RESUMO
While mutational signatures provide a plethora of prognostic and therapeutic insights, their application in clinical-setting, targeted gene panels is extremely limited. We develop a mutational representation model (which learns and embeds specific mutation signature connections) that enables prediction of dominant signatures with only a few mutations. We predict the dominant signatures across more than 60,000 tumors with gene panels, delineating their landscape across different cancers. Dominant signature predictions in gene panels are of clinical importance. These included UV, tobacco, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) signatures that are associated with better survival, independently from mutational burden. Further analyses reveal gene and mutation associations with signatures, such as SBS5 with TP53 and APOBEC with FGFR3S249C. In a clinical use case, APOBEC signature is a robust and specific predictor for resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Our model provides an easy-to-use way to detect signatures in clinical setting assays with many possible clinical implications for an unprecedented number of cancer patients.
Assuntos
Mutação , Neoplasias , Humanos , Mutação/genética , Neoplasias/genética , Receptores ErbB/genética , Inibidores de Proteínas Quinases/farmacologia , Proteína Supressora de Tumor p53/genética , Redes Neurais de Computação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
Genomic analysis, performed on tumoral tissue DNA and on circulating tumor DNA (ctDNA) from blood, is the cornerstone of precision cancer medicine. Herein, we characterized the clinical prognostic implications of the concordance of alterations in major cancer genes between tissue- and blood-derived DNA in a pan-cancer cohort. The molecular profiles of both liquid (Guardant Health) and tissue (Foundation Medicine) biopsies from 433 patients were analyzed. Mutations and amplifications of cancer genes scored by these two tests were assessed. In 184 (42.5%) patients, there was at least one mutual gene alteration. The mean number of mutual gene-level alterations in the samples was 0.67 per patient (range: 0-5). A higher mutual gene-level alteration number correlated with shorter overall survival (OS). As confirmed in multivariable analysis, patients with ≥2 mutual gene-level alterations in blood and tissue had a hazard ratio (HR) of death of 1.49 (95% confidence interval [CI]=1-2.2; P=0.047), whereas patients with ≥3 mutual gene-level alterations had an HR of death 2.38 (95% CI=1.47-3.87; P=0.0005). Together, our results show that gene-level concordance between tissue DNA and ctDNA analysis is prevalent and is an independent factor predicting significantly shorter patient survival.
Assuntos
DNA Tumoral Circulante , Neoplasias , Humanos , DNA Tumoral Circulante/genética , Biomarcadores Tumorais/genética , Neoplasias/patologia , DNA de Neoplasias/genética , Mutação/genética , OncogenesRESUMO
Driver mutations endow tumors with selective advantages and produce an array of pathogenic effects. Determining the function of somatic variants is important for understanding cancer biology and identifying optimal therapies. Here, we compiled a shared dataset from several cancer genomic databases. Two measures were applied to 535 cancer genes based on observed and expected frequencies of driver variants as derived from cancer-specific rates of somatic mutagenesis. The first measure comprised a binary classifier based on a binomial test; the second was tumor variant amplitude (TVA), a continuous measure representing the selective advantage of individual variants. TVA outperformed all other computational tools in terms of its correlation with experimentally derived functional scores of cancer mutations. TVA also highly correlated with drug response, overall survival, and other clinical implications in relevant cancer genes. This study demonstrates how a selective advantage measure based on a large cancer dataset significantly impacts our understanding of the spectral effect of driver variants in cancer. The impact of this information will increase as cancer treatment becomes more precise and personalized to tumor-specific mutations. SIGNIFICANCE: A new selective advantage estimation assists in oncogenic driver identification and relative effect measurements, enabling better prognostication, therapy selection, and prioritization.
Assuntos
Biologia Computacional , Neoplasias , Humanos , Mutação , Neoplasias/genética , OncogenesRESUMO
Correctly identifying the true driver mutations in a patient's tumor is a major challenge in precision oncology. Most efforts address frequent mutations, leaving medium- and low-frequency variants mostly unaddressed. For TP53, this identification is crucial for both somatic and germline mutations, with the latter associated with the Li-Fraumeni syndrome (LFS), a multiorgan cancer predisposition. We present TP53_PROF (prediction of functionality), a gene specific machine learning model to predict the functional consequences of every possible missense mutation in TP53, integrating human cell- and yeast-based functional assays scores along with computational scores. Variants were labeled for the training set using well-defined criteria of prevalence in four cancer genomics databases. The model's predictions provided accuracy of 96.5%. They were validated experimentally, and were compared to population data, LFS datasets, ClinVar annotations and to TCGA survival data. Very high accuracy was shown through all methods of validation. TP53_PROF allows accurate classification of TP53 missense mutations applicable for clinical practice. Our gene specific approach integrated machine learning, highly reliable features and biological knowledge, to create an unprecedented, thoroughly validated and clinically oriented classification model. This approach currently addresses TP53 mutations and will be applied in the future to other important cancer genes.