Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI.

نویسندگان

  • Marco Carraro
  • Giovanni Minervini
  • Manuel Giollo
  • Yana Bromberg
  • Emidio Capriotti
  • Rita Casadio
  • Roland Dunbrack
  • Lisa Elefanti
  • Pietro Fariselli
  • Carlo Ferrari
  • Julian Gough
  • Panagiotis Katsonis
  • Emanuela Leonardi
  • Olivier Lichtarge
  • Chiara Menin
  • Pier Luigi Martelli
  • Abhishek Niroula
  • Lipika R Pal
  • Susanna Repo
  • Maria Chiara Scaini
  • Mauno Vihinen
  • Qiong Wei
  • Qifang Xu
  • Yuedong Yang
  • Yizhou Yin
  • Jan Zaucha
  • Huiying Zhao
  • Yaoqi Zhou
  • Steven E Brenner
  • John Moult
  • Silvio C E Tosatto
چکیده

Correct phenotypic interpretation of variants of unknown significance for cancer-associated genes is a diagnostic challenge as genetic screenings gain in popularity in the next-generation sequencing era. The Critical Assessment of Genome Interpretation (CAGI) experiment aims to test and define the state of the art of genotype-phenotype interpretation. Here, we present the assessment of the CAGI p16INK4a challenge. Participants were asked to predict the effect on cellular proliferation of 10 variants for the p16INK4a tumor suppressor, a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene. Twenty-two pathogenicity predictors were assessed with a variety of accuracy measures for reliability in a medical context. Different assessment measures were combined in an overall ranking to provide more robust results. The R scripts used for assessment are publicly available from a GitHub repository for future use in similar assessment exercises. Despite a limited test-set size, our findings show a variety of results, with some methods performing significantly better. Methods combining different strategies frequently outperform simpler approaches. The best predictor, Yang&Zhou lab, uses a machine learning method combining an empirical energy function measuring protein stability with an evolutionary conservation term. The p16INK4a challenge highlights how subtle structural effects can neutralize otherwise deleterious variants.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

In-silico study to identify the pathogenic single nucleotide polymorphisms in the coding region of CDKN2A gene

Background: CDKN2A, encoding two important tumor suppressor proteins p16 and p14, is a tumor suppressor gene. Mutations in this gene and subsequently the defect in p16 and p14 proteins lead to the downregulation of RB1/p53 and cancer malignancy. To identify the structural and functional effects of mutations, various powerful bioinformatics tools are available. The aim of this study is the ident...

متن کامل

In silico analysis for determining the deleterious nonsynonymous single nucleotide polymorphisms of BRCA genes

Recent advances in DNA sequencing techniques have led to an increase in the identification of single nucleotide polymorphisms (SNPs) in BRCA1 and BRCA2 genes, but no further information regarding the deleterious probability of many of them is available (Variants of Unknown Significance/VUS). As a result, in the current study, different sequence- and structure-based computation...

متن کامل

Computational approach towards identification of pathogenic missense mutations in AMELX gene and their possible association with amelogenesis imperfecta

Amelogenin gene (AMEL-X) encodes an enamel protein called amelogenin, which plays a vital role in tooth development. Any mutations in this gene or the associated pathway lead to developmental abnormalities of the tooth. The present study aims to analyze functional missense mutations in AMEL-X genes and derive an association with amelogenesis imperfecta. The information on miss...

متن کامل

Functional investigation of the BRCA1 Val1714Gly and Asp1733Gly variants by computational tools and yeast transcription activation assay

Mutations in the BRCA1 gene are known to be a major cause of hereditary breast cancer. However, characterizing the point mutationsassociated with cancer in BRCA1 is challenging because the functional impact of most of them is still unknown. Nowadays, a variety of methods are employed to identify cancer-associated mutations in BRCA1. This study is aimed to ass...

متن کامل

Comparison of the inhibitory effects of three transcriptional variants of CDKN2A in human lung cancer cell line A549

BACKGROUND The tumor suppressor gene CDKN2A generates at least three different transcriptional variants, each of which is thought to encode a tumor suppressor. However, the inhibitory activities of these variants have not yet been compared in the same cells. Protein therapy is known to have several advantages over gene therapy. Thus, investigation of the exogenous protein molecule of the most e...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Human mutation

دوره 38 9  شماره 

صفحات  -

تاریخ انتشار 2017