Evidence for etiologic field changes in tongue distant from tumor in patients with squamous cell carcinoma of the oral tongue

Abstract

Oral cancer is a paradigm of Slaughter's concept of field cancerization, where tumors are thought to originate within an area of cells containing genetic alterations that predispose to cancer development. The field size is unclear but may represent a large area of tissue, and the origin of mutations is also unclear. Here, we analyzed whole exome and transcriptome features in contralateral tumor-distal tongue (i.e. distant from the tumor, not tumor-adjacent) and corresponding tumor tissues of 15 patients with squamous cell carcinoma of the oral tongue. The number of point mutations ranged from 41 to 237 in tumors and from one to 78 in tumor-distal samples. Tumor-distal samples showed mainly clock-like (associated with aging) or tobacco smoking mutational signatures. Tumors additionally showed mutations that associate with cytidine deaminase AID/APOBEC enzyme activities or a UV-like signature. Importantly, no point mutations were shared between a tumor and the matched tumor-distal sample in any patient. TP53 was the most frequently mutated gene in tumors (67%), whereas a TP53 mutation was detected in only one tumor-distal sample, and this mutation was not shared with the matched tumor. Arm-level copy number variation (CNV) was found in 12 tumors, with loss of chromosome (Chr) 8p or gain of 8q being the most frequent events. Two tumor-distal samples showed a gain of Chr8, which was associated with increased expression of Chr8-located genes in these samples, although gene ontology did not show a role for these genes in oncogenic processes. In situ hybridization revealed a mixed pattern of Chr8 gain and neutral copy number in both tumor cells and adjacent nontumor epithelium in one patient. We conclude that distant field cancerization exists but does not present as tumor-related mutational events. The data are compatible with etiologic field effects, rather than classical monoclonal field cancerization theory.

Field Effect Detection by Light Scattering in the Breast Cancer Risk Determination

“…Exogenous agents include chemicals such as tobacco smoke, physical agents such as ultraviolet radiation, and infectious agents such as Helicobacter pylori, human papillomavirus, and hepatitis B. Endocrine secretions (for example estrogens, testosterone), exocrine secretions (for example gastric acid), and even inherited cancer mutations (BRCA 1,2) constitute the endogenous causal factors of the field effect. 20 Our interpretation of field cancerization was proposed in 2016 as an amplification of biochemical abnormalities in tissues. 21 This interpretation considers that all tissue alteration can be explained as the product of biochemical changes that we call biochemical abnormalities, and normal tissue amplifies, through a complex signaling process, abnormalities initiated by abnormal cells (cancer).…”