding colon premalignant lesions and for identifying genomic clues for differential diagnosis and therapy options for colon adenomas and carcinomas.

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Section: Resultssupporting

confidence: 62%

Whole-exome sequencing identified mutational profiles of high-grade colon adenomas

et al. 2016

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“…GNAS mutations are the second most common and occur in approximately 40-79% of IPMNs [53,54,55,56], and this can be used to differentiate IPMNs from other pancreatic cystic lesions including MCNs, solid pseudopapillary neoplasms, and serous cystic neoplasms [10]. RNF43 mutations are detected in 14-38% of IPMNs [53,55,56,57].…”

Section: Ipmnmentioning

confidence: 99%

Precursor Lesions of Pancreatic Cancer

Kim

Hong

2018

Oncol Res Treat

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Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death. Although the treatment modalities are improving, the prognosis of PDAC continues to be poor. Therefore, early detection of PDAC or its precursor lesions may be the best way to improve patient survival. PDACs have several different precursor lesions, including pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), intraductal tubulopapillary neoplasms (ITPNs), intraductal oncocytic papillary neoplasms (IOPNs), and mucinous cystic neoplasms (MCNs). PanINs cannot be identified using imaging modalities, while the other lesions are radiologically detectable. These precursor lesions are categorized based on structural and cytological atypia as low-grade and high-grade lesions. We discuss recent updates regarding histopathological and molecular pathological overviews of PDAC precursor lesions. Better understanding of such lesions may contribute to earlier detection of PDAC or its precursor lesions and improve PDAC patient survival.

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“…SMADs mediate transcriptional responses to transforming growth factor ␤ (TGF-␤) and bone morphogenic protein (BMP) and are divided into 3 classes: the receptor-regulated SMADs that transmit TGF-␤ signaling (SMAD2 and -3) and bone morphogenetic protein signaling (SMAD1, -5, and -8), the inhibitory SMADs (SMAD6 and -7), and a common SMAD, SMAD4, that partners with the other SMADs to form the transcriptionally active trimeric complex (66). Inactivation of SMAD4 is common in pancreatic and colorectal cancers but less so in other human cancers (67,68). GSK-3 phosphorylation of SMAD4 has not been investigated.…”

Section: Establishment Of the Screening Assaymentioning

confidence: 99%

A Screen for Extracellular Signal-Regulated Kinase-Primed Glycogen Synthase Kinase 3 Substrates Identifies the p53 Inhibitor iASPP

Woodard

Liao

Goodwin

et al. 2015

J Virol

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The Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein is essential for the replication and maintenance of virus genomes in latently KSHV-infected cells. LANA also drives dysregulated cell growth through a multiplicity of mechanisms that include altering the activity of the cellular kinases extracellular signal-regulated kinase (ERK) and glycogen synthase kinase 3 (GSK-3). To investigate the potential impact of these changes in enzyme activity, we used protein microarrays to identify cell proteins that were phosphorylated by the combination of ERK and GSK-3. The assays identified 58 potential ERK-primed GSK-3 substrates, of which 23 had evidence for in vivo phosphorylation in mass spectrometry databases. Two of these, SMAD4 and iASPP, were selected for further analysis and were confirmed as ERK-primed GSK-3 substrates. Cotransfection experiments revealed that iASPP, but not SMAD4, was targeted for degradation in the presence of GSK-3. iASPP interferes with apoptosis induced by p53 family members. To determine the importance of iASPP to KSHV-infected-cell growth, primary effusion lymphoma (PEL) cells were treated with an iASPP inhibitor in the presence or absence of the MDM2 inhibitor Nutlin-3. Drug inhibition of iASPP activity induced apoptosis in BC3 and BCBL1 PEL cells but did not induce poly(ADP-ribose) polymerase (PARP) cleavage in virus-negative BJAB cells. The effect of iASPP inhibition was additive with that of Nutlin-3. Interfering with iASPP function is therefore another mechanism that can sensitize KSHV-positive PEL cells to cell death. IMPORTANCEKSHV is associated with several malignancies, including primary effusion lymphoma (PEL). The KSHV-encoded LANA protein is multifunctional and promotes both cell growth and resistance to cell death. LANA is known to activate ERK and limit the activity of another kinase, GSK-3. To discover ways in which LANA manipulation of these two kinases might impact PEL cell survival, we screened a human protein microarray for ERK-primed GSK-3 substrates. One of the proteins identified, iASPP, showed reduced levels in the presence of GSK-3. Further, blocking iASPP activity increased cell death, particularly in p53 wild-type BC3 PEL cells.T he Kaposi's sarcoma-associated herpesvirus (KSHV) latencyassociated nuclear antigen (LANA) is expressed in all KSHVinfected cells, including the tumor cells of the KSHV-associated malignancies Kaposi's sarcoma, primary effusion lymphoma (PEL), and muticentric Castleman disease. LANA functions in the replication and maintenance of latent, episomal KSHV genomes (1, 2) by binding to the KSHV origin of replication in the terminal repeats (3, 4), recruiting cellular replication proteins (5-11), and tethering the KSHV episomal genomes to host chromosomes (12-18). Sequences in the KSHV terminal repeats are bound by the C terminus of LANA, and the X-ray crystal structures of the human and murine gammaherpesvirus 68 (MHV68) LANA DNA-binding domains have been solved (19)(20)(21).KSHV infection leads to a global reprogramming of cel...

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Molecular Genetics of Pancreatic Neoplasms and Their Morphologic Correlates

Abstract: When combined with morphologic observations, molecular studies will increase our understanding of the pathogenesis and morphomolecular signatures associated with specific neoplasms and provide new horizons for precision medicine and targeted therapies.

Cited by 73 publications

References 90 publications

Whole-exome sequencing identified mutational profiles of high-grade colon adenomas

Whole-exome sequencing identified mutational profiles of high-grade colon adenomas

Precursor Lesions of Pancreatic Cancer

A Screen for Extracellular Signal-Regulated Kinase-Primed Glycogen Synthase Kinase 3 Substrates Identifies the p53 Inhibitor iASPP

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