Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms.
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ABSTRACT:
SUBMITTER: Nishikawa G
PROVIDER: S-EPMC3590682 | biostudies-other | 2013 Mar
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Occasionally, low-grade appendiceal mucinous neoplasms (LAMN) present with mucinous peritoneal deposits (MPD) localized to periappendiceal tissue or diffused throughout the peritoneum. OBJECTIVE:This study was aimed at evaluating the relevance of mucin cellularity for predicting outcomes of LAMN with remote MPD. METHODS:The records of patients with LAMN and remote MPD who underwent initial assessment at a comprehensive cancer center from 1990 to 2015 were reviewed, and diagnostic procedures, treatments, and outcomes were analyzed. RESULTS:Of 48 patients included in the analysis, 19 had cellular MPD (CMPD) and 29 had acellular MPD. Of 33 patients who underwent cytoreductive surgery, 30 had a complete cytoreduction; the 3 patients with an incomplete cytoreduction had CMPD. In the follow-up period (median, 4 years), 6 patients died of the disease, all of whom had CMPD. Of 11 patients who had progression of disease, 10 had CMPD. CONCLUSION:Cellularity of remote MPD is an important determinant of disease outcome in LAMN. Approaches such as active surveillance may have a role in selected patients with LAMN and AMPD.
| S-EPMC6339600 | biostudies-literature
Project description:Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic cystic neoplasm that is often invasive and metastatic, resulting in a poor prognosis. Few molecular alterations unique to IPMN are known. We performed whole-exome sequencing for a primary IPMN tissue, which uncovered somatic mutations in KCNF1, DYNC1H1, PGCP, STAB1, PTPRM, PRPF8, RNASE3, SPHKAP, MLXIPL, VPS13C, PRCC, GNAS, KRAS, RBM10, RNF43, DOCK2, and CENPF. We further analyzed GNAS mutations in archival cases of 118 IPMNs and 32 pancreatic ductal adenocarcinomas (PDAs), which revealed that 48 (40.7%) of the 118 IPMNs but none of the 32 PDAs harbored GNAS mutations. G-protein alpha-subunit encoded by GNAS and its downstream targets, phosphorylated substrates of protein kinase A, were evidently expressed in IPMN; the latter was associated with neoplastic grade. These results indicate that GNAS mutations are common and specific for IPMN, and activation of G-protein signaling appears to play a pivotal role in IPMN.
| S-EPMC3240977 | biostudies-literature
Project description:Background: There is a paucity of targeted therapies for patients with pseudomyxoma peritonei (PMP) secondary to low-grade appendiceal mucinous neoplasms (LAMNs). Dysregulated metabolism has emerged as a hallmark of cancer, and the relationship of metabolomics and cancer is an area of active scientific exploration. We sought to characterize phenotypic differences found in peritoneal metastases (PM) derived from LAMN versus adenocarcinoma. Methods: Tumors were washed with phosphate-buffered saline (PBS), microdissected, then dissociated in ice-cold methanol dried and reconstituted in pyridine. Samples were derivatized in tert-butyldimethylsilyl (TBDMS) and subjected to gas chromatography-coupled mass spectrometry. Metabolites were assessed based on a standard library. RNA sequencing was performed, with pathway and network analyses on differentially expressed genes.Results: Eight peritoneal tumor samples were obtained and analyzed: LAMNs (4), and moderate to poorly differentiated adenocarcinoma (colon [1], appendix [3]). Decreases in pyroglutamate, fumarate, and cysteine in PM from LAMNs were found compared with adenocarcinoma. Analyses showed the differential gene expression was dominated by the prevalence of metabolic pathways, particularly lipid metabolism. The gene retinol saturase (RETSAT), downregulated by LAMN, was involved in the multiple metabolic pathways that involve lipids. Using network mapping, we found IL1B signaling to be a potential top-level modulation candidate. Conclusions: Distinct metabolic signatures may exist for PM from LAMN versus adenocarcinoma. A multitude of genes are differentially regulated, many of which are involved in metabolic pathways. Additional research is needed to identify the significance and applicability of targeting metabolic pathways in the potential development of novel therapeutics for these challenging tumors.
2024-05-01 | GSE266352 | GEO
Project description:Mucinous cystic neoplasms (MCNs) are rare, potentially curable, mucin-producing neoplasms of the pancreas. We have previously reported PIK3CA (phosphoinositide-3-kinase catalytic subunit, p110?) mutations in intraductal papillary mucinous neoplasms, another mucin-producing neoplasm of the pancreas. In this study, we analyzed the presence of PIK3CA and AKT1/PKB (V-akt murine thymoma viral oncogene homolog 1) hot-spot mutations in MCN specimens.Using the genomic DNA sequencing of tumor tissues isolated by laser capture microdissection, we evaluated 15 well-characterized MCNs for the E542K, E545K (exon 9), and H1047R (exon 20) hot-spot mutations in the PIK3CA gene and the E17K mutation in the AKT1 gene.A hot-spot mutation (E545K) of the PIK3CA gene was detected in 1 of the 15 MCNs and further confirmed by a mutant-enriched method. Interestingly, this mutation was found to be present only in the high-grade but not in low-grade dysplastic epithelium obtained from this neoplasm and coexisted with a KRAS mutation. No mutations were identified in the AKT1 gene.Our data, when combined with previous reports on intraductal papillary mucinous neoplasms, indicate that oncogenic activation of the PI3K pathway involving PIK3CA gene mutations can contribute to the progression of mucin-producing neoplasms but not pancreatic intraepithelial neoplasia. PIK3CA status could be useful for understanding their progression to malignancy.
| S-EPMC4109032 | biostudies-literature
Project description:Inverted urothelial papilloma (IUP) is an uncommon neoplasm of the urinary bladder with distinct morphologic features. Studies regarding the role of human papillomavirus (HPV) in the etiology of IUP have provided conflicting evidence of HPV infection. In addition, little is known regarding the molecular alterations present in IUP or other urothelial neoplasms, which might demonstrate inverted growth pattern like low-grade or high-grade urothelial carcinoma (UCA). Here, we evaluated for the presence of common driving somatic mutations and HPV within a cohort of IUPs, (n = 7) noninvasive low-grade papillary UCAs with inverted growth pattern (n = 5), and noninvasive high-grade papillary UCAs with inverted growth pattern (n = 8). HPV was not detected in any case of IUP or inverted UCA by either in situ hybridization or by polymerase chain reaction. Next-generation sequencing identified recurrent mutations in HRAS (Q61R) in 3 of 5 IUPs, described for the first time in this neoplasm. Additional mutations of Ras pathway members were detected including HRAS, KRAS, and BRAF. The presence of Ras pathway member mutations at a relatively high rate suggests this pathway may contribute to pathogenesis of inverted urothelial neoplasms. In addition, we did not find any evidence supporting a role for HPV in the etiology of IUP.
| S-EPMC4241848 | biostudies-literature
Project description:PurposeThe incidence of neuroendocrine neoplasms is increasing. This work aimed at: (i) establishing worldwide incidence trend of low-grade neuroendocrine neoplasms; (ii) defining the incidence and temporal trend of high-grade neuroendocrine neoplasms in USA utilizing the Surveillance Epidemiology and End Results database; (iii) comparing trends for low-grade vs. high-grade neuroendocrine neoplasms.MethodsWe conducted a literature search on MEDLINE and Scopus databases and incidence trends were plotted for 1973-2012. The Surveillance Epidemiology and End Results database was used to identify incidence rates in USA for 1973-2012. Incidence rates were stratified according to histological grade, gender and ethnicity. Trends were summarized as annual percent change and corresponding 95% confidence interval.Results11 studies were identified involving 72,048 cases; neuroendocrine neoplasm incidence rates increased over time in all countries for all sites, except for appendix. In Surveillance Epidemiology and End Results low-grade neuroendocrine neoplasm incidence rate increased from 1.09 in 1973 to 3.51 per 100,000 in 2012. During this interval, high-grade neuroendocrine neoplasm incidence rate increased from 2.54 to 10.52 per 100,000. African Americans had the highest rates of digestive neuroendocrine neoplasms with male prevalence in high-grade.ConclusionsOur data indicate an increase in the incidence of neuroendocrine neoplasms as a worldwide phenomenon, affecting most anatomical sites and involving both low-grade and high-grade neoplasms.
| S-EPMC5671554 | biostudies-literature
Project description:BACKGROUND & AIMS:Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS:We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS:We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS:In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.
| S-EPMC6756950 | biostudies-literature
Project description:BACKGROUND & AIMS:Many patients with pancreatic adenocarcinoma carry germline mutations associated with increased risk of cancer. It is not clear whether patients with intraductal papillary mucinous neoplasms (IPMNs), which are precursors to some pancreatic cancers, also carry these mutations. We assessed the prevalence of germline mutations associated with cancer risk in patients with histologically confirmed IPMN. METHODS:We obtained nontumor tissue samples from 315 patients with surgically resected IPMNs from 1997 through 2017, and we sequenced 94 genes with variants associated with cancer risk. Mutations associated with increased risk of cancer were identified and compared with individuals from the Exome Aggregation Consortium. RESULTS:We identified 23 patients with a germline mutation associated with cancer risk (7.3%; 95% confidence interval, 4.9-10.8). Nine patients had a germline mutation associated with pancreatic cancer susceptibility (2.9%; 95% confidence interval, 1.4-5.4). More patients with IPMNs carried germline mutations in ATM (P < .0001), PTCH1 (P < .0001), and SUFU (P < .0001) compared with controls. Patients with IPMNs and germline mutations associated with pancreatic cancer were more like to have concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations (P < .0320). CONCLUSIONS:In sequence analyses of 315 patients with surgically resected IPMNs, we found that almost 3% to carry mutations associated with pancreatic cancer risk. More patients with IPMNs and germline mutations associated with pancreatic cancer had concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations. Genetic analysis of patients with IPMNs might identify those at greatest risk for cancer.
| S-EPMC6475492 | biostudies-literature
Project description:BackgroundLow-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian carcinoma. Limited data regarding the molecular-genetic background exist beyond mutations in the RAS signaling pathway. There is a growing need to better characterize these tumors due to chemoresistance and limited therapeutic options in advanced or recurrent disease.MethodsWe performed genome-wide copy number aberration (CNA) profiles and mutation hotspot screening (KRAS, BRAF, NRAS, ERBB2, PIK3CA, TP53) in 38 LGSOC tumor samples.ResultsWe detected mutations in the RAS-signaling pathway in 36.8% of cases, including seven KRAS, four BRAF, and three NRAS mutations. We identified two mutations in PIK3CA and one mutation in MAP3K1, EGFR, and TP53. CNAs were detected in 86.5% of cases. None of the focal aberrations was correlated with specific clinical characteristics. The most frequently detected CNA was loss of 1p36.33 in 54.1% of cases, with a trend towards lower progression-free survival and overall survival in patients with 1p36.33 loss.ConclusionsActivating RAS mutations were dominant in our series, with supplementary detection of two PIK3CA mutations which may lead to therapeutic options. Furthermore, we detected 1p36.33 deletions in half of the cases, indicating a role in tumorigenesis, and these deletions may serve as a prognostic marker.
| S-EPMC6500912 | biostudies-literature
Project description:ImportanceBranch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) are common pancreatic preneoplastic lesions, but their surveillance is not personalized.ObjectiveTo investigate patient- and cyst-related factors associated with progression into worrisome features (WFs) or high-risk stigmata (HRS) categories of BD-IPMNs.Design, setting, and participantsCyst- and patient-related factors of consecutive BD-IPMNs without WFs or HRS in 540 patients diagnosed from 2009 to 2018 with at least 12 months' surveillance until February 28, 2020, were registered in a 2-center ambispective cohort study in Italy. In a subgroup, the ABO blood group was studied for the first time in this setting.ExposureCyst-related and patients-related factors and ABO blood group.Main outcomes and measuresThe study outcome was the appearance of WFs or HRS according to the 2017 International Association of Pancreatology guidelines. Survival probability was calculated using Kaplan-Meier curve and risk factors identified by Cox proportional hazards regression. ABO blood group was inferred through genotypes with DNA extraction.ResultsOf 540 patients with BD-IPMNs (median age, 66 years [interquartile range, 58.5-72.0 years]; 337 women [62.4%]) undergoing surveillance for a median of 51.5 months (interquartile range, 28-84 months) for 2758 person-years, 130 patients (24.1%) experienced progression. Probability of progression was 3.7% at 1 year, 23.4% at 5 years, and 43.3% at 10 years; 15 patients (2.8%) underwent surgery, 7 patients (1.3%) had malignant histologic findings, and 3 patients (0.56%) died of pancreatic-associated disease. Initial cyst size greater than 15 mm (hazard ratio [HR], 2.05; 95% CI, 1.44-2.91), body mass index greater than 26.4 (HR, 1.72; 95% CI, 1.19-2.50), and heavy smoking (HR, 1.81; 95% CI, 1.14-2.86) were significant independent factors associated with progression risk. The AA blood genotype was also associated with progression risk (HR, 3.49; 95% CI, 1.04-11.71) compared with the OO genotype in the investigated subgroup.Conclusions and relevanceThis analysis of factors associated with progression of BD-IPMNs according to recent guidelines suggests that cyst size alone is not a reliable factor for estimation of progression risk; however, along with other readily available data, size is helpful for planning personalized surveillance of BD-IPMNs.
| S-EPMC7705592 | biostudies-literature