PIKing Oncogenic Mutations

Abstract Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

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Toward a Personalized Therapy in Soft-Tissue Sarcomas: State of the Art and Future Directions

Cancers ◽

10.3390/cancers13102359 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2359

Author(s):

Liliana Montella ◽

Lucia Altucci ◽

Federica Sarno ◽

Carlo Buonerba ◽

Stefano De Simone ◽

...

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcomas ◽

Chromosomal Translocations ◽

Intrinsic Variability ◽

Poor Survival ◽

Genomic Alterations ◽

Future Directions ◽

Oncogenic Mutations ◽

Targeted Treatments ◽

Innovative Therapies

Soft-tissue sarcomas are rare tumors characterized by pathogenetic, morphological, and clinical intrinsic variability. Median survival of patients with advanced tumors are usually chemo- and radio-resistant, and standard treatments yield low response rates and poor survival results. The identification of defined genomic alterations in sarcoma could represent the premise for targeted treatments. Summarizing, soft-tissue sarcomas can be differentiated into histotypes with reciprocal chromosomal translocations, with defined oncogenic mutations and complex karyotypes. If the latter are improbably approached with targeted treatments, many suggest that innovative therapies interfering with the identified fusion oncoproteins and altered pathways could be potentially resolutive. In most cases, the characteristic genetic signature is discouragingly defined as “undruggable”, which poses a challenge for the development of novel pharmacological approaches. In this review, a summary of genomic alterations recognized in most common soft-tissue sarcoma is reported together with current and future therapeutic opportunities.

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Oncogenic mutations Q61L and Q61H confer active form-like structural features to the inactive state (state 1) conformation of H-Ras protein

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2021.05.084 ◽

2021 ◽

Vol 565 ◽

pp. 85-90

Author(s):

Shigeyuki Matsumoto ◽

Haruka Taniguchi-Tamura ◽

Mitsugu Araki ◽

Takashi Kawamura ◽

Ryo Miyamoto ◽

...

Keyword(s):

Active Form ◽

Structural Features ◽

Ras Protein ◽

Inactive State ◽

Oncogenic Mutations ◽

State 1

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35MO Discovery and characterization of selective, FGFR1-sparing, inhibitors of FGFR2/3 oncogenic mutations for the treatment of cancers

Annals of Oncology ◽

10.1016/j.annonc.2021.01.050 ◽

2021 ◽

Vol 32 ◽

pp. S15

Author(s):

E. Dardenne ◽

F. Padilla ◽

S. Rasmussen ◽

S.N. Yang ◽

A. Mentes ◽

...

Keyword(s):

Oncogenic Mutations

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miR-146a promotes the initiation and progression of melanoma by activating Notch signaling

eLife ◽

10.7554/elife.01460 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 67

Author(s):

Matteo Forloni ◽

Shaillay Kumar Dogra ◽

Yuying Dong ◽

Darryl Conte ◽

Jianhong Ou ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Notch Signaling ◽

Cell Lines ◽

Somatic Mutation ◽

Melanoma Cell ◽

Human Melanoma ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Oncogenic Mutations ◽

Melanoma Cell Lines

Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. In this study, we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma.

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

Journal of Clinical Oncology ◽

10.1200/jco.2010.29.6038 ◽

2010 ◽

Vol 28 (30) ◽

pp. 4616-4620 ◽

Cited By ~ 229

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.

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