Revisit of Field Cancerization in Squamous Cell Carcinoma of Upper Aerodigestive Tract: Better Risk Assessment with Epigenetic Markers

Abstract

We quantified field cancerization of squamous cell carcinoma in the upper aerodigestive tract with epigenetic markers and evaluated their performance for risk assessment. Methylation levels were analyzed by quantitative methylation-specific PCR of biopsied specimens from a training set of 255 patients and a validation set of 224 patients. We also measured traditional risk factors based on demographics, lifestyle, serology, genetic polymorphisms, and endoscopy. The methylation levels of four markers increased stepwise, with the lowest levels in normal esophageal mucosae from healthy subjects without carcinogen exposure, then normal mucosae from healthy subjects with carcinogen exposure, then normal mucosae from cancer patients, and the highest levels were in cancerous mucosae (P < 0.05). Cumulative exposure to alcohol increased methylation of homeobox A9 in normal mucosae (P < 0.01). Drinkers had higher methylation of ubiquitin carboxyl-terminal esterase L1 and metallothionein 1M (P < 0.05), and users of betel quid had higher methylation of homeobox A9 (P ¼ 0.01). Smokers had increased methylation of all four markers (P < 0.05). Traditional risk factors allowed us to discriminate between patients with and without cancers with 74% sensitivity (95% CI: 67%-81%), 74% specificity (66%-82%), and 80% area under the curve (67%-91%); epigenetic markers in normal esophageal mucosa had values of 74% (69%-79%), 75% (67%-83%), and 83% (79%-87%); and both together had values of 82% (76%-88%), 81% (74%-88%), and 91% (88%-94%). Epigenetic markers done well in the validation set with 80% area under the curve (73%-85%). We concluded that epigenetics could improve the accuracies of risk assessment.

Molecular Pathways: Involvement of Helicobacter pylori–Triggered Inflammation in the Formation of an Epigenetic Field Defect, and Its Usefulness as Cancer Risk and Exposure Markers

“…In the case of esophageal adenocarcinoma, the presence of APC and CDKN2A methylation in Barrett's metaplasia has been reported (33), and such methylation was shown to be associated with progression of Barrett's metaplasia (34). Also in the case of esophageal squamous cell carcinoma, methylation of specific genes, such as UCHL1 and HOXA9, in esophageal mucosae was associated with the risk of developing esophageal squamous cell carcinoma (35,36). In ulcerative colitis, the driver gene CDKN2A and passenger genes such as MYOD and ESR were shown to be methylated in colonic mucosae, which are predisposed to colon cancers (37,38).…”

“…A history of smoking is associated with methylation of UCHL1 and HOXA9, which are also considered to be passengers, in esophageal mucosae (35,36). Once the specificity of methylation signatures to various carcinogenic agents is clarified, past exposure to such carcinogenic factors can be estimated by the methylation signature.…”

Epidemiology and Molecular Biology of Head and Neck Cancer

“…Field cancerization is associated with traditional risk factors and insufficient alcohol metabolism [22,23], and several studies support the assumption that the majority of HPV-negative but not HPV-positive HNSCC develop within local fields of premalignant cells [1]. Indeed, almost no recurrences were found in high-risk patients after postoperative radiochemotherapy whose tumors were positive for HPV [24].…”

How Close Are We to Real Time Optical Margin Control in Head and Neck Oncologic Surgery?

“…In fact even the concept that tumors grow radially and that resecting a certain distance from the tumor will "ensure negative margins" is a flawed concept [4,5] . Even the concept of "negative margins" while seeming to be conceptually obvious, is technically highly variable in real practice due to sampling issues during specimen submission, pathological processing errors, and the fact that tumor cells may often be left within the surgical bed despite the fact that the final pathology report has a negative margin designation [6,7] . What has been shown, with significant reliability, is that No surface imaging ability * Specificity varied when combining targeted and morphologic criteria vs. either alone.…”