AUTHOR=Gong Xiao-yang , Chen Hai-bin , Zhang Li-qing , Chen Dong-sheng , Li Wang , Chen Dong-hui , Xu Jin , Zhou Han , Zhao Le-le , Song Yun-jie , Xiao Ming-zhe , Deng Wang-long , Qi Chuang , Wang Xue-rong , Chen Xi 

TITLE=NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.920253

DOI=10.3389/fimmu.2022.920253

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Patients with early-stage laryngeal cancer, even stage T1-2N0, are at considerable risk of recurrence and death. The genetic and immunologic characteristics of recurrent laryngeal cancer remain unclear.</p></sec><sec><title>Methods</title><p>A total of 52 T1-2N0 laryngeal cancer patients were enrolled. Of these, 42 tissue samples were performed by targeted DNA sequencing, and 21 cases were performed by NanoString immuno-oncology targeted RNA sequencing to identify the distinct molecular bases and immunologic features associated with relapse in patients with early laryngeal cancer, respectively.</p></sec><sec><title>Results</title><p>To the best to our knowledge, we present for the first time an overview of the genomic mutation spectrum of early-stage laryngeal cancers. A total of 469 genomic alterations were detected in 211 distinct cancer-relevant genes, and the genes found to be mutated in more than five patients (&gt;10%) included <italic>tumor protein p53</italic> (<italic>TP53</italic>, 78.5%), <uri xlink:href="https://www.ncbi.nlm.nih.gov/gene/2195" xmlns:xlink="http://www.w3.org/1999/xlink">FAT atypical cadherin 1</uri> (<italic>FAT1</italic>, 26%), <uri xlink:href="https://www.ncbi.nlm.nih.gov/gene/53353" xmlns:xlink="http://www.w3.org/1999/xlink">LDL receptor related protein 1B</uri> (<italic>LRP1B</italic>, 19%), <uri xlink:href="https://www.ncbi.nlm.nih.gov/gene/1029" xmlns:xlink="http://www.w3.org/1999/xlink">cyclin dependent kinase inhibitor 2A</uri> (<italic>CDKN2A</italic>, 17%), <uri xlink:href="https://www.ncbi.nlm.nih.gov/gene/54790" xmlns:xlink="http://www.w3.org/1999/xlink">tet methylcytosine dioxygenase 2</uri> (<italic>TET2</italic>, 17%), <uri xlink:href="https://www.ncbi.nlm.nih.gov/gene/4851" xmlns:xlink="http://www.w3.org/1999/xlink">notch receptor 1</uri> (<italic>NOTCH1</italic>, 12%) and <uri xlink:href="https://www.ncbi.nlm.nih.gov/gene/3084" xmlns:xlink="http://www.w3.org/1999/xlink">neuregulin 1</uri> (<italic>NRG1</italic>, 12%). Recurrent laryngeal cancer demonstrated a higher tumor mutation burden (TMB), as well as higher <italic>LRP1B</italic> mutation and <italic>NOTCH1</italic> mutation rates. Univariate and multivariate analyses revealed that high TMB (TMB-H) and <italic>NOTCH1</italic> mutation are independent genetic factors that are significantly associated with shorter relapse-free survival (RFS). Simultaneously, the results of the transcriptome analysis presented recurrent tumors with <italic>NOTCH1</italic> mutation displayed upregulation of the cell cycle pathway, along with decreased B cells score, T cells score, immune signature score and tumor-infiltrating lymphocytes (TILs) score. The Cancer Genome Atlas (TCGA)-laryngeal cancer dataset also revealed weakened immune response and impaired adhesion functions in <italic>NOTCH1</italic>-mutant patients.</p></sec><sec><title>Conclusions</title><p>Genomic instability and impaired immune response are key features of the immunosurveillance escape and recurrence of early laryngeal cancer after surgery. These findings revealed immunophenotypic attenuation in recurrent tumors and provided valuable information for improving the management of these high-risk patients. Due to the small number of patients in this study, these differences need to be further validated in a larger cohort.</p></sec>