Exome sequencing of oral leukoplakia and oral squamous cell carcinoma implicates DNA damage repair gene defects in malignant transformation

Camile S. Farah, Maryam Jessri, Nigel C. Bennett, Andrew J. Dalley, Kate D. Shearston, Simon A. Fox

Research output: Contribution to journalArticle

1 Citation (Scopus)

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, BRCA2 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).

Original languageEnglish
Pages (from-to)42-50
Number of pages9
JournalOral Oncology
Volume96
DOIs
Publication statusPublished - 1 Sep 2019

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Oral Leukoplakia
Exome
DNA Repair
DNA Damage
Squamous Cell Carcinoma
Fanconi Anemia
Genes
Discriminant Analysis
Least-Squares Analysis
Mutation Rate
Neoplasms
Multivariate Analysis
Immunohistochemistry
Mutation

Cite this

@article{7e8ca7bdf4614c90962f3e4f8dd09376,
title = "Exome sequencing of oral leukoplakia and oral squamous cell carcinoma implicates DNA damage repair gene defects in malignant transformation",
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, BRCA2 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).",
keywords = "BRCA1, DNA damage repair, Double strand break, Fanconi anaemia, Malignant transformation, Oral cancer, Oral dysplasia, Oral leukoplakia, Progression to cancer, Whole exome sequencing",
author = "Farah, {Camile S.} and Maryam Jessri and Bennett, {Nigel C.} and Dalley, {Andrew J.} and Shearston, {Kate D.} and Fox, {Simon A.}",
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Exome sequencing of oral leukoplakia and oral squamous cell carcinoma implicates DNA damage repair gene defects in malignant transformation. / Farah, Camile S.; Jessri, Maryam; Bennett, Nigel C.; Dalley, Andrew J.; Shearston, Kate D.; Fox, Simon A.

In: Oral Oncology, Vol. 96, 01.09.2019, p. 42-50.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Exome sequencing of oral leukoplakia and oral squamous cell carcinoma implicates DNA damage repair gene defects in malignant transformation

AU - Farah, Camile S.

AU - Jessri, Maryam

AU - Bennett, Nigel C.

AU - Dalley, Andrew J.

AU - Shearston, Kate D.

AU - Fox, Simon A.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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, BRCA2 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).

AB - 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, BRCA2 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).

KW - BRCA1

KW - DNA damage repair

KW - Double strand break

KW - Fanconi anaemia

KW - Malignant transformation

KW - Oral cancer

KW - Oral dysplasia

KW - Oral leukoplakia

KW - Progression to cancer

KW - Whole exome sequencing

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U2 - 10.1016/j.oraloncology.2019.07.005

DO - 10.1016/j.oraloncology.2019.07.005

M3 - Article

VL - 96

SP - 42

EP - 50

JO - Oral Oncology

JF - Oral Oncology

SN - 1368-8375

ER -