Exome sequencing of oral leukoplakia and oral squamous cell carcinoma implicates DNA damage repair gene defects in malignant transformation. (September 2019)

• Record Type: Journal Article
• Authors: Farah, Camile S.; Jessri, Maryam; Bennett, Nigel C.; Dalley, Andrew J.; Shearston, Kate D.; Fox, Simon A.
• Is Part Of: Oral oncology. Volume 96(2019)
• Page Start: 42
• Page End: 50
• Publication Date: 2019-09
• Subjects: Oral leukoplakia -- Oral dysplasia -- Progression to cancer -- Oral cancer -- Malignant transformation -- Whole exome sequencing -- BRCA1 -- Fanconi anaemia -- DNA damage repair -- Double strand break; Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2019.07.005
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: BRCA1 /2 variants are significant discriminators of malignant progression. FA/BRCA pathway is implicated in malignant transformation of oral epithelial dysplasia. Variants in DNA damage repair genes can be used to predict malignant progression. Abstract: Objectives: To map the genomic pathways of patients with oral leukoplakia (OLK) which transformed to cancer (progressive) and those which did not (non-progressive), and to compare their exomic profiles. Materials and methods: Whole exome sequencing was performed on 42 sequential samples from five progressive and eight non-progressive patients. Association of genomic variant frequencies with progression or lesion severity were analysed by non-parametric tests (Kruskal-Wallis and Mann-Whitney-Wilcoxon) and multivariate sparse partial least squares discriminant analysis (sPLS-DA). Enrichment analysis was used to characterise the effect of mutations upon biological pathways. Confirmatory studies used qPCR and immunohistochemistry. Results: Using sPLS-DA, the variant frequency of a small number of genes could be used to classify the samples based on lesion severity or progressive status. Enrichment analysis showed that DNA damage repair gene related pathways were highly impacted in lesions which progressed to cancer. Multivariate analysis of a set of 148 DNA damage repair genes could be used to classify progressive lesions using mutation frequency. BRCA1, BRCA 2 and other double strand break (DSB) repair Fanconi anaemia (FA)/BRCA pathway genes were prominent contributors to this classification. Conclusion: Patients with progressive and non-progressive OLK can be differentiated using the frequency of exomic variants, particularly in DNA damage repair pathway genes. To our knowledge, this is the first report of FA/BRCA (DSB) pathway involvement in malignant transformation of OLK to oral squamous cell carcinoma (OSCC).