PIK3CA Mutations are Common in Many Tumor Types and are Often Associated With Other Driver Mutations

2016 ◽  
Vol 24 (5) ◽  
pp. 313-319 ◽  
Author(s):  
Matthew D. Stachler ◽  
Elizabeth M. Rinehart ◽  
Elizabeth Garcia ◽  
Neal I. Lindeman
Keyword(s):  
Driver Mutations ◽  
Pik3ca Mutations ◽  
Tumor Types

Multigene Combined Detection by RT-qPCR Using Cytological Specimens

2021 ◽  
pp. 1-10
Author(s):  
Yang Ma ◽  
Jingxia Zhao ◽  
Yun Du ◽  
Rui Wang ◽  
Xiaokun Ji ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Smoking Status ◽  
Single Gene ◽  
Rna Extraction ◽  
Pcr Amplification ◽  
Driver Mutations ◽  
Amplification Refractory Mutation System ◽  
Driver Genes ◽  
Mutation Status ◽  
Pik3ca Mutations

<b><i>Objective:</i></b> The aim of the study was to investigate the mutation status of multiple driver genes by RT-qPCR and their significance in advanced lung adenocarcinoma using cytological specimens. <b><i>Materials and Methods:</i></b> 155 cytological specimens that had been diagnosed with lung adenocarcinoma in the Fourth Hospital of Hebei Medical University were selected from April to November 2019. The cytological specimens included serous cavity effusion and fine-needle aspiration biopsies. Among cytological specimens, 108 cases were processed by using the cell block method (CBM), and 47 cases were processed by the disposable membrane cell collector method (MCM) before DNA/RNA extraction. Ten drive genes of EGFR, ALK, ROS1, BRAF, KRAS, NRAS, HER2, RET, PIK3CA, and MET were combined detected at one step by the amplification refractory mutation system and ABI 7500 RT-qPCR. <b><i>Results:</i></b> The purity of RNA (<i>p</i> = 0.005) and DNA (<i>p</i> = 0.001) extracted by using the MCM was both significantly higher than that extracted by using the CBM. Forty-seven cases of fresh cell specimens processed by the MCM all succeeded in multigene detections, while of 108 specimens processed by the CBM, 6 cases failed in multigene detections. Among 149 specimens, single-gene mutation rates of EGFR, ALK, ROS1, RET, HER2, MET, KRAS, NRAS, BRAF, and PIK3CA mutations were 57.71%, 6.04%, 3.36%, 2.68%, 2.01%, 2.01%, 1.34%, 0.67%, 0% and 0% respectively, and 6 cases including 2 coexistence mutations. We found that mutation status was correlated with gender (<i>p</i> = 0.047), but not correlated with age (<i>p</i> = 0.141) and smoking status (<i>p</i> = 0.083). We found that the EGFR mutation status was correlated with gender (<i>p</i> = 0.003), age (<i>p</i> = 0.015) and smoking habits (<i>p</i> = 0.007), and ALK mutation status was correlated with age (<i>p</i> = 0.002). <b><i>Conclusion:</i></b> Compared with the CBM, the MCM can improve the efficiency of DNA/RNA extraction and PCR amplification by removing impurities and enriching tumor cells. And we speculate that the successful detection rate of fresh cytological specimens was higher than that of paraffin-embedded specimens. EGFR, ALK, and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma. We speculate that EGFR and ALK are more prone to concomitant mutations, respectively. Targeted therapies for patients with coexisting mutations need further study.

scholarly journals Lung Adenocarcinoma From East Asian Never-Smokers Is a Disease Largely Defined by Targetable Oncogenic Mutant Kinases

2010 ◽  
Vol 28 (30) ◽  
pp. 4616-4620 ◽  
Author(s):  
Yihua Sun ◽  
Yan Ren ◽  
Zhaoyuan Fang ◽  
Chenguang Li ◽  
Rong Fang ◽  
...  
Keyword(s):  
East Asian ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Single Institution ◽  
Pik3ca Mutations ◽  
Oncogenic Mutations ◽  
Oncogenic Driver ◽  
Never Smokers ◽  
Lung Adenocarcinomas ◽  
Concurrent Analysis

Purpose To determine the proportion of lung adenocarcinomas from East Asian never-smokers who harbor known oncogenic driver mutations. Patients and Methods In this surgical series, 52 resected lung adenocarcinomas from never-smokers (< 100 cigarettes in a lifetime) at a single institution (Fudan University, Shanghai, China) were analyzed concurrently for mutations in EGFR, KRAS, NRAS, HRAS, HER2, BRAF, ALK, PIK3CA, TP53 and LKB1. Results Forty-one tumors harbored EGFR mutations, three harbored EML4-ALK fusions, two harbored HER2 insertions, and one harbored a KRAS mutation. All mutations were mutually exclusive. Thus, 90% (47 of 52; 95% CI, 0.7896 to 0.9625) of lung adenocarcinomas from never-smokers were found to harbor well-known oncogenic mutations in just four genes. No BRAF, NRAS, HRAS, or LKB1 mutations were detected, while 15 had TP53 mutations. Four tumors contained PIK3CA mutations, always together with EGFR mutations. Conclusion To our knowledge, this study represents the first comprehensive and concurrent analysis of major recurrent oncogenic mutations found in a large cohort of lung adenocarcinomas from East Asian never-smokers. Since drugs are now available that target mutant EGFR, HER2, and ALK, respectively, this result indicates that prospective mutation testing in these patients should successfully assign a targeted therapy in the majority of cases.

scholarly journals Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors

Science ◽  
2019 ◽  
Vol 366 (6466) ◽  
pp. 714-723 ◽  
Author(s):  
Neil Vasan ◽  
Pedram Razavi ◽  
Jared L. Johnson ◽  
Hong Shao ◽  
Hardik Shah ◽  
...  
Keyword(s):  
Membrane Lipid ◽  
Lipid Binding ◽  
Breast Cancers ◽  
Pik3ca Mutations ◽  
Downstream Signaling ◽  
Activating Mutations ◽  
Increased Sensitivity ◽  
Phosphoinositide 3 Kinase ◽  
Tumor Types ◽  
In Cis

Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.

scholarly journals Pathway and network analysis of more than 2,500 whole cancer genomes

2018 ◽  
Author(s):  
Matthew A. Reyna ◽  
David Haan ◽  
Marta Paczkowska ◽  
Lieven P.C. Verbeke ◽  
Miguel Vazquez ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Driver Mutations ◽  
Cancer Genes ◽  
Protein Coding ◽  
Cancer Driver ◽  
Network Analyses ◽  
Protein Coding Genes ◽  
Cancer Genomes ◽  
Tumor Types ◽  
Promoter Mutations

AbstractThe catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notablyTERTpromoter mutations, have been reported. Motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes, we performed multi-faceted pathway and network analyses of non-coding mutations across 2,583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project. While few non-coding genomic elements were recurrently mutated in this cohort, we identified 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression inTP53, TLE4, andTCF4. We found that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing was primarily targeted by non-coding mutations in this cohort, with samples containing non-coding mutations exhibiting similar gene expression signatures as coding mutations in well-known RNA splicing factors. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.

Association of PIK3CA mutations and age with the occurence of second primary lung cancer (SPLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1589-1589
Author(s):  
Marc Christiaan Allardt Bos ◽  
Masyar Gardizi ◽  
Matthias Scheffler ◽  
Lucia Nogova ◽  
Thomas Zander ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Logistic Regression ◽  
Regression Analysis ◽  
Logistic Regression Analysis ◽  
Clinical Characteristics ◽  
Pik3ca Mutation ◽  
Primary Lung Cancer ◽  
Driver Mutations ◽  
Second Primary ◽  
Pik3ca Mutations

1589 Background: The incidence of SPLC in Germany was reported to be 1.2 per 100,000 inhabitants in 2007 and the prevalence of second primary cancers reported by the US International Cancer Institute's Surveillance, Epidemiology and End Results Program has more than doubled over the last 25 years. Recently there has been tremendous progress in the ability to detect driver mutations in lung cancer and large studies presented the frequencies of driver mutations in unselected patient populations. We conducted an association study of known genetic driver events and clinical characteristics with the occurence of SPLC. Methods: Within the Network Genomic Medicine Lung Cancer, a local molecular screening network encompassing hospitals and office-based oncologists in the catchment area of the Center for Integrated Oncology Köln Bonn, we retrospectively reviewed the medical records of 375 molecularly annotated NSCLC patients for their SPLC status and clinical characteristics (age at diagnosis, histology, sex, smoking status). Molecular analysis for lung adenocarcinoma included the EGFR, ALK, BRAF, KRAS and PIK3CA status and for squamous cell lung cancer the FGFR1 and PIK3CA status. Results: 84 of 375 (22,4%) patients were SPLCs. The median age of SPLC diagnosis was 70 yrs. (Range 53 - 85 yrs.) and differed significantly from the rest of the population with a median age of 65 yrs. (Range 28 - 86 yrs.). The frequency of SPLCs was not significantly different between males and females (p = 0,259). In univariate logistic regression analysis active and former smoking, positive PIK3CA mutation and FGFR1 amplification status as well as age were significantly associated with the occurrence of SPLC. In a multivariate logistic regression analysis including the variables mentioned above only PIK3CA mutations (OR 9,48 95% CI 1,83 - 49,1) (p = 0,007) and age (OR 1,06 95% CI 1,03 - 1,1) (p = 0,015) could be confirmed to be independent prognosticators for the occurrence of SPLCs. Conclusions: The occurrence of SPLC was associated with age and PIK3CA mutations in our study population. Further comprehensive investigations on this topic are needed to confirm our findings and to further understand the association between mutation status and SPLCs.

Genomic architecture of gallbladder cancer: Results of a first prospective study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16628-e16628
Author(s):  
Amol Patel ◽  
H P Singh ◽  
Suresh Pandalanghat ◽  
Manish Kumar ◽  
Bhupesh Guleria ◽  
...  
Keyword(s):  
Prospective Study ◽  
Gallbladder Cancer ◽  
Resistance Mechanisms ◽  
Driver Mutations ◽  
Genomic Profiling ◽  
Female Ratio ◽  
Pik3ca Mutations ◽  
Phase 2 Trial ◽  
Comprehensive Genomic Profiling

e16628 Background: Rarity in western countries precluded Gallbladder cancer (GBC) from prospective research. Comprehensive Genomic profiling carries potential to determine oncogenic pathways, driver mutations and possible resistance mechanisms. This study is evaluating the role of comprehensive genomic profiling and role of targeted therapies therein. Methods: This is a single center, prospective, study conducted from Aug2018-Dec2019. All consecutive patients of unresectable and/or metastatic GBC of age ≥18 years were enrolled. Hybrid capture based comprehensive genomic profiling was performed by Foundation Medicine CDx. Microsatellite instability and PDL1 expression were studied. Results: Median age was 56 years (range:26-83) with male to female ratio of 1:1.6. NGS information was available for 50 patients. ERBB pathway was aberrated in 44% of patients. ERBB2 & ERBB3 amplification was seen in 9(18%) and 2(4%) patients respectively. ERBB2 mutations were present concurrently with amplification in 3 patients. MET amplification was present in 3 (6%) PIK3CA mutations were seen in 14% of cases. PIK3CA mutations were independent of ERBB aberrations. FGFR2 mutation, FGFR2 and FGFR3 amplification was present in one patient each. NF1 and NF2 mutations were seen in three and two patients respectively. Median TMB (n = 39) was 5 mut/Mb with range of 1-14 mut/Mb. PDL1 (n = 31) of ≥ 1% was present in 32% of cases and it ranged from 1-100%. MSI (n = 39) was stable in all cases. Other somatic mutations and/or amplifications are shown in Table. Conclusions: GBC is enriched in 28% of patients with ERBB2 & ERBB3 amplifications and/or mutations. FGFR2 mutation is rare in GBC. PIK3CA aberrations are common. Phase 2 trial of frontline Trastuzumab combined with chemotherapy is ongoing. [Table: see text]

Oncogenic FGFR3 gene fusions in solid tumors among Chinese cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15072-e15072
Author(s):  
Libin Xu ◽  
Ming Liu ◽  
Jingxian Duan ◽  
Tao Wang
Keyword(s):  
Cancer Patients ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Coiled Coil ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Driver Mutations ◽  
Gene Fusions ◽  
Fgfr3 Gene ◽  
Tumor Types

e15072 Background: Oncogenic FGFR3 (fibroblast growth factor receptor 3) gene fusions have been identified as driver mutations that lead to the activation of FGFR3 in many solid tumor types and serve as a novel therapeutic target for FGFR inhibitors in clinical development. TACC3 (transforming acid coiled coil 3) is the most common partner of these FGFR3 fusions. Methods: The study enrolled over ten thousand cases of Chinese patients with different types of solid tumors. We performed targeted sequencing assay with our 605 gene panel that covered all the exon and intron regions of the FGFR3 gene, so that we could identify nearly all the FGFR3 translocation events. Results: The prevalence and form of FGFR3 fusions in different tumor types were shown in Table. We identified seven patients harboring FGFR3 fusion events, with six cases of FGFR3-TACC3 and one case of FGFR3-UBE2K. In the seven patients, three of them were also harbored concomitant TP53 gene mutations, and six of them were microsatellite stability (MSS), and one was microsatellite instability-low (MSI-L). Conclusions: FGFR3 gene rearrangements were identified in different solid tumor types in our study, and they were relatively rare compared to other novel mutations. However, clinical testing for the identification of FGFR3 fusions should be prioritized in bladder cancer patients. Consistent with other studies, the most common FGFR3 fusion form was FGFR3-TACC3. Co-occurring genetic alterations in FGFR3 gene fusions cases were also common. From our limited number of cases, most of FGFR3 gene fusions patients were MSS.[Table: see text]

scholarly journals GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors

2019 ◽  
Author(s):  
Krishna Sriram ◽  
Kevin Moyung ◽  
Ross Corriden ◽  
Hannah Carter ◽  
Paul A. Insel
Keyword(s):  
Copy Number Variation ◽  
Mrna Expression ◽  
Solid Tumors ◽  
Copy Number ◽  
Driver Mutations ◽  
Specific Tumor ◽  
Elevated Expression ◽  
Number Variation ◽  
Approved Drugs ◽  
Tumor Types

AbstractG protein-coupled receptors (GPCRs) are the most widely targeted gene family for FDA-approved drugs. To assess possible roles for GPCRs in cancer, we analyzed Cancer Genome Atlas data for mRNA expression, mutations, and copy number variation (CNV) in 20 categories/45 sub-types of solid tumors and quantified differential expression of GPCRs by comparing tumors against normal tissue from the GTEx database. GPCRs are over-represented among coding genes with elevated expression in solid tumors; most tumor types differentially express >50 GPCRs, including many targets for approved drugs, hitherto largely unrecognized as targets of interest in cancer. GPCR mRNA signatures characterize specific tumor types, indicate survival and correlate with expression of cancer-related pathways. Tumor GPCR mRNA signatures have prognostic relevance for survival and correlate with expression of numerous cancer-related genes and pathways. GPCR expression in tumors is largely independent of staging/grading/metastasis/driver mutations and GPCRs expressed in cancer cell lines parallels that measured in tumors. Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage. CNV of GPCRs while common, does not generally correlate with mRNA expression. We suggest a previously under-appreciated role for GPCRs in cancer, perhaps as functional oncogenes, biomarkers, surface antigens and pharmacological targets.

scholarly journals ctDNA MRD Detection and Personalized Oncogenomic Analysis in Oligometastatic Colorectal Cancer From Plasma and Urine

2021 ◽  
pp. 378-388
Author(s):  
Bruna Pellini ◽  
Nadja Pejovic ◽  
Wenjia Feng ◽  
Noah Earland ◽  
Peter K. Harris ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Residual Disease ◽  
White Blood Cells ◽  
Driver Mutations ◽  
Curative Intent ◽  
Surgical Specimen ◽  
Pik3ca Mutations ◽  
Age Related ◽  
Ctdna Analysis

PURPOSE We hypothesized that circulating tumor DNA (ctDNA) molecular residual disease (MRD) analysis without prior mutational knowledge could be performed after neoadjuvant chemotherapy to assess oligometastatic colorectal cancer (CRC) treated surgically with curative intent. We also investigated urine as an alternative analyte for ctDNA MRD detection in this nongenitourinary setting. PATIENTS AND METHODS We applied AVENIO targeted next-generation sequencing to plasma, tumor, and urine samples acquired on the day of curative-intent surgery from 24 prospectively enrolled patients with oligometastatic CRC. Age-related clonal hematopoiesis was accounted for by removing variants also present in white blood cells. Plasma and urine ctDNA MRD were correlated with tumor cells detected in the surgical specimen, and adjuvant treatment strategies were proposed based on ctDNA-inferred tumor mutational burden (iTMB) and targetable alterations. RESULTS Seventy-one percent of patients were treated with neoadjuvant chemotherapy. Tumor-naive plasma ctDNA analysis detected MRD at a median level of 0.62% with 95% sensitivity and 100% specificity, and 94% and 77% sensitivity when only considering patients treated with neoadjuvant chemotherapy and putative driver mutations, respectively. In urine, ctDNA MRD detection specificity remained high at 100%, but sensitivity decreased to 64% with median levels being 11-fold lower than in plasma ( P < .0001). Personalized ctDNA MRD oncogenomic analysis revealed 81% of patients might have been candidates for adjuvant immunotherapy based on high iTMB or targeted therapy based on actionable PIK3CA mutations. CONCLUSION Tumor-naive plasma ctDNA analysis can sensitively and specifically detect MRD in patients with oligometastatic CRC after neoadjuvant chemotherapy. Urine-based ctDNA MRD detection is also feasible; however, it is less sensitive than plasma because of significantly lower levels. Oligometastatic patients with detectable MRD may benefit from additional personalized treatment based on ctDNA-derived oncogenomic profiling.

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