GNAS

Gene Summary

Gene:GNAS; GNAS complex locus
Aliases: AHO, GSA, GSP, POH, GPSA, NESP, SCG6, SgVI, GNAS1, C20orf45
Location:20q13.3
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, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein ALEX; protein GNAS; protein SCG6 (secretogranin VI)
HPRD
Source:NCBIAccessed: 20 August, 2015

Ontology:

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 (1990-2015)
Graph generated 20 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 20 August, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: GNAS (cancer-related)

Tan MC, Basturk O, Brannon AR, et al.
GNAS and KRAS Mutations Define Separate Progression Pathways in Intraductal Papillary Mucinous Neoplasm-Associated Carcinoma.
J Am Coll Surg. 2015; 220(5):845-54.e1 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) are being increasingly recognized as important precursors to pancreatic adenocarcinoma. Elucidation of the genetic changes underlying IPMN carcinogenesis may improve the diagnosis and management of IPMN. We sought to determine whether different histologic subtypes of IPMN would exhibit different frequencies of specific genetic mutations.
STUDY DESIGN: Patients with resected IPMN-associated invasive carcinoma (IPMN-INV) between 1997 and 2012 were reviewed. Areas of carcinoma, high-grade dysplasia, and low-grade dysplasia were micro-dissected from each pathologic specimen. Targeted, massively parallel sequencing was then performed on a panel of 275 genes (including KRAS, GNAS, and RNF43).
RESULTS: Thirty-eight patients with resected IPMN-INV and sufficient tissue for micro-dissection were identified. Median follow-up was 2.6 years. Mutations in GNAS were more prevalent in colloid-type IPMN-INV than tubular-type IPMN-INV (89% vs 32% respectively; p = 0.0003). Conversely, KRAS mutations were more prevalent in tubular-type than colloid-type IPMN-INV (89% vs 52%, respectively; p = 0.01). For noninvasive IPMN subtypes, GNAS mutations were more prevalent in intestinal (74%) compared with pancreatobiliary (31%) and gastric (50%) subtypes (p = 0.02). The presence of these mutations did not vary according to the degree of dysplasia (GNAS: invasive 61%, high-grade 59%, low-grade 53%; KRAS: invasive 71%, high-grade 62%, low-grade 74%), suggesting that mutations in these genes occur early in IPMN carcinogenesis.
CONCLUSIONS: Colloid carcinoma associated with IPMN and its intestinal-type preinvasive precursor are associated with high frequencies of GNAS mutations. The mutation profile of tubular carcinoma resembles that of conventional pancreatic adenocarcinoma. Preoperative determination of mutational status may assist with clinical treatment decisions.

Stachler MD, Rinehart E, Lindeman N, et al.
Novel molecular insights from routine genotyping of colorectal carcinomas.
Hum Pathol. 2015; 46(4):507-13 [PubMed] Related Publications
Routine tumor genotyping enables identification of concurrent mutations in tumors and reveals low-frequency mutations that may be associated with a particular tumor phenotype. We genotyped 311 colorectal carcinomas (CRCs) for 471 mutation hot spots in 41 cancer-associated genes. At least 1 mutation was present in 239 (77%) of 311 tumors. Two concurrent mutations were identified in 89 (29%) tumors, 3 mutations in 24 (8%), 4 mutations in 6 (2%), and 5 mutations in 1 tumor. KRAS mutations were most frequent and identified in 132 (42%) tumors, followed by APC in 79 (25%) and TP53 in 64 (21%) tumors. Mutations in PIK3CA, BRAF, CTNNB1, and NRAS were identified in 41, 27, 11, and 9 cases, respectively. Rare mutations not typically associated with CRC included AKT1 (4), AKT2 (1), IDH1 (1), KIT (1), MAP2K1 (1), PTEN (2), and GNAS (6). GNAS mutations in CRC correlated with a mucinous phenotype and were present in 20% of all mucinous adenocarcinomas evaluated in this study. Among CRCs with a PIK3CA mutation, 77% showed concurrent mutations in other cancer-associated genes, and 4% of CRC did not neatly fit into either the chromosomal instability pathway or CpG island methylator phenotype/microsatellite instability pathway, suggesting overlapping mutational profile in some tumors. Our findings indicate that routine tumor genotyping is helpful in identifying low-frequency mutations, such as GNAS, that may correlate with a specific morphological phenotype and also reveal multiplicity of concurrent mutations in a significant proportion of CRC that may have significant implications for clinical trial design and personalized therapy.

Deb S, Wong SQ, Li J, et al.
Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations.
Br J Cancer. 2014; 111(12):2351-60 [PubMed] Article available free on PMC after 09/12/2015 Related Publications
BACKGROUND: Male breast cancer (MBC) is still poorly understood with a large proportion arising in families with a history of breast cancer. Genomic studies have focused on germline determinants of MBC risk, with minimal knowledge of somatic changes in these cancers.
METHODS: Using a TruSeq amplicon cancer panel, this study evaluated 48 familial MBCs (3 BRCA1 germline mutant, 17 BRCA2 germline mutant and 28 BRCAX) for hotspot somatic mutations and copy number changes in 48 common cancer genes.
RESULTS: Twelve missense mutations included nine PIK3CA mutations (seven in BRCAX patients), two TP53 mutations (both in BRCA2 patients) and one PTEN mutation. Common gains were seen in GNAS (34.1%) and losses were seen in GNAQ (36.4%), ABL1 (47.7%) and ATM (34.1%). Gains of HRAS (37.5% vs 3%, P=0.006), STK11 (25.0% vs 0%, P=0.01) and SMARCB1 (18.8% vs 0%, P=0.04) and the loss of RB1 (43.8% vs 13%, P=0.03) were specific to BRCA2 tumours.
CONCLUSIONS: This study is the first to perform high-throughput somatic sequencing on familial MBCs. Overall, PIK3CA mutations are most commonly seen, with fewer TP53 and PTEN mutations, similar to the profile seen in luminal A female breast cancers. Differences in mutation profiles and patterns of gene gains/losses are seen between BRCA2 (associated with TP53/PTEN mutations, loss of RB1 and gain of HRAS, STK11 and SMARCB1) and BRCAX (associated with PIK3CA mutations) tumours, suggesting that BRCA2 and BRCAX MBCs may be distinct and arise from different tumour pathways. This has implications on potential therapies, depending on the BRCA status of MBC patients.

Juhlin CC, Goh G, Healy JM, et al.
Whole-exome sequencing characterizes the landscape of somatic mutations and copy number alterations in adrenocortical carcinoma.
J Clin Endocrinol Metab. 2015; 100(3):E493-502 [PubMed] Related Publications
CONTEXT: Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood.
OBJECTIVE: To utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations present in ACC.
DESIGN: Screening for somatic mutation events and copy number alterations (CNAs) was performed by comparative analysis of tumors and matched normal samples from 41 patients with ACC.
RESULTS: In total, 966 nonsynonymous somatic mutations were detected, including 40 tumors with a mean of 16 mutations per sample and one tumor with 314 mutations. Somatic mutations in ACC-associated genes included TP53 (8/41 tumors, 19.5%) and CTNNB1 (4/41, 9.8%). Genes with potential disease-causing mutations included GNAS, NF2, and RB1, and recurrently mutated genes with unknown roles in tumorigenesis comprised CDC27, SCN7A, and SDK1. Recurrent CNAs included amplification at 5p15.33 including TERT (6/41, 14.6%) and homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 (4/41 9.8% and 3/41, 7.3%, respectively). Somatic mutations in ACC-established genes and recurrent ZNRF3 and TERT loci CNAs were mutually exclusive in the majority of cases. Moreover, gene ontology identified Wnt signaling as the most frequently mutated pathway in ACCs.
CONCLUSIONS: These findings highlight the importance of Wnt pathway dysregulation in ACC and corroborate the finding of homozygous deletion of Wnt repressors ZNRF3 and KREMEN1. Overall, mutations in either TP53 or CTNNB1 as well as focal CNAs at the ZNRF3 or TERT loci denote mutually exclusive events, suggesting separate mechanisms underlying the development of these tumors.

Fragoso MC, Alencar GA, Lerario AM, et al.
Genetics of primary macronodular adrenal hyperplasia.
J Endocrinol. 2015; 224(1):R31-43 [PubMed] Related Publications
ACTH-independent macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome (CS), accounting for <2% of all endogenous CS cases; however it is more frequently identified incidentally with sub-clinical cortisol secretion. Recently, cortisol secretion has been shown to be regulated by ectopic corticotropin, which is in turn produced by clusters of steroidogenic cells of the hyperplastic adrenal nodules. Hence, the term 'ACTH-independent' is not entirely appropriate for this disorder. Accordingly, the disease is designated primary macronodular adrenal hyperplasia (PMAH) in this review article. The means by which cortisol production is regulated in PMAH despite the suppressed levels of ACTH of pituitary origin is exceedingly complex. Several molecular events have been proposed to explain the enhanced cortisol secretion, increased cell proliferation, and nodule formation in PMAH. Nonetheless, the precise sequence of events and the molecular mechanisms underlying this condition remain unclear. The purpose of this review is therefore to present new insights on the molecular and genetic profile of PMAH pathophysiology, and to discuss the implications for disease progression.

Reid MD, Choi H, Balci S, et al.
Serous cystic neoplasms of the pancreas: clinicopathologic and molecular characteristics.
Semin Diagn Pathol. 2014; 31(6):475-83 [PubMed] Related Publications
We herein summarize the pathology and most recent advances in the molecular genetics of serous cystic neoplasms of the pancreas. They typically present as relatively large, well-demarcated tumors (mean size, 6cm), predominantly occurring in females. Pre-operative diagnosis remains challenging; imaging findings and cyst fluid analysis often prove non-specific and fine-needle aspiration often does not yield diagnostic cells. Pathologically, they are characterized by a distinctive cytology referred to as "serous." Although they have ductal differentiation, they distinctly lack the mucin production that characterizes most other pancreatic ductal tumors, including ductal adenocarcinoma and its variants, intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). They instead produce abundant glycogen (glycogen-rich adenoma). Serous cystadenomas also lack the molecular alterations that characterize ductal neoplasms, such as mutation of KRAS (high prevalence in most mucinous ductal neoplasms), inactivation of SMAD4 (seen in ductal adenocarcinomas), and mutations in GNAS (seen in some IPMNs) and RNF43 (detected in MCNs and IPMNs). Instead, new molecular and immunohistochemical observations place serous pancreatic tumors closer to "clear cell neoplasms" seen in various other organs that are associated with the von Hippel-Lindau (VHL) pathway, such as clear cell renal cell carcinomas and capillary hemangioblastomas. Patients with VHL syndrome have an increased risk of developing serous pancreatic tumors and somatic mutations of the VHL gene are common in these tumors along with modification of its downstream effectors including hypoxia-inducible factor (HIF1), glucose uptake and transporter-1 (GLUT-1), a common factor in clear cell (glycogen-rich) tumors, as well as expression of vascular endothelial growth factor (VEGF), thought to be a factor in the striking capillarization of serous cystadenomas and other non-pancreatic clear cell tumors. VEGF may prove to be of significant diagnostic value since its elevation in cyst fluid has recently been found highly sensitive and specific for serous neoplasms. These molecular alterations establish serous tumors as prototypes of clear cell tumorigenesis and angiogenesis and may prove helpful both as diagnostic and non-surgical therapeutic targets.

Duan K, Gomez Hernandez K, Mete O
Clinicopathological correlates of adrenal Cushing's syndrome.
J Clin Pathol. 2015; 68(3):175-86 [PubMed] Related Publications
Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal (80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein-coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease.

Xie M, Lu C, Wang J, et al.
Age-related mutations associated with clonal hematopoietic expansion and malignancies.
Nat Med. 2014; 20(12):1472-8 [PubMed] Article available free on PMC after 09/12/2015 Related Publications
Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.

Nomura R, Saito T, Mitomi H, et al.
GNAS mutation as an alternative mechanism of activation of the Wnt/β-catenin signaling pathway in gastric adenocarcinoma of the fundic gland type.
Hum Pathol. 2014; 45(12):2488-96 [PubMed] Related Publications
Gastric adenocarcinoma of the fundic gland type (GAFG) is a rare variant of gastric tumor. We have recently reported the frequent accumulation of β-catenin in GAFGs and showed that approximately half of the cases studied harbored at least 1 mutation in CTNNB1/AXINs/APC, leading to the constitutive activation of the Wnt/β-catenin pathway. However, the mechanisms of Wnt signaling activation in the remaining cases are unknown. Accumulating evidence showed that the activating mutation in GNAS promotes tumorigenesis via the activation of the Wnt/β-catenin pathway or the ERK1/2 MAPK pathway. Therefore, we analyzed the mutations in GNAS (exons 8 and 9) and in KRAS (exon 2) in 26 GAFGs. Immunohistochemistry revealed nuclear β-catenin expression in 22 of 26 GAFGs, and 10 (38.5%) of 26 cases harbored at least 1 mutation in CTNNB1/AXINs/APC. Activating mutations in GNAS were found in 5 (19.2%) of 26 GAFGs, all of which harbored R201C mutations. Activating mutations in KRAS were found in 2 (7.7%) of 26 GAFGs, and both of these also contained GNAS activating mutations. Four of 5 cases with GNAS mutation showed nuclear β-catenin expression, and presence of GNAS mutation was associated with β-catenin nuclear expression (P = .01). Furthermore, 3 of these 4 cases did not harbor mutations in CTNNB1, APC, or AXINs, suggesting that mutations in the Wnt component genes and those in GNAS occur almost exclusively. These results suggest that GNAS mutation might occur in a small subset of GAFG as an alternative mechanism of activating the Wnt/β-catenin signaling pathway.

Klöppel G, Basturk O, Schlitter AM, et al.
Intraductal neoplasms of the pancreas.
Semin Diagn Pathol. 2014; 31(6):452-66 [PubMed] Related Publications
There are three types of pancreatic neoplasms that predominantly have an intraductal growth pattern: the common, usually cystic, intraductal papillary mucinous neoplasms (IPMNs); the rare, usually solid intraductal tubulopapillary neoplasms (ITPNs); and the rare intraductal tubular pyloric gland-type adenoma. In addition to these three tumor types, pancreatic neoplasms with a usually solid growth pattern such as acinar cell carcinomas, neuroendocrine tumors, and undifferentiated carcinomas may present, though very rarely, as predominantly intraductally growing neoplasms. IPMNs can be subclassified into main duct and branch duct tumors; into low- and high-grade dysplasia groups; and into tumors with intestinal, pancreatobiliary, oncocytic, or gastric cellular differentiation. The intestinal-, pancreatobiliary-, and oncocytic-type IPMNs occur predominantly in the main duct of the head of the pancreas and more commonly progress to invasive adenocarcinomas. The gastric-type IPMNs are frequently multifocal, occur predominantly in the branch ducts of the uncinate process, and have a low risk of progressing to invasive carcinoma. The prognosis for patients with an IPMN depends largely on the subtype and the presence and the stage of an invasive carcinoma. ITPNs are nodular tumors, often in the pancreatic head, and composed of densely packed tubular glands. Molecular genetics reveal KRAS, GNAS, and RNF43 as the most frequently mutated genes in IPMNs, while ITPNs show wild-type KRAS. Recent progress in genetic sequencing of pancreatic neoplasms and the identification of specific genetic mutations also holds promise for the future development of novel gene-based diagnostic tests in intraductal neoplasms of the pancreas that might even be used in preoperative conditions.

Nummela P, Saarinen L, Thiel A, et al.
Genomic profile of pseudomyxoma peritonei analyzed using next-generation sequencing and immunohistochemistry.
Int J Cancer. 2015; 136(5):E282-9 [PubMed] Related Publications
Pseudomyxoma peritonei (PMP) is a relatively rare clinical syndrome characterized by neoplastic epithelial cells growing in the peritoneal cavity and secreting mucinous ascites. Our aim was to explore the molecular events behind this fatal but under-investigated disease. We extracted DNA from 19 appendix-derived PMP tumors and nine corresponding normal tissues, and analyzed the mutational hotspot areas of 48 cancer-related genes by amplicon-based next-generation sequencing (NGS). Further, we analyzed the protein expression of V600E mutated BRAF, MLH1, MSH2, MSH6 and p53 from a larger set of PMP tumors (n = 74) using immunohistochemistry. With NGS, we detected activating somatic KRAS mutations in all of the tumors studied. GNAS was mutated in 63% of the tumors with no marked difference between low-grade and high-grade tumors. Only one (5.3%) tumor showed oncogenic PIK3CA mutation, one showed oncogenic AKT1 mutation, three (15.8%) showed SMAD4 mutations and none showed an APC mutation. P53 protein was aberrantly expressed in higher proportion of high-grade tumors as compared with low-grade ones (31.3 vs. 7.1%, respectively; p = 0.012) and aberrant expression was an independent factor for reduced overall survival (p = 0.002). BRAF V600E mutation was only found in one (1.4%) high-grade tumor by immunohistochemistry (n = 74). All the studied tumors expressed mismatch repair proteins MLH1, MSH2 and MSH6. Our results indicate that KRAS mutations are evident in all and GNAS mutations in most of the PMPs, but BRAF V600E, PIK3CA and APC mutations are rare. Aberrantly expressed p53 is associated with high-grade histology and reduced survival.

Larkin SJ, Ferraù F, Karavitaki N, et al.
Sequence analysis of the catalytic subunit of PKA in somatotroph adenomas.
Eur J Endocrinol. 2014; 171(6):705-10 [PubMed] Related Publications
OBJECTIVE: The pathogenetic mechanisms of sporadic somatotroph adenomas are not well understood, but derangements of the cAMP pathway have been implicated. Recent studies have identified L206R mutations in the alpha catalytic subunit of protein kinase A (PRKACA) in cortisol-producing adrenocortical adenomas and amplification of the beta catalytic subunit of protein kinase A PRKACB in acromegaly associated with Carney complex. Given that both adrenocortical adenomas and somatotroph adenomas are known to be reliant on the cAMP signalling pathway, we sought to determine the relevance of the L206R mutation in both PRKACA and PRKACB for the pathogenesis of sporadic somatotroph adenomas.
DESIGN: Somatotroph adenoma specimens, both frozen and formalin-fixed, from patients who underwent surgery for their acromegaly between 1995 and 2012, were used in the study.
METHODS: The DNA sequence at codon 206 of PRKACA and PRKACB was determined by PCR amplification and sequencing. The results were compared with patient characteristics, the mutational status of the GNAS complex locus and the tumour granulation pattern.
RESULTS: No mutations at codon 206 of PRKACA or PRKACB were found in a total of 92 specimens, comprising both WT and mutant GNAS cases, and densely, sparsely and mixed granulation patterns.
CONCLUSIONS: It is unlikely that mutation at this locus is involved in the pathogenesis of sporadic somatotroph adenoma; however, gene amplification or mutations at other loci or in other components of the cAMP signalling pathway, while unlikely, cannot be ruled out.

Khodakarim S, Tabatabaei SM, AlaviMajd H
The multivariate nonparametric methods for identifying gene sets with differential expression.
Gene. 2014; 552(1):18-23 [PubMed] Related Publications
BACKGROUND: Gene Set Analysis (GSA) identifies differential expression gene sets amid the different phenotypes. The results of published papers in this filed are inconsistent and there is no consensus on the best method. In this paper two new methods, in comparison to the previous ones, are introduced for GSA.
METHODS: The MMGSA and MRGSA methods based on multivariate nonparametric techniques were presented. The implementation of five GSA methods (Hotelling's T(2), Globaltest, Abs_Cat, Med_Cat and Rs_Cat) and the novel methods to detect differential gene expression between phenotypes were compared using simulated and real microarray data sets.
RESULTS: In a real dataset, the results showed that the powers of MMGSA and MRGSA were as well as Globaltest and Tsai. The MRGSA method has not a good performance in the simulation dataset.
CONCLUSIONS: The Globaltest method is the best method in the real or simulation datasets. The performance of MMGSA in simulation dataset is good in small-size gene sets. The GLS methods are not good in the simulated data, except the Med_Cat method in large-size gene sets.

He X, Zhang L, Chen Y, et al.
The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.
Nat Med. 2014; 20(9):1035-42 [PubMed] Article available free on PMC after 09/12/2015 Related Publications
Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a Gαs effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.

Gao C, Peng FH, Peng LK
MiR-200c sensitizes clear-cell renal cell carcinoma cells to sorafenib and imatinib by targeting heme oxygenase-1.
Neoplasma. 2014; 61(6):680-9 [PubMed] Related Publications
Clear-cell renal cell carcinoma is a highly treatment-resistant tumor type. Heme oxygenase-1 plays an anti-apoptotic role in cancer chemotherapeutic inducing tumor-progression. The miR-200 family was involved in the process of mesenchymal-epithelial transition (MET) during renal development. In the present study, we demonstrated the regulatory relationship between miR-200c and HO-1. We provided evidences to elucidate that miR-200c could sensitize ccRCC cells to sorafenib or imatinib to inhibit cell proliferation, at least partly by targeting HO-1. Moreover, the correlation between miR-200c and HO-1 expression level and drug resistance in ccRCC was also determined. Combined application with chemotherapeutic drugs, miR-200c, a HO-1 inhibitor, may enhance the efficiency of therapy by promoting both apoptosis and autophagy.

Wiland HO, Shadrach B, Allende D, et al.
Morphologic and molecular characterization of traditional serrated adenomas of the distal colon and rectum.
Am J Surg Pathol. 2014; 38(9):1290-7 [PubMed] Related Publications
Of the serrated polyps, the origin, morphologic features, molecular alterations, and natural history of traditional serrated adenomas (TSAs) are the least understood. Recent studies suggest that these polyps may arise from precursor lesions. The frequencies of KRAS and BRAF mutations vary between these studies, and only 1 small study has measured CpG island methylation using current markers of methylation. Mutations in GNAS, a gene commonly mutated in colorectal villous adenomas, have not been fully evaluated in TSAs. Finally, the expression of annexin A10 (ANXA10), a recently discovered marker of sessile serrated adenomas/polyps, has not been studied in these polyps. To further characterize these polyps, 5 gastrointestinal pathologists reviewed 55 left-sided polyps diagnosed as TSA at a single institution. Pathologists assessed various histologic features including cytoplasmic eosinophilia, ectopic crypt foci, presence of conventional dysplasia, and presence of precursor serrated lesions. KRAS, BRAF, and GNAS mutational analysis was performed, as well as CpG island methylation and ANXA10 immunohistochemistry. Ectopic crypt foci were seen in 62% of TSAs. Precursor lesions were seen in 24% of the study polyps, most of which were hyperplastic polyps. KRAS and BRAF mutations were common and were present in 42% and 48% of polyps, respectively. GNAS mutations occurred in 8% of polyps, often in conjunction with a BRAF mutation. Unlike sessile serrated adenomas/polyps, TSAs rarely had diffuse expression of ANXA10. Importantly, BRAF-mutated TSAs had more widespread methylation of a 5-marker CpG island panel compared with KRAS-mutated polyps. However, ectopic crypt foci, a proposed defining feature of TSA, were not associated with any specific molecular alteration.

Lee M, Song JS, Chun SM, et al.
Protuberant fibro-osseous lesions of the temporal bone: two additional case reports.
Am J Surg Pathol. 2014; 38(11):1510-5 [PubMed] Related Publications
The most commonly encountered fibro-osseous lesions of the skull bone are fibrous dysplasia and ossifying fibroma. Two cases of a unique "protuberant fibro-osseous lesion of the temporal bone" were first described by Selesnick and colleagues in 1999, and 2 further cases were reported in 2010 under the name "Bullough lesion". We recently found 2 new cases of this rare entity. Two Korean female patients aged 70 and 54 years presented with slow growing postauricular masses without pain or tenderness for 6 and 7 years, respectively. Computed tomography revealed a 2.9 cm calcified mass in the temporal bone of the first patient, and a 5.5 cm enhancing mass with internal cartilaginous matrix in the temporal bone of the second patient. Intramedullary or intracranial extension was not found in either case, and en bloc removals were performed. Microscopically, multiple round to oval osseous islands were scattered throughout the bland fibrous stroma in both cases. The osseous islands varied in size and were lamellar or woven, without osteoblastic rimming, and surrounded by fibroblastic bands. Neither patient has shown evidence of postoperative recurrence for 18 months. The location, histology, and clinical course of these 2 cases were identical to the 4 cases previously reported, although age and sex varied. The lesions were tested for the R201H mutation in the GNAS gene, which is present in fibrous dysplasia. No mutations were found, suggesting a different genetic background for these lesions.

Anastasaki C, Gutmann DH
Neuronal NF1/RAS regulation of cyclic AMP requires atypical PKC activation.
Hum Mol Genet. 2014; 23(25):6712-21 [PubMed] Article available free on PMC after 20/12/2015 Related Publications
Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder in which affected individuals are prone to learning, attention and behavioral problems. Previous studies in mice and flies have yielded conflicting results regarding the specific effector pathways responsible for NF1 protein (neurofibromin) regulation of neuronal function, with both cyclic AMP (cAMP)- and RAS-dependent mechanisms described. Herein, we leverage a combination of induced pluripotent stem cell-derived NF1 patient neural progenitor cells and Nf1 genetically engineered mice to establish, for the first time, that neurofibromin regulation of cAMP requires RAS activation in human and mouse neurons. However, instead of involving RAS-mediated MEK/AKT signaling, RAS regulation of cAMP homeostasis operates through the activation of atypical protein kinase C zeta, leading to GRK2-driven Gαs inactivation. These findings reveal a novel mechanism by which RAS can regulate cAMP levels in the mammalian brain.

Towle R, Tsui IF, Zhu Y, et al.
Recurring DNA copy number gain at chromosome 9p13 plays a role in the activation of multiple candidate oncogenes in progressing oral premalignant lesions.
Cancer Med. 2014; 3(5):1170-84 [PubMed] Article available free on PMC after 20/12/2015 Related Publications
Genomic alteration at chromosome 9p has been previously reported as a frequent and critical event in oral premalignancy. While this alteration is typically reported as a loss driven by selection for CDKN2A deactivation (at 9p21.3), we detect a recurrent DNA copy number gain of ~2.49 Mbp at chromosome 9p13 in oral premalignant lesions (OPLs) that later progressed to invasive lesions. This recurrent alteration event has been validated using fluorescence in situ hybridization in an independent set of OPLs. Analysis of publicly available gene expression datasets aided in identifying three oncogene candidates that may have driven selection for DNA copy number increases in this region (VCP, DCTN3, and STOML2). We performed in vitro silencing and activation experiments for each of these genes in oral cancer cell lines and found that each gene is independently capable of upregulating proliferation and anchorage-independent growth. We next analyzed the activity of each of these genes in biopsies of varying histological grades that were obtained from a diseased oral tissue field in a single patient, finding further molecular evidence of parallel activation of VCP, DCTN3, and STOML2 during progression from normal healthy tissue to invasive oral carcinoma. Our results support the conclusion that DNA gain at 9p13 is important to the earliest stages of oral tumorigenesis and that this alteration event likely contributes to the activation of multiple oncogene candidates capable of governing oral cancer phenotypes.

Mitsui T, Kim OH, Hall CM, et al.
Acroscyphodysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2.
Am J Med Genet A. 2014; 164A(10):2529-34 [PubMed] Related Publications
Acroscyphodysplasia (OMIM250215) is a distinctive form of metaphyseal dysplasia characterized by the distal femoral and proximal tibial epiphyses embedded in cup-shaped, large metaphyses known as metaphyseal scypho ("scypho" = cup) deformity. It is also associated with severe growth retardation and brachydactyly. The underlying molecular mechanism of acroscyphodysplasia has not yet been elucidated, although scypho-deformity of the knee has been reported in three patients with acrodysostosis due to a mutation in the PDE4D gene. We report on the clinical, radiological, and molecular findings of five female patients with acroscyphodysplasia; two were diagnosed as pseudohypoparathyroidism (PHP) or Albright hereditary osteodystropy, and the other three as acrodysostosis. They all had radiological findings consistent with severe metaphyseal scypho-deformity and brachydactyly. Heterozygous mutations were identified in the PHP patients consisting of one novel (p.Q19X) and one recurrent (p.R231C) mutation of the GNAS gene, as well as, in the acrodysostosis patients consisting of two novel mutations (p.T224I and p.I333T) of the PDE4D gene. We conclude that metaphyseal acroscyphodysplasia is a phenotypic variation of PHP or acrodysostosis caused by either a GNAS or PDE4D mutation, respectively.

Koster R, Mitra N, D'Andrea K, et al.
Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors.
Hum Mol Genet. 2014; 23(22):6061-8 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We analyzed a custom-built sex determination gene set consisting of 32 genes using three different methods of pathway-based analysis. The sex determination gene set ranked highly compared with canonical gene sets, and it was associated with TGCT (FDRG = 2.28 × 10(-5), FDRM = 0.014 and FDRI = 0.008 for Gene Set Analysis-SNP (GSA-SNP), Meta-Analysis Gene Set Enrichment of Variant Associations (MAGENTA) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) analysis, respectively). The association remained after removal of DMRT1 from the gene set (FDRG = 0.0002, FDRM = 0.055 and FDRI = 0.009). Using data from the NCI GWA scan (582 TGCT cases and 1056 controls) and UK scan (986 TGCT cases and 4946 controls), we replicated these findings (NCI: FDRG = 0.006, FDRM = 0.014, FDRI = 0.033, and UK: FDRG = 1.04 × 10(-6), FDRM = 0.016, FDRI = 0.025). After removal of DMRT1 from the gene set, the sex determination gene set remains associated with TGCT in the NCI (FDRG = 0.039, FDRM = 0.050 and FDRI = 0.055) and UK scans (FDRG = 3.00 × 10(-5), FDRM = 0.056 and FDRI = 0.044). With the exception of DMRT1, genes in the sex determination gene set have not previously been identified as TGCT susceptibility loci in these GWA scans, demonstrating the complementary nature of a pathway-based approach for genome-wide analysis of TGCT.

Mishra P, Törönen P, Leino Y, Holm L
Gene set analysis: limitations in popular existing methods and proposed improvements.
Bioinformatics. 2014; 30(19):2747-56 [PubMed] Related Publications
MOTIVATION: Gene set analysis is the analysis of a set of genes that collectively contribute to a biological process. Most popular gene set analysis methods are based on empirical P-value that requires large number of permutations. Despite numerous gene set analysis methods developed in the past decade, the most popular methods still suffer from serious limitations.
RESULTS: We present a gene set analysis method (mGSZ) based on Gene Set Z-scoring function (GSZ) and asymptotic P-values. Asymptotic P-value calculation requires fewer permutations, and thus speeds up the gene set analysis process. We compare the GSZ-scoring function with seven popular gene set scoring functions and show that GSZ stands out as the best scoring function. In addition, we show improved performance of the GSA method when the max-mean statistics is replaced by the GSZ scoring function. We demonstrate the importance of both gene and sample permutations by showing the consequences in the absence of one or the other. A comparison of asymptotic and empirical methods of P-value estimation demonstrates a clear advantage of asymptotic P-value over empirical P-value. We show that mGSZ outperforms the state-of-the-art methods based on two different evaluations. We compared mGSZ results with permutation and rotation tests and show that rotation does not improve our asymptotic P-values. We also propose well-known asymptotic distribution models for three of the compared methods.
AVAILABILITY AND IMPLEMENTATION: mGSZ is available as R package from cran.r-project.org.

Takano S, Fukasawa M, Maekawa S, et al.
Deep sequencing of cancer-related genes revealed GNAS mutations to be associated with intraductal papillary mucinous neoplasms and its main pancreatic duct dilation.
PLoS One. 2014; 9(6):e98718 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
BACKGROUND: To clarify the genetic mutations associated with intraductal papillary mucinous neoplasms (IPMN) and IPMN-related pancreatic tumours, we conducted cancer-related gene profiling analyses using pure pancreatic juice and resected pancreatic tissues.
METHODS: Pure pancreatic juice was collected from 152 patients [nine with a normal pancreas, 22 with chronic pancreatitis (CP), 39 with pancreatic ductal adenocarcinoma (PDAC), and 82 with IPMN], and resected tissues from the pancreas were collected from 48 patients (six IPMNs and 42 PDACs). The extracted DNA was amplified by multiplexed polymerase chain reaction (PCR) targeting 46 cancer-related genes containing 739 mutational hotspots. The mutations were analysed using a semiconductor-based DNA sequencer.
RESULTS: Among the 46 cancer-related genes, KRAS and GNAS mutations were most frequently detected in both PDAC and IPMN cases. In pure pancreatic juice, GNAS mutations were detected in 7.7% of PDAC cases and 41.5% of IPMN cases (p<0.001 vs. others). All PDAC cases with GNAS mutations (n = 3) were accompanied by IPMN. Multivariate analysis revealed that GNAS mutations in IPMN cases were associated with dilated main pancreatic ducts (MPD, p = 0.016), while no statistically independent associations with clinical variables were observed for KRAS mutations. In the resected pancreatic tissues, GNAS mutations were detected in 50% of PDAC cases concomitant with IPMN, 33.3% of PDAC cases derived from IPMN, and 66.7% of IPMN cases, while no GNAS mutations were detected in cases of PDAC without IPMN.
CONCLUSIONS: The GNAS mutation was specifically found in the cases with IPMN and it was speculated that some PDACs might be influenced by the concomitant but separately-located IPMN in their pathogenic mechanism. Furthermore, the GNAS mutation was significantly associated with MPD dilatation in IPMN cases, suggesting its role in mucus hypersecretion.

Varghese AM, Zakowski MF, Yu HA, et al.
Small-cell lung cancers in patients who never smoked cigarettes.
J Thorac Oncol. 2014; 9(6):892-6 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
INTRODUCTION: We describe clinical, pathologic, and molecular characteristics of never-smoker patients with small-cell lung cancers (SCLCs).
METHODS: We identified cases of SCLCs evaluated at our institution from 2005 to 2012. We collected smoking history, demographic, treatment, and survival data. EGFR, KRAS, PIK3CA, ALK testing, RB protein expression, and next generation sequencing were performed on available samples.
RESULTS: Two percent (23 of 1040) of patients with SCLCs were never-smokers. Eighty-three percent (19 of 23) had de novo SCLCs, whereas 17% had SCLC transformation as acquired resistance to erlotinib after treatment for EGFR-mutant lung carcinomas. Median survival from SCLC diagnosis was 23 months. Of de novo SCLCs, ALK rearrangement, KRAS mutations, EGFR mutations, and RB loss were identified in zero of five, zero of eight, two of eight, and six of seven, respectively. Two de novo samples underwent next generation sequencing. One had mutations in p53 and RB1 with amplification in TERT, and a second had mutations in CBL and GNAS with amplification in MYCL1.
CONCLUSIONS: Two percent of patients with SCLCs are never-smokers. Although transformation to SCLC can rarely occur in acquired resistance to erlotinib, 83% of never-smokers with SCLCs had de novo SCLC. RB loss was noted in 86% of cases. Multiplexed genotyping can be performed on tissues to identify potentially actionable oncogenic drivers.

Liu X, Mody K, de Abreu FB, et al.
Molecular profiling of appendiceal epithelial tumors using massively parallel sequencing to identify somatic mutations.
Clin Chem. 2014; 60(7):1004-11 [PubMed] Related Publications
BACKGROUND: Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2.
METHODS: Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer.
RESULTS: A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes.
CONCLUSIONS: Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts have identified mutational spectra in several subtypes of these tumors that may suggest a phenotypic heterogeneity showing mutations that are relevant for targeted therapies.

Bagchi D, Swaroop A, Preuss HG, Bagchi M
Free radical scavenging, antioxidant and cancer chemoprevention by grape seed proanthocyanidin: an overview.
Mutat Res. 2014; 768:69-73 [PubMed] Related Publications
A large number of investigations have demonstrated a broad spectrum of pharmacological and therapeutic benefits of grape seed proanthocyanidins (GSP) against oxidative stress and degenerative diseases including cardiovascular dysfunctions, acute and chronic stress, gastrointestinal distress, neurological disorders, pancreatitis, various stages of neoplastic processes and carcinogenesis including detoxification of carcinogenic metabolites. GSP exhibited potent free radical scavenging abilities in both in vitro and in vivo models. GSP exerted significant in vivo protection against structurally diverse drug and chemical-induced hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity and spleentoxicity. GSP also protected against idarubicin and 4-hydroxyperoxy-cyclophosphamide-induced cytotoxicity toward human normal liver cells. GSP exhibited selective cytotoxicity toward selected human cancer cells, while enhancing the growth and viability of normal cells. GSP exhibited potent modulatory effects of pro-apoptotic and apoptotic regulatory bcl-XL, p53, c-myc, c-JUN, JNK-1 and CD36 genes. Long-term exposure to GSP may serve as a novel chemoprotectant against three stages of DMN-induced liver carcinogenesis and tumorigenesis including initiation, promotion and progression. GSP may selectively protect against oxidative stress, genomic integrity and cell death patterns in vivo. These results demonstrate that GSP may serve as a novel therapeutic intervention against carcinogenesis.

Goh G, Scholl UI, Healy JM, et al.
Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.
Nat Genet. 2014; 46(6):613-7 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Adrenal tumors autonomously producing cortisol cause Cushing's syndrome. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Eight tumors (including three carcinomas) had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Six of these had known gain-of-function mutations in CTNNB1 (β-catenin) or GNAS (Gαs). Six others had somatic mutations in PRKACA (protein kinase A (PKA) catalytic subunit) resulting in a p.Leu206Arg substitution. Further sequencing identified this mutation in 13 of 63 tumors (35% of adenomas with overt Cushing's syndrome). PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Leu206 directly interacts with the regulatory subunit of PKA, PRKAR1A. Leu206Arg PRKACA loses PRKAR1A binding, increasing the phosphorylation of downstream targets. PKA activity induces cortisol production and cell proliferation, providing a mechanism for tumor development. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors.

Wang L, Jin G, He C, et al.
Gαs protein expression is an independent predictor of recurrence in prostate cancer.
J Immunol Res. 2014; 2014:301376 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
BACKGROUND: T393C polymorphism in the gene GNAS1, which encodes the G-protein alpha s subunit (Gαs) of heterotrimeric G protein, is significantly associated with the clinical outcome of patients suffering from several cancers. However, studies on the role and protein expression of Gαs subunit in prostate cancer were still unavailable.
METHODS: The immunohistochemical staining was used to assess Gαs expression through tissue microarray procedure of 56 metastatic PCas, 291 localized PCas, and 67 benign hyperplasia (BPH). Gαs expression was semiquantitatively scored and evaluated the correlation with pathologic parameters and biochemical recurrence of prostate-specific antigen (PSA).
RESULTS: Gαs expression was localized in nuclear and cytoplasm in prostate cancer cells and downregulated in metastatic PCa compared to localized PCa and BPH (P < 0.001). Gαs was inversely associated with PSA level and Gleason scores; patients with low expression of Gαs had adverse clincopathological features. In multivariable Cox regression analysis, high Gαs expression and Gleason scores were independent predictors of both PSA progression-free and overall survival.
CONCLUSIONS: Gαs down-expression is associated with adverse pathologic features and clinical PSA biochemical recurrence of prostate cancer. Gαs is an independent predictor to help determine the risk of PSA progression and death.

Abdul-Jalil KI, Sheehan KM, Toomey S, et al.
The frequencies and clinical implications of mutations in 33 kinase-related genes in locally advanced rectal cancer: a pilot study.
Ann Surg Oncol. 2014; 21(8):2642-9 [PubMed] Related Publications
BACKGROUND: Locally advanced rectal cancer (LARC: T3/4 and/or node-positive) is treated with preoperative/neoadjuvant chemoradiotherapy (CRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and related pathways are implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic mutations in these pathways and LARC clinical outcomes.
METHODS: We genotyped 234 potentially clinically relevant nonsynonymous mutations in 33 PI3K and MAPK pathway-related genes, including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET, and NRAS, using the Sequenom platform. DNA samples were extracted from pretreatment LARC biopsy samples taken from 201 patients who were then treated with long-course neoadjuvant CRT followed by surgical resection.
RESULTS: Sixty-two mutations were detected in 15 genes, with the highest frequencies occurring in KRAS (47 %), PIK3CA (14 %), STK11 (6.5 %), and CTNNB1 (6 %). Mutations were detected in BRAF, NRAS, AKT1, PIK3R1, EGFR, GNAS, MEK1, PDGFRA, ALK, and TNK2, but at frequencies of <5 %. As expected, a pathologic complete response (pCR) was associated with improved 5-year recurrence-free survival (RFS; hazard ratio, 0.074; 95 % CI 0.01-0.54; p = 0.001). Mutations in PI3K pathway-related genes (odds ratio, 5.146; 95 % CI 1.17-22.58; p = 0.030), but not MAPK pathway-related genes (p = 0.911), were associated with absence of pCR after neoadjuvant CRT. In contrast, in patients who did not achieve pCR, mutations in PI3K pathway-related genes were not associated with recurrence-free survival (p = 0.987). However, in these patients, codon 12 (G12D/G12 V/G12S) and 13 mutations in KRAS were associated with poor recurrence-free survival (hazard ratio, 1.579; 95 % confidence ratio, 1.00-2.48; p = 0.048).
CONCLUSIONS: Mutations in kinase signaling pathways modulate treatment responsiveness and clinical outcomes in LARC and may constitute rational targets for novel therapies.

Layfield LJ, Ehya H, Filie AC, et al.
Utilization of ancillary studies in the cytologic diagnosis of biliary and pancreatic lesions: the Papanicolaou Society of Cytopathology guidelines for pancreatobiliary cytology.
Diagn Cytopathol. 2014; 42(4):351-62 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound-guided fine-needle aspiration, terminology and nomenclature of pancreatobiliary disease, ancillary testing, and post-biopsy management. All documents are based on the expertise of the authors, a review of the literature, discussions of the draft document at several national and international meetings, and synthesis of selected online comments of the draft document. This document presents the results of these discussions regarding the use of ancillary testing in the cytologic diagnosis of biliary and pancreatic lesions. Currently, fluorescence in situ hybridization (FISH) appears to be the most clinically relevant ancillary technique for cytology of bile duct strictures. The addition of FISH analysis to routine cytologic evaluation appears to yield the highest sensitivity without loss in specificity. Loss of immunohistochemical staining for the protein product of the SMAD4 gene and positive staining for mesothelin support a diagnosis of ductal adenocarcinoma. Immunohistochemical markers for endocrine and exocrine differentiation are sufficient for a diagnosis of endocrine and acinar tumors. Nuclear staining for beta-catenin supports a diagnosis of solid-pseudopapilary neoplasm. Cyst fluid analysis for amylase and carcinoembryonic antigen aids in the preoperative classification of pancreatic cysts. Many gene mutations (KRAS, GNAS, VHL, RNF43, and CTNNB1) may be of aid in the diagnosis of cystic neoplasms. Other ancillary techniques do not appear to improve diagnostic sensitivity sufficiently to justify their increased costs.

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