X-Meeting presentations

ARE SOMATIC SNVS/INDELS IN HLA CLASS-I GENES A FREQUENT MUTATIONAL MECHANISM IN PRIMARY TUMORS?

Published in 08/11/2023 - ISBN: 978-65-272-0061-1

Paper Title

ARE SOMATIC SNVS/INDELS IN HLA CLASS-I GENES A FREQUENT MUTATIONAL MECHANISM IN PRIMARY TUMORS?

Authors

Amanda Muniz
Lucca Alipio Pagnan
Ramon Torreglosa do Carmo
Vandeclécio Lira
Erick da Cruz Castelli
Cibele Masotti

Modality

Poster

Subject area

DNA and Genomics

Publishing Date

08/11/2023

Country of Publishing

Brazil | Brasil

Language of Publishing

Inglês

Paper Page

https://www.even3.com.br/anais/xmeeting2023/636975-are-somatic-snvsindels-in-hla-class-i-genes-a-frequent-mutational-mechanism-in-primary-tumors

ISBN

978-65-272-0061-1

Keywords

HLA, mutations, cancer

Summary

A hallmark of cancer is its ability to evade the immune system. Different mutational mechanisms can affect antigen presentation, including mutations in HLA-I molecules that present neoantigens to cytotoxic CD8+ T cells. Such mutations may reduce tumor immunogenicity and, consequently, the anti-tumoral immune response. The HLA locus is known to be the most polymorphic locus in the human genome, which makes the characterization of somatic mutations in this region a major methodological challenge using NGS. In routine cancer somatic diagnosis, the tumor-only analysis poses an additional difficulty, as we do not have paired-normal tissue sequencing for germinative variants exclusion. To improve HLA somatic diagnosis and better understand the immune-escape mechanisms in tumor progression, this study sought to validate a tumor-only computational strategy, using multi-referenced analysis, capable of characterizing somatic mutations of the SNVs/INDELs type in genes HLA-I. The identification of somatic mutations in this framework is mainly based on databases of human polymorphisms, which provide information on the observed variants and their frequencies in human populations. Using public genomic data from The Cancer Genome Atlas (TCGA) consortium, we analyzed 2,102 samples from 5 different tumor types. In our preliminary results, we identified 143 somatic mutations, 80 in classical HLA-I and 63 in non-classical HLA-I. In classic genes, most mutations (27.5%) occurred in the a3 domain, which could affect the HLA-CD8 interaction. Regarding non-classical genes, the transmembrane domain and the cytoplasmic tail were mostly affected (34.93%), what may interfere in the immunological tolerance mechanism. Finally, we observed that on average 10% of the tumor neoantigens had their presentation hampered by deleterious mutations in HLA. Using a tumor-only strategy we reached a similar mutational frequency observed in the studies using Polysolver (the most used tool in TCGA for HLA somatic screening with paired tumor-normal approach). Our findings indicate that HLA-I point mutations occur in ~6% of the analyzed primary tumors, and ~26% of these have the potential to affect tumor immunogenicity. Our pipeline may contribute to the implementation of HLA somatic diagnosis in precision oncology, as several commercial comprehensive cancer gene panels includes HLA Class I genes, but none reports mutations due to methodological limitations in tumor-only analyses. We are currently correlating our findings to clinical data.

Title of the Event: X-Meeting / BSB 2023
City of the Event: Curitiba
Title of the Proceedings of the event: X-Meeting presentations
Name of the Publisher: Even3
Means of Dissemination: Meio Digital

How to cite

MUNIZ, Amanda et al.. ARE SOMATIC SNVS/INDELS IN HLA CLASS-I GENES A FREQUENT MUTATIONAL MECHANISM IN PRIMARY TUMORS?.. In: X-Meeting presentations. Anais...Curitiba(PR) Campus da indústria, 2023. Available in: https//www.even3.com.br/anais/xmeeting2023/636975-ARE-SOMATIC-SNVSINDELS-IN-HLA-CLASS-I-GENES-A-FREQUENT-MUTATIONAL-MECHANISM-IN-PRIMARY-TUMORS. Access in: 10/08/2025

Paper