Cargando…

Multidimensional Mutational Profiling of the Indian HNSCC Sub-Population Provides IRAK1, a Novel Driver Gene and Potential Druggable Target

Head and neck squamous cell carcinomas (HNSCC) include heterogeneous group of tumors, classified according to their anatomical site. It is the sixth most prevalent cancer globally. Among South Asian countries, India accounts for 40% of HNC malignancies with significant morbidity and mortality. In th...

Descripción completa

Detalles Bibliográficos
Autores principales: Desai, Sagar Sanjiv, K, Raksha Rao, Jain, Anika, Bawa, Pushpinder Singh, Dutta, Priyatam, Atre, Gaurav, Subhash, Anand, Rao, Vishal U. S., J, Suvratha, Srinivasan, Subhashini, Choudhary, Bibha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593415/
https://www.ncbi.nlm.nih.gov/pubmed/34796107
http://dx.doi.org/10.3389/fonc.2021.723162
_version_ 1784599734880567296
author Desai, Sagar Sanjiv
K, Raksha Rao
Jain, Anika
Bawa, Pushpinder Singh
Dutta, Priyatam
Atre, Gaurav
Subhash, Anand
Rao, Vishal U. S.
J, Suvratha
Srinivasan, Subhashini
Choudhary, Bibha
author_facet Desai, Sagar Sanjiv
K, Raksha Rao
Jain, Anika
Bawa, Pushpinder Singh
Dutta, Priyatam
Atre, Gaurav
Subhash, Anand
Rao, Vishal U. S.
J, Suvratha
Srinivasan, Subhashini
Choudhary, Bibha
author_sort Desai, Sagar Sanjiv
collection PubMed
description Head and neck squamous cell carcinomas (HNSCC) include heterogeneous group of tumors, classified according to their anatomical site. It is the sixth most prevalent cancer globally. Among South Asian countries, India accounts for 40% of HNC malignancies with significant morbidity and mortality. In the present study, we have performed exome sequencing and analysis of 51 Head and Neck squamous cell carcinoma samples. Besides known mutations in the oncogenes and tumour suppressors, we have identified novel gene signatures differentiating buccal, alveolar, and tongue cancers. Around 50% of the patients showed mutation in tumour suppressor genes TP53 and TP63. Apart from the known mutations, we report novel mutations in the genes AKT1, SPECC1, and LRP1B, which are linked with tumour progression and patient survival. A highly curated process was developed to identify survival signatures. 36 survival-related genes were identified based on the correlation of functional impact of variants identified using exome-seq with gene expression from transcriptome data (GEPIA database) and survival. An independent LASSO regression analysis was also performed. Survival signatures common to both the methods led to identification of 4 dead and 3 alive gene signatures, the accuracy of which was confirmed by performing a ROC analysis (AUC=0.79 and 0.91, respectively). Also, machine learning-based driver gene prediction tool resulted in the identification of IRAK1 as the driver (p-value = 9.7 e-08) and also as an actionable mutation. Modelling of the IRAK1 mutation showed a decrease in its binding to known IRAK1 inhibitors.
format Online
Article
Text
id pubmed-8593415
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-85934152021-11-17 Multidimensional Mutational Profiling of the Indian HNSCC Sub-Population Provides IRAK1, a Novel Driver Gene and Potential Druggable Target Desai, Sagar Sanjiv K, Raksha Rao Jain, Anika Bawa, Pushpinder Singh Dutta, Priyatam Atre, Gaurav Subhash, Anand Rao, Vishal U. S. J, Suvratha Srinivasan, Subhashini Choudhary, Bibha Front Oncol Oncology Head and neck squamous cell carcinomas (HNSCC) include heterogeneous group of tumors, classified according to their anatomical site. It is the sixth most prevalent cancer globally. Among South Asian countries, India accounts for 40% of HNC malignancies with significant morbidity and mortality. In the present study, we have performed exome sequencing and analysis of 51 Head and Neck squamous cell carcinoma samples. Besides known mutations in the oncogenes and tumour suppressors, we have identified novel gene signatures differentiating buccal, alveolar, and tongue cancers. Around 50% of the patients showed mutation in tumour suppressor genes TP53 and TP63. Apart from the known mutations, we report novel mutations in the genes AKT1, SPECC1, and LRP1B, which are linked with tumour progression and patient survival. A highly curated process was developed to identify survival signatures. 36 survival-related genes were identified based on the correlation of functional impact of variants identified using exome-seq with gene expression from transcriptome data (GEPIA database) and survival. An independent LASSO regression analysis was also performed. Survival signatures common to both the methods led to identification of 4 dead and 3 alive gene signatures, the accuracy of which was confirmed by performing a ROC analysis (AUC=0.79 and 0.91, respectively). Also, machine learning-based driver gene prediction tool resulted in the identification of IRAK1 as the driver (p-value = 9.7 e-08) and also as an actionable mutation. Modelling of the IRAK1 mutation showed a decrease in its binding to known IRAK1 inhibitors. Frontiers Media S.A. 2021-11-02 /pmc/articles/PMC8593415/ /pubmed/34796107 http://dx.doi.org/10.3389/fonc.2021.723162 Text en Copyright © 2021 Desai, K, Jain, Bawa, Dutta, Atre, Subhash, Rao, J, Srinivasan and Choudhary https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Desai, Sagar Sanjiv
K, Raksha Rao
Jain, Anika
Bawa, Pushpinder Singh
Dutta, Priyatam
Atre, Gaurav
Subhash, Anand
Rao, Vishal U. S.
J, Suvratha
Srinivasan, Subhashini
Choudhary, Bibha
Multidimensional Mutational Profiling of the Indian HNSCC Sub-Population Provides IRAK1, a Novel Driver Gene and Potential Druggable Target
title Multidimensional Mutational Profiling of the Indian HNSCC Sub-Population Provides IRAK1, a Novel Driver Gene and Potential Druggable Target
title_full Multidimensional Mutational Profiling of the Indian HNSCC Sub-Population Provides IRAK1, a Novel Driver Gene and Potential Druggable Target
title_fullStr Multidimensional Mutational Profiling of the Indian HNSCC Sub-Population Provides IRAK1, a Novel Driver Gene and Potential Druggable Target
title_full_unstemmed Multidimensional Mutational Profiling of the Indian HNSCC Sub-Population Provides IRAK1, a Novel Driver Gene and Potential Druggable Target
title_short Multidimensional Mutational Profiling of the Indian HNSCC Sub-Population Provides IRAK1, a Novel Driver Gene and Potential Druggable Target
title_sort multidimensional mutational profiling of the indian hnscc sub-population provides irak1, a novel driver gene and potential druggable target
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593415/
https://www.ncbi.nlm.nih.gov/pubmed/34796107
http://dx.doi.org/10.3389/fonc.2021.723162
work_keys_str_mv AT desaisagarsanjiv multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget
AT kraksharao multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget
AT jainanika multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget
AT bawapushpindersingh multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget
AT duttapriyatam multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget
AT atregaurav multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget
AT subhashanand multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget
AT raovishalus multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget
AT jsuvratha multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget
AT srinivasansubhashini multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget
AT choudharybibha multidimensionalmutationalprofilingoftheindianhnsccsubpopulationprovidesirak1anoveldrivergeneandpotentialdruggabletarget