J Pathol. 2022 Mar 31. doi: 10.1002/path.5900. Online ahead of print.
ABSTRACT
A thickened, white patch – leukoplakia – in the oral cavity is usually benign, but sometimes (in ~9% of individuals) progresses to malignant tumour. Because the genomic basis of this progression is poorly understood, we undertook this study and collected samples of four tissues – leukoplakia, tumour, adjacent normal and blood -from each of 28 patients suffering from gingivobuccal oral cancer. We performed multi-omics analysis of the 112 collected tissues (4 tissues per patient from 28 patients) and integrated information on progressive changes in mutational and transcriptional profiles of each patient to create this genomic narrative. Additionally, we generated and analysed whole-exome sequence data from leukoplakia tissues collected from 11 individuals not suffering from oral cancer. Non-synonymous somatic mutations in CASP8 gene were identified as the likely events to initiate malignant transformation, since these were frequently shared between tumour and co-occurring leukoplakia. CASP8 alterations were also shown to enhance expressions of genes that favours lateral spread of mutant cells. During malignant transformation, additional pathogenic mutations are acquired in key genes (TP53, NOTCH1, HRAS) (41% of patients); chromosomal-instability (arm-level deletions of 19p and q, focal-deletion of DNA-repair pathway genes and NOTCH1, amplification of EGFR) (77%) and increased APOBEC-activity (23%) are also observed. These additional alterations were present singly (18% of patients) or in combination (68%). Some of these alterations likely impact on immune-dynamics of the evolving transformed tissue; progression to malignancy is associated with immune suppression through infiltration of regulatory T-cells (56%), depletion of cytotoxic T-cells (68%) and antigen presenting dendritic cells (72%) with concomitant increase in inflammation (92%). Patients can be grouped into three clusters by the estimated time to development of cancer from precancer by acquiring additional mutations (Range: 4-10 years). Our findings provide deep molecular insights into the evolutionary processes and trajectories of oral cancer initiation and progression. This article is protected by copyright. All rights reserved.
PMID:35358331 | DOI:10.1002/path.5900
