PIK3CA Mutations Frequently Coexist with RAS and BRAF Mutations in Patients with Advanced Cancers

Janků, Filip; Lee, John; Tsimberidou, Apostolia M.; Hong, David S.; Naing, Aung; Falchook, Gerald S.; Fu, Siqing; Luthra, Rajyalakshmi; Garrido‐Laguna, Ignacio; Kurzrock, Razelle

doi:10.1371/journal.pone.0022769

Cited by 174 publications

(131 citation statements)

References 47 publications

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“…Concomitant BRAF and RAS mutations may allow simultaneous activation of the MAPK and PI3K/Akt signaling pathways in cancer cells, providing a growth advantage (47,48). Long-term follow-up revealed that patients with concomitant mutations had a poorer response to treatment and reduced disease-free survival times (49), indicating that activation of the two genes may have a synergistic effect on disease progression (50).…”

Section: Hras Status N (%) -----------------------------------------mentioning

confidence: 99%

Identification of a novel HRAS variant and its association with papillary thyroid carcinoma

Dou

Zhang

et al. 2018

Oncol Lett

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Abstract. HRas proto-oncogene (HRAS) is one of the most commonly mutated genes in thyroid cancer, with mutations frequently occurring in the follicular and Hurthle cell subtypes. However, the contribution of mutations in HRAS to papillary thyroid carcinoma (PTC) progression and the tall-cell variant (TCV) is poorly understood. The aim of the present study was to investigate the somatic genetic variants present in HRAS in patients with PTC, and to investigate the association of these mutations with PTC. The present study is a retrospective case-control study using tumor samples collected from 139 patients with PTC and blood samples from 195 healthy individuals. All patient samples were screened for mutations in 'hotspot' regions of HRAS and B-raf proto-oncogene (BRAF) by single-stranded conformational polymorphism analysis, followed by direct sequencing. A novel variant (IVS1-82del gctgggcctggg) in the HRAS 5'-untranslated region was identified. There was no difference in age or sex of patients with PTC and the healthy controls; however, the HRAS variant was more frequently detected in PTC tissue than in the healthy control samples (37 vs. 26%, P=0.04). There was no association between the HRAS variant and age, sex, tumor size, encapsulation, multifocality/intra-thyroidal spread, Tumor-Node-Metastasis stage, history of Hashimoto's disease, BRAF V600E mutation or PTC subtype (all P>0.05). There were differences of BRAF V600E distribution among different subtypes (χ 2 =6.390, P=0.041). HRAS variant co-occurring with the BRAF V600E mutation accounted for 31.6% of the total number (P=0.196). Therefore, this novel variant of HRAS (IVS1-82del gctgggcctggg) may be associated with PTC; however, larger scale studies are required to assess the contribution of this novel HRAS variant to PTC progression.

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Section: Hras Status N (%) -----------------------------------------mentioning

confidence: 99%

Identification of a novel HRAS variant and its association with papillary thyroid carcinoma

Dou

Zhang

et al. 2018

Oncol Lett

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“…Another perspective for this issue derives from studies showing that, in colorectal cancer patients, aberrations in the KRAS/BRAF axis often coexist with aberrations in the PI3K/AKT/mTOR axis (83)(84)(85), with each being a resistance pathway for the other (86,87). These co-mutations occur in other cancers as well, but not as frequently.…”

Section: Role Of the Pi3k/akt/mtor Axismentioning

confidence: 99%

Genomically Driven Tumors and Actionability across Histologies:BRAF-Mutant Cancers as a Paradigm

Turski¹,

Vidwans²,

Janků

et al. 2016

Molecular Cancer Therapeutics

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The diagnosis, classification, and management of cancer are traditionally dictated by the site of tumor origin, for example, breast or lung, and by specific histologic subtypes of site-oforigin cancers (e.g., non-small cell versus small cell lung cancer). However, with the advent of sequencing technologies allowing for rapid, low cost, and accurate sequencing of clinical samples, new observations suggest an expanded or different approach to the diagnosis and treatment of cancer-one driven by the unique molecular features of the tumor. We discuss a genomically driven strategy for cancer treatment using BRAF as an example. Several key points are highlighted: (i) molecular aberrations can be shared across cancers; (ii) approximately 15% of all cancers harbor BRAF mutations; and (iii) BRAF inhibitors, while approved only for melanoma, have reported activity across numerous cancers and related disease types bearing BRAF aberrations. However, BRAF-mutated colorectal cancer has shown poor response rate to BRAF inhibitor monotherapy, striking a cautionary note. Yet, even in this case, emerging data suggest BRAF-mutated colorectal cancers can respond well to BRAF inhibitors, albeit when administered in combination with other agents that impact resistance pathways. Taken together, these data suggest that molecular aberrations may be the basis for a new nosology for cancer. Mol Cancer Ther; 15(4); 533-47. Ó2016 AACR.

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“…Loss of PTEN expression, assessed by immunohistochemistry, is found in as many as 40% of colorectal cancer tumors (4)(5)(6). Importantly, the RAS/RAF/MEK and PI3K/AKT/ mTOR pathways also interact extensively: (i) each shows activation of upstream receptor tyrosine kinases; (ii) mutations in KRAS or BRAF and PIK3CA coexist in a significant percentage of colorectal tumors; and (iii) complex networks allow compensatory parallel signaling when one or the other pathway is inhibited (7).…”

Section: Introductionmentioning

confidence: 99%

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Dienstmann

Serpico

Rodón

et al. 2012

Molecular Cancer Therapeutics

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Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n ¼ 10; or low PTEN, n ¼ 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n ¼ 10; or BRAF mutation, n ¼ 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n ¼ 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n ¼ 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n ¼ 5), and BRAF inhibitor (if BRAF mutation, n ¼ 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P < 0.001). Partial response was seen in 1 patient [1.2%, PI3K inhibitor with PIK3CA mutation] and stable disease >16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit. Mol Cancer Ther; 11(9); 2062-71. Ó2012 AACR.

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PIK3CA Mutations Frequently Coexist with RAS and BRAF Mutations in Patients with Advanced Cancers

Cited by 174 publications

References 47 publications

Identification of a novel HRAS variant and its association with papillary thyroid carcinoma

Identification of a novel HRAS variant and its association with papillary thyroid carcinoma

Genomically Driven Tumors and Actionability across Histologies:BRAF-Mutant Cancers as a Paradigm

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

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