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1.
Nat Commun ; 13(1): 5478, 2022 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-36117191

RESUMO

Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In addition, we find that patients with ARID1A mutations, at baseline, are associated with worse outcome when treated with cetuximab- but not bevacizumab-containing therapies; thus, this suggests that ARID1A mutations may provide both an acquired and intrinsic mechanism of resistance to anti-EGFR therapies. We find that, ARID1A and EGFR-pathway genetic alterations are mutually exclusive across lung and colorectal cancers, further supporting a functional connection between these pathways. Our results not only suggest that ARID1A could be potentially used as a predictive biomarker for cetuximab treatment decisions but also provide a rationale for exploring therapeutic MAPK inhibition in an unexpected but genetically defined segment of CRC patients.


Assuntos
Antineoplásicos Imunológicos , Cetuximab , Neoplasias Colorretais , Proteínas de Ligação a DNA , Resistencia a Medicamentos Antineoplásicos , Fatores de Transcrição , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/efeitos adversos , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/genética
2.
BMC Bioinformatics ; 17 Suppl 1: 6, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26818556

RESUMO

BACKGROUND: Thyroid carcinomas are known to harbor oncogenic driver mutations and advances in sequencing technology now allow the detection of these in fine needle aspiration biopsies (FNA). Recent work by The Cancer Genome Atlas (TCGA) Research Network has expanded the number of genetic alterations detected in papillary thyroid carcinomas (PTC). We sought to investigate the prevalence of these and other genetic alterations in diverse subtypes of thyroid nodules beyond PTC, including a variety of samples with benign histopathology. This is the first clinical evaluation of a large panel of TCGA-reported genomic alterations in thyroid FNAs. RESULTS: In FNAs, genetic alterations were detected in 19/44 malignant samples (43% sensitivity) and in 7/44 histopathology benign samples (84% specificity). Overall, after adding a cohort of tissue samples, 38/76 (50%) of histopathology malignant samples were found to harbor a genetic alteration, while 15/75 (20%) of benign samples were also mutated. The most frequently mutated malignant subtypes were medullary thyroid carcinoma (9/12, 75%) and PTC (14/30, 47%). Additionally, follicular adenoma, a benign subtype of thyroid neoplasm, was also found to harbor mutations (12/29, 41%). Frequently mutated genes in malignant samples included BRAF (20/76, 26%) and RAS (9/76, 12%). Of the TSHR variants detected, (6/7, 86%) were in benign nodules. In a direct comparison of the same FNA also tested by an RNA-based gene expression classifier (GEC), the sensitivity of genetic alterations alone was 42%, compared to the 91% sensitivity achieved by the GEC. The specificity based only on genetic alterations was 84%, compared to 77% specificity with the GEC. CONCLUSIONS: While the genomic landscape of all thyroid neoplasm subtypes will inevitably be elucidated, caution should be used in the early adoption of published mutations as the sole predictor of malignancy in thyroid. The largest set of such mutations known to date detects only a portion of thyroid carcinomas in preoperative FNAs in our cohort and thus is not sufficient to rule out cancer. Due to the finding that variants are also found in benign nodules, testing only GEC suspicious nodules may be helpful in avoiding false positives and altering the extent of treatment when selected mutations are found.


Assuntos
Adenocarcinoma Folicular/diagnóstico , Carcinoma Neuroendócrino/diagnóstico , Carcinoma/diagnóstico , Fusão Gênica/genética , Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias da Glândula Tireoide/diagnóstico , Adenocarcinoma Folicular/genética , Biomarcadores Tumorais/genética , Biópsia por Agulha Fina , Carcinoma/genética , Carcinoma Neuroendócrino/genética , Carcinoma Papilar , Humanos , Estudos Prospectivos , Curva ROC , Análise de Sequência de RNA/métodos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/genética
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