Recurrent genomic alterations in sequential progressive leukoplakia and oral cancer: drivers of oral tumorigenesis?

Abstract

A significant proportion (up to 62%) of oral squamous cell carcinomas (OSCCs) may arise from oral potential malignant lesions (OPMLs), such as leukoplakia. Patient outcomes may thus be improved through detection of lesions at a risk for malignant transformation, by identifying and categorizing genetic changes in sequential, progressive OPMLs. We conducted array comparative genomic hybridization analysis of 25 sequential, progressive OPMLs and same-site OSCCs from five patients. Recurrent DNA copy number gains were identified on 1p in 20/25 cases (80%) with minimal, high-level amplification regions on 1p35 and 1p36. Other regions of gains were frequently observed: 11q13.4 (68%), 9q34.13 (64%), 21q22.3 (60%), 6p21 and 6q25 (56%) and 10q24, 19q13.2, 22q12, 5q31.2, 7p13, 10q24 and 14q22 (48%). DNA losses were observed in >20% of samples and mainly detected on 5q31.2 (35%), 16p13.2 (30%), 9q33.1 and 9q33.29 (25%) and 17q11.2, 3p26.2, 18q21.1, 4q34.1 and 8p23.2 (20%). Such copy number alterations (CNAs) were mapped in all grades of dysplasia that progressed, and their corresponding OSCCs, in 70% of patients, indicating that these CNAs may be associated with disease progression. Amplified genes mapping within recurrent CNAs (KHDRBS1, PARP1, RAB1A, HBEGF, PAIP2, BTBD7) were selected for validation, by quantitative real-time PCR, in an independent set of 32 progressive leukoplakia, 32 OSSCs and 21 non-progressive leukoplakia samples. Amplification of BTBD7, KHDRBS1, PARP1 and RAB1A was exclusively detected in progressive leukoplakia and corresponding OSCC. BTBD7, KHDRBS1, PARP1 and RAB1A may be associated with OSCC progression. Protein–protein interaction networks were created to identify possible pathways associated with OSCC progression.

Risk analysis of malignant potential of oral verrucous hyperplasia: A follow‐up study of 269 patients and copy number variation analysis

“…In contrast, we observed several distinct pathways in progressive oral verrucous hyperplasia. For example, Cervigne et al found amplification of BTBD7, KHDRBS1, PARP1 , and RAB1A in progressive leukoplakia and corresponding OSCC, however, we did not find these genes in progressive oral verrucous hyperplasia. In addition, we found that there was no published study addressing the role of folate receptors (FRs) in OSCC, but we identified amplification of FOLR1 (FRα ), FOLR2 (FRβ ), and FOLR3 (FRγ ) in progressive oral verrucous hyperplasia.…”

“…Therefore, we conducted a genetic analysis of copy number variations in progressive oral verrucous hyperplasias and OSCCs from the same patients in an attempt to identify potential driver changes associated with malignant transformation of progressive oral verrucous hyperplasias. Our results showed that progressive oral verrucous hyperplasia already possessed many genetic changes present in OSCC, which agrees with previous findings that the majority of genetic alterations arise at oral precursor lesions and in the early stage of head and neck cancer . Using a bioinformatics analysis, we mapped potential pathways that lead to the malignant transformation of oral verrucous hyperplasia (Supporting Information Figure S5).…”

“…This is because many oncogenes are localized in this region, including the C CND1‐FGF19‐FGF4‐FGF3 gene cluster, CTTN , and ORAOV1 . In addition, we found several common copy number variation regions between progressive oral verrucous hyperplasia and leukoplakia, including 1p35, 1p36, 11q13, 6p21, 14q22, and 22q12 . The evidence also indicates that regardless of the etiologies, certain common copy number variations are associated with malignant transformation of oral potentially malignant disorders.…”

Oral leukoplakia remains a challenging condition

“…Oral dysplasias are associated with a significant rate of malignant transformation (5%–36%) (Cowan et al., ; Hsue et al., ; Lian Ie et al., ; Liu et al., ; Lumerman et al., ; Silverman et al., ), yet the underlying molecular mechanisms and pathways involved in oral cancer development have not been fully elucidated (Warnakulasuriya & Ariyawardana, ). Recent research suggests that the progression from dysplasia into invasive cancer, based on models established at other sites (e.g., melanoma and cervical cancer), involves a stepwise accumulation of genetic and epigenetic alterations (including somatic gene mutations, DNA double‐strand breaks, and copy‐number alterations) (Cervigne et al., ; Jessri, Dalley, & Farah, ; Vogelstein & Kinzler, ). The main steps that lead to the development of cancer include a breakthrough phase, an expansion phase, and an invasive phase (Kuffer & Lombardi, ; Vogelstein & Kinzler, ; Woo, Cashman, & Lerman, ).…”

Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1

“…Other genes containing Tra2α/Tra2β target exons with G2 and S phase checkpoint that is essential in many cancer cells to prevent damaged chromosomes from entering mitosis [38] Vigilin (HDLBP) Represses proto-oncogene c-fms in breast cancer [43][44][45] KDM5A, KDM3A Histone methylases, erase epigenetic information, tumour promoters [46,47] NCOA Chromatin remodeling protein involved in breast cancer [48] ATRX Frequently mutated in paediatric cancer [49] SMC4 Key role in lung cancer, over-expressed in liver cancer [50,51] Nap1L1…”