Gene Summary

Gene:GNAS; GNAS complex locus
Aliases: AHO, GSA, GSP, POH, GPSA, NESP, SCG6, SgVI, GNAS1, PITA3, C20orf45
Summary:This locus has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5' exons. Some transcripts contain a differentially methylated region (DMR) at their 5' exons, and this DMR is commonly found in imprinted genes and correlates with transcript expression. An antisense transcript is produced from an overlapping locus on the opposite strand. One of the transcripts produced from this locus, and the antisense transcript, are paternally expressed noncoding RNAs, and may regulate imprinting in this region. In addition, one of the transcripts contains a second overlapping ORF, which encodes a structurally unrelated protein - Alex. Alternative splicing of downstream exons is also observed, which results in different forms of the stimulatory G-protein alpha subunit, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular reponses. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene result in pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors. [provided by RefSeq, Aug 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein ALEX; protein GNAS; protein SCG6 (secretogranin VI)
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: GNAS (cancer-related)

Liu JB, Jian T, Yue C, et al.
Chemo-resistant Gastric Cancer Associated Gene Expression Signature: Bioinformatics Analysis Based on Gene Expression Omnibus.
Anticancer Res. 2019; 39(4):1689-1698 [PubMed] Related Publications
BACKGROUND/AIM: This study aimed to identify biomarkers for predicting the prognosis of advanced gastric cancer patients who received docetaxel, cisplatin, and S-1 (DCS).
MATERIALS AND METHODS: Gene expression profiles were obtained from the Gene Expression Omnibus database (GSE31811). Gene-Ontology-enrichment and KEGG-pathway analysis were used for evaluating the biological functions of differentially-expressed genes. Protein-protein interaction (PPI) network and Kaplan-Meier survival analyses were employed to assess the prognostic values of hub genes.
RESULTS: A total of 1,486 differentially expressed genes (DEGs) were identified, including 13 up-regulated and 1,473 down-regulated genes. KEGG pathways such as metabolic pathways, cell adhesion molecules (CAMs), PI3K-Akt signaling pathway and pathways in cancer were significantly represented. In the PPI network, the top ten hub genes ranked by degree were GNG7, PLCB1, CALML5, FGFR4, GRB2, JAK3, ADCY7, ADCY9, GNAS and KDR. Five DEGs, including ANTXR1, EFNA5, GAMT, E2F2 and NRCAM, were associated with relapse-free survival and overall survival.
CONCLUSION: ANTXR1, EFNA5, GAMT, E2F2 and NRCAM are potential biomarkers and therapeutic targets for DCS treatment in GC.

Bekers EM, Eijkelenboom A, Rombout P, et al.
Identification of novel GNAS mutations in intramuscular myxoma using next-generation sequencing with single-molecule tagged molecular inversion probes.
Diagn Pathol. 2019; 14(1):15 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Intramuscular myxoma (IM) is a hypocellular benign soft tissue neoplasm characterized by abundant myxoid stroma and occasional hypercellular areas. These tumors can, especially on biopsy material, be difficult to distinguish from low-grade fibromyxoid sarcoma or low-grade myxofibrosarcoma. GNAS mutations are frequently involved in IM, in contrast to these other malignant tumors. Therefore, sensitive molecular techniques for detection of GNAS aberrations in IM, which frequently yield low amounts of DNA due to poor cellularity, will be beneficial for differential diagnosis.
METHODS: In our study, a total of 34 IM samples from 33 patients were analyzed for the presence of GNAS mutations, of which 29 samples were analyzed using a gene-specific TaqMan genotyping assay for the detection of GNAS hotspot mutations c.601C > T and c602G > A in IM, and 32 samples using a novel next generation sequencing (NGS)-based approach employing single-molecule tagged molecular inversion probes (smMIP) to identify mutations in exon 8 and 9 of GNAS. Results between the two assays were compared for their ability to detect GNAS mutations with high confidence.
RESULTS: In total, 23 of 34 samples were successfully analyzed with both techniques showing GNAS mutations in 12 out of 23 (52%) samples. The remaining 11 samples were analyzed with either TaqMan assay or smMIP assay only. The TaqMan assay revealed GNAS mutations in 16 out of 29 samples (55%), with six samples c.601C > T (p.R201C; 38%) and ten samples c.602G > A (p.R201H; 62%) missense mutations. The smMIP assay identified mutations in 16 out of 28 samples (57%), with five samples c.601C > T (p.R201C; 31%) and seven samples c.602G > A (p.R201H; 44%) missense mutations. In addition, four samples (25%) revealed novel IM-associated mutations, including c.601C > A (p.R201S), c.602G > T (p.R201L), c.602G > C (p.R201P) and c.680A > G (p.Q227R). Combining the results of both tests, 23 out of 34 sporadic IM samples (68%) showed a GNAS mutation.
CONCLUSIONS: Both the TaqMan and the smMIP assay a show a high degree of concordance in detecting GNAS hotspot mutations in IM with comparable sensitivity. However, since the NGS-based smMIP assay permits mutation detection in whole exons of GNAS, a broader range of GNAS mutations can be identified by the smMIP approach.

Zhang Z, Chng KR, Lingadahalli S, et al.
An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells.
Genome Res. 2019; 29(2):223-235 [PubMed] Free Access to Full Article Related Publications
The aberrant activities of transcription factors such as the androgen receptor (AR) underpin prostate cancer development. While the AR

Singla H, Kaur RP, Shafi G, et al.
Genomic alterations associated with HER2+ breast cancer risk and clinical outcome in response to trastuzumab.
Mol Biol Rep. 2019; 46(1):823-831 [PubMed] Related Publications
Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is an aggressive BC subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. Here, we aimed at identifying germline and somatic alterations associated with HER2+ BC and evaluating their association with clinical outcome in response to trastuzumab therapy given to HER2+ BC patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes in HER2+ BC. In addition, 20 formalin fixed paraffin-embedded tissue samples were also evaluated by GSA for identifying significant variations associated with HER + BC as well as response to trastuzumab therapy. A germline variant in HER2 (I655V) was found to be significantly associated with the risk of the disease (p < 0.01). A nonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a hotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 (R249S); were observed in 25%, 75%, 30% and 40% of the HER2+ BC tissue samples, respectively. Mutant CCND1 (P241P) and PIK3CA (E542K) were found to be significantly associated with reduced disease-free survival (DFS) in patients treated with trastuzumab (p: 0.018 and 0.005, respectively). These results indicate that HER2, PTPN11, CCND1 and PIK3CA genes are important biomarkers in HER2+ BC. Moreover, the patients harboring mutant CCND1 and PIK3CA exhibit a poorer clinical outcome as compared to those carrying wild-type CCND1 and PIK3CA.

Lu Y, Kweon SS, Tanikawa C, et al.
Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.
Gastroenterology. 2019; 156(5):1455-1466 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.
METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.
RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10
CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

Omori Y, Ono Y, Tanino M, et al.
Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features.
Gastroenterology. 2019; 156(3):647-661.e2 [PubMed] Related Publications
BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses.
METHODS: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs, and 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors.
RESULTS: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes.
CONCLUSIONS: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs-we call these the sequential, branch-off, and de novo subtypes. Subtypes might be associated with clinical and pathologic features and be used to select surveillance programs for patients with IPMNs.

Shiu JS, Hsieh MJ, Chiou HL, et al.
Impact of ADAM10 gene polymorphisms on hepatocellular carcinoma development and clinical characteristics.
Int J Med Sci. 2018; 15(12):1334-1340 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
A disintegrin and metalloprotease (ADAM) family proteins are type-I transmembrane glycoproteins with multiple functions in cell adhesion, migration, proteolysis and signaling. ADAM10 is a member of the ADAM family reportedly involved in cancer progression and has been shown to be overexpressed in hepatocellular carcinoma (HCC) tissues and significantly associated with tumor progression and shortened survival. This study investigated ADAM10's single nucleotide polymorphisms (SNPs) and their association to HCC development and regulation. Real-time polymerase chain reaction was used to analyze five SNPs of ADAM10 in 333 patients with HCC and 1196 controls without cancer. The results indicated that of the 333 patients with HCC, those who carried ADAM10 rs514049 (AC + CC) variants had a higher risk of developing lymph node metastasis (odds ratio [OR] = 5.087, p = 0.027), and those who carried ADAM10 rs653765 (GA + AA) variants had a higher risk of developing distant metastasis (OR = 3.346, p = 0.020) and higher levels of α-fetoprotein. In conclusion, our study demonstrated that the SNPs of ADAM10 are involved in HCC progression. ADAM10 SNPs may be used as therapeutic targets to evaluate poor prognoses for HCC.

Huhtaniemi R, Oksala R, Knuuttila M, et al.
Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts.
Am J Pathol. 2018; 188(12):2890-2901 [PubMed] Related Publications
The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in humans is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, because mouse adrenals do not produce steroids activating the androgen receptor. In this study, we confirmed the expression of enzymes essential for de novo synthesis of androgens in mouse adrenals, with high intratissue concentration of progesterone (P

Volckmar AL, Endris V, Gaida MM, et al.
Next generation sequencing of the cellular and liquid fraction of pancreatic cyst fluid supports discrimination of IPMN from pseudocysts and reveals cases with multiple mutated driver clones: First findings from the prospective ZYSTEUS biomarker study.
Genes Chromosomes Cancer. 2019; 58(1):3-11 [PubMed] Related Publications
Approximately half of all pancreatic cysts are neoplastic, mainly comprising intraductal papillary mucinous neoplasms (IPMN), which can progress to invasive carcinoma. Current Fukuoka guidelines have limited sensitivity and specificity in predicting progression of asymptomatic pancreatic cysts. We present first results of the prospective ZYSTEUS biomarker study investigating (i) whether detection of driver mutations in IPMN by liquid biopsy is technically feasible, (ii) which compartment of IPMN is most suitable for analysis, and (iii) implications for clinical diagnostics. Twenty-two patients with clinical inclusion criteria were enrolled in ZYSTEUS. Fifteen cases underwent endoscopic ultrasound (EUS)-guided fine-needle aspiration and cytological diagnostics. Cellular and liquid fraction of the cysts of each case were separated and subjected to deep targeted next generation sequencing (NGS). Clinical parameters, imaging findings (EUS and MRI), and follow-up data were collected continuously. All IPMN cases (n = 12) showed at least one mutation in either KRAS (n = 11) or GNAS (n = 4). Three cases showed both KRAS and GNAS mutations. Six cases harbored multiple KRAS/GNAS mutations. In the three cases with pseudocysts, no KRAS or GNAS mutations were detected. DNA yields were higher and showed higher mutation diversity in the cellular fraction. In conclusion, mutation detection in pancreatic cyst fluid is technically feasible with more robust results in the cellular than in the liquid fraction. Current results suggest that, together with imaging, targeted sequencing supports discrimination of IPMN from pseudocysts. The prospective design of ZYSTEUS will provide insight into diagnostic value of NGS in preoperative risk stratification. Our data provide evidence for an oligoclonal nature of IPMN.

Lu XJD, Liu KYP, Soares RC, et al.
Potential clinical implications of HPV status and expressions of p53 and cyclin D1 among oropharyngeal cancer patients.
J Oral Pathol Med. 2018; 47(10):945-953 [PubMed] Related Publications
BACKGROUND: There is increasing evidence that high-risk human papillomavirus plays significant role in oropharyngeal cancer; however, there is lack of knowledge on the interplay between the virus and its downstream-related molecules and their possible prognostic values. The objectives of the study are to better understand the interplay of the HR-HPV and its associated downstream molecules and to evaluate potential biomarkers for patient outcomes.
METHODS: We conducted a retrospective study with available formalin-fixed, paraffin-embedded tissue from 244 oropharyngeal cancer patients that received curative radiotherapy or concurrent chemoradiotherapy from 2000 to 2008. In addition to chart review, we performed HPV DNA and RNA in situ hybridization and immunohistochemistry for p53, the retinoblastoma protein, p16, and cyclin D1 analysis. Cox proportional hazard and Kaplan-Meier survival analysis were used to determine the prognostic markers for clinical outcomes.
RESULTS: Patients averaged 57.3 ± 9.4 year-old and were mostly males (76.2%) and ever-smokers (76.2%). All patients received curative radiotherapy, and 44.3% received concurrent chemoradiotherapy. We detected the human papillomavirus in 77.9% of study patients. Ever-smokers, more advanced tumor stage, and receiving radiotherapy only had poorer 5-year overall survival, disease-specific survival, and loco-regional recurrence. Cases with positive human papillomavirus and p53 overexpression had poorer disease-specific survival. Cases without human papillomavirus, but cyclin D1 overexpression, were associated with poorer 5-year overall survival.
CONCLUSIONS: Our data suggest that additional p53 and cyclin D1 testing may benefit oropharyngeal cancer patients with known human papillomavirus status.

Ideno N, Yamaguchi H, Ghosh B, et al.
Gastroenterology. 2018; 155(5):1593-1607.e12 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND & AIMS: Mutations at hotspots in GNAS, which encodes stimulatory G-protein, α subunits, are detected in approximately 60% of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. We generated mice with KRAS-induced IPMNs that also express a constitutively active form of GNAS in pancreas and studied tumor development.
METHODS: We generated p48-Cre; LSL-KrasG12D; Rosa26R-LSL-rtTA-TetO-GnasR201C mice (Kras;Gnas mice); pancreatic tissues of these mice express activated KRAS and also express a mutant form of GNAS (GNAS
RESULTS: All Kras;Gnas mice developed pancreatic cystic lesions that resemble human IPMNs; the grade of epithelial dysplasia increased with time. None of the control mice developed cystic lesions. Approximately one third of Kras;Gnas mice developed PDACs at a median of 30 weeks after doxycycline administration, whereas 33% of control mice developed PDACs. Expression of GNAS
CONCLUSIONS: In mice that express activated KRAS in the pancreas, we found expression of GNAS

Candida Barisson Villares Fragoso M, Pontes Cavalcante I, Meneses Ferreira A, et al.
Genetics of primary macronodular adrenal hyperplasia.
Presse Med. 2018 Jul - Aug; 47(7-8 Pt 2):e139-e149 [PubMed] Related Publications
Recent advances in molecular genetics investigations of primary macronodular adrenal hyperplasia (PMAH) have been providing new insights for the research on this issue. The cAMP-dependent pathway is physiologically triggered by ACTH and its receptor, MC2-R, in adrenocortical cells. Different mechanisms of this cascade may be altered in some functioning adrenal cortical disorders. Activating somatic mutations of the GNAS gene (known as gsp oncogene) which encodes the stimulatory G protein alpha-subunit (Gsα) have been found in a small number of adrenocortical secreting adenomas and rarely in PMAH. Lately, ARMC5 was linked to the cyclic AMP signaling pathway, which could be implicated in all of mechanisms of cortisol-secreting by macronodules adrenal hyperplasia and the molecular defects in: G protein aberrant receptors; MC2R; GNAS; PRKAR1A; PDE11A; PDE8B. Around 50 % of patient's relatives with PMAH and 30 % of apparently sporadic hypercortisolism carried ARMC5 mutations. Therefore, PMAH is genetically determined more frequently than previously believed. This review summarizes the most important molecular mechanisms involved in PMAH.

Saarinen L, Nummela P, Leinonen H, et al.
Glycomic Profiling Highlights Increased Fucosylation in Pseudomyxoma Peritonei.
Mol Cell Proteomics. 2018; 17(11):2107-2118 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Pseudomyxoma peritonei (PMP) is a subtype of mucinous adenocarcinoma that most often originates from the appendix, and grows in the peritoneal cavity filling it with mucinous ascites.

Figueiredo J, Melo S, Gamet K, et al.
E-cadherin signal sequence disruption: a novel mechanism underlying hereditary cancer.
Mol Cancer. 2018; 17(1):112 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The aim of this study was to uncover the pathogenic relevance and the underlying molecular mechanism of a novel CDH1 variant found in a Hereditary Diffuse Gastric Cancer family (p.L13_L15del), which affects the signal peptide of E-cadherin without changing the remaining predicted sequence. We verified that p.L13_L15del cells yield low levels of E-cadherin, decreased cell adhesion and enhanced cell invasion. Further, we demonstrated that the disruption of the highly conserved hydrophobic core of the signal peptide hampers the binding of cellular components crucial for E-cadherin translation and translocation into the endoplasmic reticulum, constituting a new molecular basis for the loss of a tumour suppressor gene causative of hereditary cancer.

Godwin TD, Kelly ST, Brew TP, et al.
E-cadherin-deficient cells have synthetic lethal vulnerabilities in plasma membrane organisation, dynamics and function.
Gastric Cancer. 2019; 22(2):273-286 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: The E-cadherin gene (CDH1) is frequently mutated in diffuse gastric cancer and lobular breast cancer, and germline mutations predispose to the cancer syndrome Hereditary Diffuse Gastric Cancer. We are taking a synthetic lethal approach to identify druggable vulnerabilities in CDH1-mutant cancers.
METHODS: Density distributions of cell viability data from a genome-wide RNAi screen of isogenic MCF10A and MCF10A-CDH1
CONCLUSIONS: E-cadherin loss leads to disturbances in receptor signalling and plasma membrane trafficking and organisation, creating druggable vulnerabilities.

Domingo E, Camps C, Kaisaki PJ, et al.
Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the QUASAR 2 clinical trial and an Australian community-based series.
Lancet Gastroenterol Hepatol. 2018; 3(9):635-643 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Molecular indicators of colorectal cancer prognosis have been assessed in several studies, but most analyses have been restricted to a handful of markers. We aimed to identify prognostic biomarkers for colorectal cancer by sequencing panels of multiple driver genes.
METHODS: In stage II or III colorectal cancers from the QUASAR 2 open-label randomised phase 3 clinical trial and an Australian community-based series, we used targeted next-generation sequencing of 82 and 113 genes, respectively, including the main colorectal cancer drivers. We investigated molecular pathways of tumorigenesis, and analysed individual driver gene mutations, combinations of mutations, or global measures such as microsatellite instability (MSI) and mutation burden (total number of non-synonymous mutations and coding indels) for associations with relapse-free survival in univariable and multivariable models, principally Cox proportional hazards models.
FINDINGS: In QUASAR 2 (511 tumours), TP53, KRAS, BRAF, and GNAS mutations were independently associated with shorter relapse-free survival (p<0·035 in all cases), and total somatic mutation burden with longer survival (hazard ratio [HR] 0·81 [95% CI 0·68-0·96]; p=0·014). MSI was not independently associated with survival (HR 1·12 [95% CI 0·57-2·19]; p=0·75). We successfully validated these associations in the Australian sample set (296 tumours). In a combined analysis of both the QUASAR 2 and the Australian sample sets, mutation burden was also associated with longer survival (HR 0·84 [95% CI 0·74-0·94]; p=0·004) after exclusion of MSI-positive and POLE mutant tumours. In an extended analysis of 1732 QUASAR 2 and Australian colorectal cancers for which KRAS, BRAF, and MSI status were available, KRAS and BRAF mutations were specifically associated with poor prognosis in MSI-negative cancers. MSI-positive cancers with KRAS or BRAF mutations had better prognosis than MSI-negative cancers that were wild-type for KRAS or BRAF. Mutations in the genes NF1 and NRAS from the MAPK pathway co-occurred, and mutations in the DNA damage-response genes TP53 and ATM were mutually exclusive. We compared a prognostic model based on the gold standard of clinicopathological variables and MSI with our new model incorporating clinicopathological variables, mutation burden, and driver mutations in KRAS, BRAF, and TP53. In both QUASAR 2 and the Australian cohort, our new model was significantly better (p=0·00004 and p=0·0057, respectively, based on a likelihood ratio test).
INTERPRETATION: Multigene panels identified two previously unreported prognostic associations in colorectal cancer involving TP53 mutation and total mutation burden, and confirmed associations with KRAS and BRAF. Even a modest-sized gene panel can provide important information for use in clinical practice and outperform MSI-based prognostic models.
FUNDING: UK Technology Strategy Board, National Institute for Health Research Oxford Biomedical Research Centre, Cancer Australia Project, Cancer Council Victoria, Ludwig Institute for Cancer Research, Victorian Government.

Goudie C, Hannah-Shmouni F, Kavak M, et al.
65 YEARS OF THE DOUBLE HELIX: Endocrine tumour syndromes in children and adolescents.
Endocr Relat Cancer. 2018; 25(8):T221-T244 [PubMed] Related Publications
As medicine is poised to be transformed by incorporating genetic data in its daily practice, it is essential that clinicians familiarise themselves with the information that is now available from more than 50 years of genetic discoveries that continue unabated and increase by the day. Endocrinology has always stood at the forefront of what is called today 'precision medicine': genetic disorders of the pituitary and the adrenal glands were among the first to be molecularly elucidated in the 1980s. The discovery of two endocrine-related genes,

Romero S, Musleh M, Bustamante M, et al.
Polymorphisms in
Anticancer Res. 2018; 38(7):3871-3877 [PubMed] Related Publications
BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) program has been linked as a driver of metastatic dissemination by conferring migratory and invasive capacity to cancer cells. Gastric cancer (GC) patients with tumors expressing altered levels of EMT markers have low survival. This study aimed to assess if polymorphisms of CDH1, TWIST1, SNAIL2, ZEB1 and ZEB2 genes are associated with survival in GC patients.
PATIENTS AND METHODS: A total of 153 individuals with diagnosis of GC were recruited in Santiago, Chile. All patients were genotyped using Infinium Global Screening Array (GSA). Twenty Tag SNPs of the studied genes were retrieved.
RESULTS: Three SNPs were associated with survival: rs2526614 (TWIST1) (genotype CA + AA, adjusted HR=0.58, 95%CI=0.37-0.93), rs6953766 (TWIST1) (genotype GG, crude HR=2.02, 95%CI=1.06-3.82, adjusted HR=2.14, 95%CI=1.07-4.25), and rs431073 (ZEB1) (genotype AC + CC, crude HR=1.62, 95%CI=1.01-2.59, adjusted HR=1.96, 95%CI=1.18-3.25).
CONCLUSION: To the best of our knowledge, this is the first study proposing a role of these SNPs in cancer prognosis. Their use as prognostic markers of GC survival warrants further investigation.

Weigand I
Pathogenesis of benign unilateral adrenocortical tumors: focus on cAMP/PKA pathway.
Minerva Endocrinol. 2019; 44(1):25-32 [PubMed] Related Publications
Somatic mutations affecting genes in the cAMP/PKA (protein kinase A) signaling pathway have been described as causative for the pathogenesis of benign unilateral adrenocortical adenomas associated with cortisol over secretion. These include predominantly somatic mutations in the PRKACA gene which encodes the catalytic subunit α of PKA. In addition, mutations in the GNAS gene, coding for the stimulatory G protein α, have been observed in approximately 10% of cortisol producing adenomas (CPA). The mutations render PKA signaling constitutively active and are therefore involved in cortisol over secretion of these tumors. Despite the prominent role of the cAMP/PKA pathway in the pathogenesis of unilateral CPA, also mutations in the CTNNB1 gene, encoding β-catenin, were identified in CPA. However, mutations in β-catenin are not limited to CPA and are not associated with cortisol secretion since they were predominantly found in endocrine-inactive adenomas (EIA) and might hence contribute to tumorigenesis in adrenocortical tissues. In this review, recent findings in the pathogenesis of benign adrenocortical tumors with a particular focus on the cAMP/PKA signaling pathway are summarized.

Foltran RK, Amorim PVGH, Duarte FH, et al.
Study of major genetic factors involved in pituitary tumorigenesis and their impact on clinical and biological characteristics of sporadic somatotropinomas and non-functioning pituitary adenomas.
Braz J Med Biol Res. 2018; 51(9):e7427 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.

Patra KC, Kato Y, Mizukami Y, et al.
Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism.
Nat Cell Biol. 2018; 20(7):811-822 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
G protein α

Kalra S, Kaur RP, Ludhiadch A, et al.
Association of CYP2C19*2 and ALDH1A1*1/*2 variants with disease outcome in breast cancer patients: results of a global screening array.
Eur J Clin Pharmacol. 2018; 74(10):1291-1298 [PubMed] Related Publications
PURPOSE: Cyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab.
METHODS: A total of 250 confirmed breast cancer patients were involved in the study. Genotyping was performed on an Illumina Infinium HD assay platform using a Global Screening Array (GSA) microchip. GenomeStudio (Illumina, Inc.) was used for data preprocessing and a p value less than or equal to 5 × 10-8 was considered statistically significant. To rule out the influence of confounding risk factors, a step-wise multivariate regression analysis was carried out to evaluate the association of genotype with overall clinical outcome.
RESULTS: Two gene variants, CYP2C19 (G681A) and ALDH1A1*2 (17 bp deletion), were found to be significantly associated with the disease outcome, including overall survival, recurrence and metastasis, in breast cancer patients on adjuvant therapy. Both these genes are involved in the pharmacokinetics of cyclophosphamide. However, none of the variants in the genes involved in pharmacokinetics and pharmacodynamics of doxorubicin were found to have any significant impact on disease outcome in the studied group.
CONCLUSION: CYP2C19 (G681A) variant and ALDH1A1*2 emerged as two important biomarkers associated with bad outcome in breast cancer patients on adjuvant therapy.

Calleja M, Amary F, O'Donnell P
Mutational analysis of high-grade spindle cell sarcoma of the femur in Mazabraud's syndrome.
Skeletal Radiol. 2019; 48(1):151-157 [PubMed] Related Publications
Mazabraud's syndrome is a rare disorder characterised by the association of fibrous dysplasia with intramuscular myxomas. We present a 36-year-old woman with right anterior knee pain and a buttock mass. Imaging showed aggressive bone destruction within an area of fibrous dysplasia in the right femur and a mass with myxoid signal characteristics in the right adductor region. Biopsy of the femur revealed both fibrous dysplasia and a high-grade spindle cell sarcoma. Biopsy of the adductor mass confirmed a soft-tissue myxoma. Molecular genetic analysis revealed an identical R201H substitution in the GNAS1 gene in the sarcoma, the myxoma, and also the conventional fibrous dysplasia.

Faias S, Duarte M, Albuquerque C, et al.
Clinical Impact of KRAS and GNAS Analysis Added to CEA and Cytology in Pancreatic Cystic Fluid Obtained by EUS-FNA.
Dig Dis Sci. 2018; 63(9):2351-2361 [PubMed] Related Publications
BACKGROUND: Pancreatic cysts are common incidental findings with malignant potential, raising diagnostic and treatment dilemmas.
AIMS: To determine the added value of KRAS and GNAS mutation analysis on cyst classification and decision making.
METHODS: We analyzed 52 frozen samples of pancreatic cystic fluid obtained by EUS-FNA between 2008 and 2014. In addition to cytology and CEA, mutations of GNAS (exons 8 and 9) and KRAS (exons 2 and 3) genes were analyzed using Sanger sequencing.
RESULTS: There were 52 patients, 67% females, with a mean age of 59 ± 15 years (29-91). Cysts were classified as mucinous in 21 patients (40%) (14 low-risk, seven malignant) and non-mucinous in 31 patients (60%). After EUS-FNA, 11 patients had surgery, six had chemotherapy or palliation, one had endoscopic drainage, and 34 are on follow-up after a mean of 57 months. KRAS mutation was detected in nine and GNAS in two samples. Patients harboring cysts with KRAS mutations were older (p = 0.01), cysts were more commonly mucinous (p = 0.001) and malignant (p = 0.01). KRAS mutations were present in both low-risk and malignant mucinous lesions. For identifying mucinous lesions, CEA > 192 ng/mL performed better (AUC ROC = 93%), whereas for malignant/high-risk mucinous lesions, EUS imaging had the best accuracy (AUC ROC = 88%). After molecular analysis, a modification in cyst classification occurred in ten patients, but was correct in only two, a pseudocyst re-classified as IPMN and a malignant cyst as a non-mucinous cyst.
CONCLUSIONS: In this cohort of patients with pancreatic cysts, KRAS and GNAS mutations had no significant diagnostic benefit in comparison with conventional testing.

Gagnon N, Cáceres-Gorriti KY, Corbeil G, et al.
Genetic Characterization of GnRH/LH-Responsive Primary Aldosteronism.
J Clin Endocrinol Metab. 2018; 103(8):2926-2935 [PubMed] Related Publications
Background: Recently, somatic β-catenin mutations (CTNNB1) identified in aldosterone-producing adenomas (APAs) from three women were suggested to be responsible for the aberrant overexpression of luteinizing hormone/choriogonadotropin receptor and gonadotropin-releasing hormone receptor in the APA.
Objective: To genetically characterize patients with primary aldosteronism (PA) evaluated in vivo for gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH)-responsive aldosterone secretion.
Method: Patients with PA were evaluated in vivo to determine the possible regulation of aldosterone secretion by GnRH or LH. Genetic analysis of the CTNNB1, KCNJ5, ATP1A1, ATP2B3, CACNA1D, and GNAS genes were performed in this cohort and a control cohort of PA not tested in vivo for GnRH response.
Results: We studied 50 patients with confirmed PA, including 36 APAs, 12 bilateral macronodular adrenal hyperplasias, 1 oncocytoma, and 1 bilateral hyperplasia with cosecretion of cortisol. Among 23 patients tested in vivo for GnRH response of aldosterone, 7 (30.4%) had a positive response, 4 (17.4%) a partial response, and 12 (52.2%) no response. No somatic CTNNB1 mutations were identified, but the disease-causing c.451G>C KCNJ5 mutation was found in two individuals with partial and no GnRH responses and an individual showing a positive response to LH. Two additional somatic pathogenic mutations, CACNA1D c.776T>A and ATP1A1 c.311T>G, were identified in two patients with no GnRH responses. In the 26 patients not tested for GnRH response, we identified 2 CTNNB1 (7.7%), 13 KCNJ5 (50%), and 1 CACNA1D (3.8%) mutations.
Conclusion: Aberrant regulation of aldosterone by GnRH is frequent in PA, but is not often associated with somatic CTNNB1, although it may be found with somatic KCNJ5 mutations.

Kaur RP, Shafi G, Benipal RPS, Munshi A
Frequency of pathogenic germline mutations in cancer susceptibility genes in breast cancer patients.
Med Oncol. 2018; 35(6):81 [PubMed] Related Publications
In this study, we evaluated the incidence of pathogenic germline mutations in 30 breast cancer susceptibility genes in breast cancer patients. Our aim was to understand the involvement of the inherited mutations in these genes in a breast cancer cohort. Two hundred ninety-six female breast cancer patients including 4.5% of familial breast cancer cases were included in the study. 200 ng of genomic DNA was used to evaluate the pathogenic mutations, detected using Global Screening Array (GSA) microchip (Illumina Inc.) according to the manufacturer's instructions. The pathogenic frameshift and nonsense mutations were observed in BRCA2 (10.9%), MLH1 (58.6%), MTHFR (50%), MSH2 (14.2%), and CYTB (52%) genes. Familial breast cancer patients (4.5%) had variations in BRCA2, MLH1, MSH2, and CYTB genes. 28% of patients with metastasis, recurrence, and death harbored mono/biallelic alterations in MSH2, MLH1, and BRCA2 genes. The results of this study can guide to develop a panel to test the breast cancer patients for pathogenic mutations, from Malwa region of Punjab. The screening of MSH2, MLH1, and BRCA2 should be carried in individuals with or without family history of breast cancer as these genes have been reported to increase the cancer risk by tenfold.

Matsuo Y, Yamamoto H, Sato Y, et al.
GNAS-mutated carcinoma arising from gastric foveolar metaplasia in the duodenum after 9 years of observation.
Clin J Gastroenterol. 2018; 11(5):391-395 [PubMed] Related Publications
This case involved an 80-year-old man. Screening with esophagogastroduodenoscopy (EGD) in 2004 revealed Brunner's gland hyperplasia (BGH), 5 mm in size, in the duodenal bulb. The size of the lesion increased and its shape has changed since then, as detected in subsequent EGDs. The lesion had increased in size to 15 mm with a depression and biopsy specimens revealed an adenocarcinoma. The patient underwent endoscopic mucosal resection. Histopathological assessments indicated an adenocarcinoma arising from gastric foveolar metaplasia (GFM) adjacent to BGH. BGH stained positive for MUC6, and GFM and the adenocarcinoma stained positive for MUC5AC. Mutations of the GNAS gene were not detected in the GFM biopsied in 2007. On the other hand, common GNAS mutations (R201H) were detected in GFM and the adenocarcinoma in the endoscopically resected specimen in 2013. Moreover, mutant allele frequencies were higher in the carcinoma than in GFM. The patient remains disease-free for 4 years after endoscopic treatment. This case report further supports the notion that GFM may be a precursor lesion in the process of GNAS-mutated, gastric-type duodenal carcinogenesis.

Chiu YM, Tsai CL, Kao JT, et al.
PD-1 and PD-L1 Up-regulation Promotes T-cell Apoptosis in Gastric Adenocarcinoma.
Anticancer Res. 2018; 38(4):2069-2078 [PubMed] Related Publications
BACKGROUND/AIM: The programmed death 1 (PD-1) receptor and its ligand (PD-L1) play pivotal roles in regulating host immune responses. However, the inhibitory effects of this pathway on the function of tumor infiltrating T lymphocytes in gastric adenocarcinoma patients are not well-defined.
MATERIALS AND METHODS: We characterized the expression of PD-1 and PD-L1 in peripheral blood and tumor infiltrating cells and analyzed the association between PD-1/PD-L1 expression and disease progression in a cohort of 60 patients with Helicobacter pylori infection, including 18 with gastric adenocarcinoma, 23 with gastritis, and 19 asymptomatic controls.
RESULTS: Relative to controls, the expression of PD-1 on peripheral blood and tumor infiltrating T cells increased with disease progression. In vitro, T cells induced PD-L1 expression on primary gastric adenocarcinoma epithelial cells in an IFN-γ-dependent manner, which in turn promoted T cells apoptosis. Blocking of PD-L1 reversed this effect.
CONCLUSION: This study provides evidence for a new therapeutic target in gastric adenocarcinoma patients.

Felsenstein M, Noë M, Masica DL, et al.
IPMNs with co-occurring invasive cancers: neighbours but not always relatives.
Gut. 2018; 67(9):1652-1662 [PubMed] Related Publications
OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated.
DESIGN: We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient.
RESULTS: We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes.
CONCLUSION: This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.

Lim CT, Korbonits M
Endocr Pract. 2018; 24(5):473-488 [PubMed] Related Publications
OBJECTIVE: Pituitary adenomas are the third most common central nervous system tumors and arise from the anterior pituitary within the pituitary fossa.
METHODS: Literature review and discussion.
RESULTS: The signs and symptoms of patients with pituitary adenomas vary from 'mass effects' caused by a large adenoma to features secondary to excess pituitary hormones produced by the functioning pituitary adenoma. Detailed histopathologic assessment, based on novel classifications and the latest World Health Organization guidelines, helps to categorize pituitary adenomas into different subtypes and identify features that, in some cases, help to predict their behavior. Most of the pituitary tumors occur sporadically without known genetic predisposition, but in a significant minority of cases, somatic mutations can be identified in the GNAS and USP8 genes. A small proportion of the cases have germline genetic defects or embryonic mutations leading to mosaicism. Genes with germ-line mutations predisposing to pituitary adenomas include AIP, GPR101, MEN1, CDKN1B, PRKAR1A, PRKAR2A, DICER1, NF1, and SDHx, whereas more recently, CABLES1 has also been implicated.
CONCLUSION: Understanding the pathogenesis of pituitary adenomas will allow clinicians to correlate the pathologic and genetic features with clinical data, helping decisions on the best management of these tumors.
ABBREVIATIONS: ACTH = adrenocorticotropic hormone; AIP = aryl hydrocarbon receptor-interacting protein; αSU = alpha-subunit; EGFR = epithelial growth factor receptor; ER = estrogen receptor; FSH = follicle-stimulating hormone; GH = growth hormone; GHRH = growth hormone-releasing hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; MEN1 = multiple endocrine neoplasia 1; MRI = magnetic resonance imaging; NFPA = nonfunctioning pituitary adenoma; PRL = prolactin; TSH = thyroid-stimulating hormone; USP8 = ubiquitin-specific peptidase 8; WHO = World Health Organization.

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