Extremely High Tp53 Mutation Load in Esophageal Squamous Cell Carcinoma in Golestan Province, Iran

Behnoush Abedi-Ardekani,Christian C Abnet,Stephen M Hewitt,Pierre Hainaut,Dariush Nasrollahzadeh,Karim Aghcheli,Farhad Islami,Farin Kamangar,Noushin Taghavi,Reza Malekzadeh,Farrokh Saidi,Sanford M Dawsey,Paolo Boffetta,Saman Fahimi,Stephanie Villar,Masoud Sotoudeh,Paul Brennan,Hassan Ashktorab

doi:10.1371/journal.pone.0029488

Abstract

BackgroundGolestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC.Methodology/Principal FindingsBiopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 “hotspots” but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence.Conclusion/SignificanceESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis.

Highlights

Esophageal Cancer is common in Persia at least since the writings of the famous Iranian physician Avicenna (980– 1037), who provided one of the earliest descriptions of this disease [1]
We report the highest rate of somatic TP53 mutations ever reported for any cancer, further supporting the notion that esophageal squamous cell carcinoma (ESCC) in this area develops as the consequence of heavy exposure to environmental mutagens, and providing molecular clues for potentially preventable risk factors
The mean age and the sex distribution are in agreement with data previously reported from Golestan, where there is an approximately equal incidence of ESCC in males and females [16]

Summary

Introduction

Esophageal Cancer is common in Persia (current Iran) at least since the writings of the famous Iranian physician Avicenna (980– 1037), who provided one of the earliest descriptions of this disease [1]. Several authors have documented this pathology in a broad region extending from the eastern shores of the Caspian Sea to Central China, forming the ‘‘Central Asian Esophageal Cancer Belt’’ [2] This region concentrates over half of the cases of esophageal squamous cell carcinoma (ESCC) detected in the world [2]. In Golestan, tobacco and alcohol do not seem to play a prominent role [5,6] and the best documented risk factors are the consumption of hot beverages [7], low socio-economic status [8] and, possibly, cultural or lifestyle habits such as the use of opium derivatives [5,9] These risk factors only partially explain the high incidence rates, and the main carcinogen(s) involved have not been identified. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC

Methods

Results

Conclusion