A Novel System for Functional Determination of Variants of Uncertain Significance using Deep Convolutional Neural Networks.

Scientific Reports
Lior ZimmermanGabi Tarcic

Abstract

Many drugs are developed for commonly occurring, well studied cancer drivers such as vemurafenib for BRAF V600E and erlotinib for EGFR exon 19 mutations. However, most tumors also harbor mutations which have an uncertain role in disease formation, commonly called Variants of Uncertain Significance (VUS), which are not studied or characterized and could play a significant role in drug resistance and relapse. Therefore, the determination of the functional significance of VUS and their response to Molecularly Targeted Agents (MTA) is essential for developing new drugs and predicting response of patients. Here we present a multi-scale deep convolutional neural network (DCNN) architecture combined with an in-vitro functional assay to investigate the functional role of VUS and their response to MTA's. Our method achieved high accuracy and precision on a hold-out set of examples (0.98 mean AUC for all tested genes) and was used to predict the oncogenicity of 195 VUS in 6 genes. 63 (32%) of the assayed VUS's were classified as pathway activating, many of them to a similar extent as known driver mutations. Finally, we show that responses of various mutations to FDA approved MTAs are accurately predicted by our platform in a dose depende...Continue Reading

References

Jan 29, 1999·Journal of the National Cancer Institute·P le CoutreC Gambacorti-Passerini
Sep 4, 2003·Genome Research·Paul D ThomasApurva Narechania
Mar 24, 2004·Cell·Paul T C WanUNKNOWN Cancer Genome Project
Feb 10, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Gregory J RielyVincent A Miller
Feb 14, 2006·Nature Genetics·Suzanne SchubbertChristian P Kratz
Mar 17, 2007·Molecular Cancer Therapeutics·Kathryn G RobertsLeonie K Ashman
Aug 30, 2007·Journal of Cell Science·Andreas HerrmannGerhard Müller-Newen
Sep 6, 2008·Nature·UNKNOWN Cancer Genome Atlas Research Network
Dec 17, 2009·Molecular Cell·Cellina Cohen-SaidonUri Alon
Dec 24, 2009·Nature Reviews. Cancer·Thomas SantariusColin S Cooper
Mar 17, 2010·Cancer Treatment Reviews·John Araujo, Christopher Logothetis
Feb 18, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Yan KongJun Guo
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Nov 16, 2011·Nature Reviews. Clinical Oncology·Miriam MartiniAlberto Bardelli
Feb 13, 2013·Nature Reviews. Clinical Oncology·Jordi RodonJosep Tabernero
Apr 4, 2013·Science Signaling·Jianjiong GaoNikolaus Schultz
Oct 3, 2014·Molecular Biology International·Nida Iqbal, Naveed Iqbal
Oct 16, 2014·JAMA Dermatology·Marina VitaPaulo De Sepulveda
Nov 27, 2014·Haematologica·Allison Galanis, Mark Levis
Mar 6, 2015·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Sue RichardsUNKNOWN ACMG Laboratory Quality Assurance Committee
Apr 22, 2015·Cell Reports·Robert T LawrenceJudit Villén
Jul 30, 2015·The Cancer Journal·Anosheh Afghahi, George W Sledge
Mar 2, 2016·Theoretical Biology & Medical Modelling·Nicolas CarelsJack Adam Tuszynski
Apr 16, 2016·World Journal of Clinical Oncology·Dominique Levêque
Aug 2, 2016·Cancer Cell·Alice H BergerJesse S Boehm
Aug 19, 2016·Drug Design, Development and Therapy·Maryam Abbaspour BabaeiFatemeh Ahmadipour
Jan 28, 2018·Cell Death & Disease·Steven CarberryJochen H M Prehn
Feb 21, 2018·Journal of Medicinal Chemistry·Bogos Agianian, Evripidis Gavathiotis
Mar 14, 2018·Proceedings of the National Academy of Sciences of the United States of America·Pooya MobadersanyLee A D Cooper
Mar 14, 2018·Cancer Cell·Patrick Kwok-Shing NgGordon B Mills

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Citations

Apr 18, 2021·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Shumei KatoRazelle Kurzrock
Sep 25, 2021·Clinical Chemistry·Daniel S HermanThomas J S Durant

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Methods Mentioned

BETA
exome sequencing
biopsies
confocal microscopy
transfection
transfections
Feature Extraction
nucleotide exchange

Software Mentioned

Mut2Vec
Keras
FATHMM
elements
Tensorflow
Word2Vec
seaborn
NIS
matplotlib
deepDriver

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