A decades-long health detective story is uncovering why a remote province has some of the highest esophageal cancer rates in the world.
In the Golestan Province of northeastern Iran, a medical mystery has puzzled scientists since the 1970s. Here, in communities nestled near the Caspian Sea, rates of oesophageal cancer are among the highest ever recorded worldwide 1 . The puzzle deepened when researchers discovered that just 300 kilometers away, the incidence of the same cancer was dramatically lower 2 .
What hidden factor—whether in the environment, diet, or lifestyle—could explain this stark disparity? The answer required an ambitious scientific undertaking: the Golestan Cohort Study, a landmark research project that has been tracking the health of 50,000 Iranians for over a decade 1 6 . This is the story of how a long-term investment in science is unraveling a medical mystery and saving lives.
The earliest clues emerged in the 1970s with the establishment of a population-based cancer registry. The data revealed a shocking concentration of oesophageal cancer in the eastern portion of the Caspian Sea littoral, an area now known as Golestan Province 1 .
Initial investigations pointed to several potential culprits, including a diet deficient in fruits and vegetables, low socioeconomic status, thermal injury from consuming very hot tea, and exposure to carcinogens from opium consumption 1 2 . Yet these early studies were inconclusive, and research was prematurely halted in 1978 due to political upheaval 2 . The mystery remained unsolved for decades.
To reopen the investigation, an international collaboration was formed in the early 2000s involving the Digestive Disease Research Center of Tehran University of Medical Sciences, the International Agency for Research on Cancer, and the US National Cancer Institute 1 2 . Their ambitious plan: to establish a prospective cohort study tracking 50,000 healthy individuals aged 40-75 years in Golestan Province 1 .
Aetiological hypotheses related to diet and lifestyle can be best addressed in prospective cohort studies, where measurement error can be reduced and recall bias is minimal 1 . Before committing to the full study, researchers conducted a pilot study from 2002 to 2003 involving 1,057 subjects 2 . This feasibility study confirmed that the research was logistically possible and that the local population was willing to participate, with a remarkable 78.4% participation rate 2 .
Participation Rate in Pilot Study
By January 2004, the main Golestan Cohort Study was launched. The research team employed innovative methods to recruit participants from both urban and rural areas, taking advantage of Iran's network of rural health houses staffed by auxiliary health personnel called Behvarz 1 . The goal was to enroll a population that was 80% rural and 74% of Turkmen ethnicity, reflecting the demographics of the high-risk area 1 .
| Characteristic | All Participants | Urban | Rural | Turkmen Ethnicity | Non-Turkmen |
|---|---|---|---|---|---|
| All Participants | 100% | 20.0% | 80.0% | 74.4% | 25.6% |
| Men | 21,241 (42.4%) | 18.5% | 81.5% | 75.6% | 24.4% |
| Women | 28,804 (57.6%) | 21.2% | 78.8% | 73.6% | 26.4% |
Each participant underwent extensive baseline assessment, including interviews using structured questionnaires on lifestyle and diet, a limited physical examination, and collection of blood, urine, hair, and nail samples 1 . These biological samples were processed and stored at -80°C, creating a valuable biospecimen bank for future molecular and genetic studies 1 .
After years of patient follow-up and data analysis, the Golestan Cohort Study began yielding crucial insights. The findings confirmed some long-suspected risk factors while uncovering new ones.
One of the most distinctive cultural practices in the region is tea consumption. The study confirmed that drinking very hot tea (≥70°C) significantly increases the risk of oesophageal cancer 2 . Researchers developed a reliable method to measure tea temperature, finding that the simple habit of consuming tea at lower temperatures could substantially reduce cancer risk.
The study provided compelling evidence about the carcinogenic effects of opium use. A 2025 analysis from the cohort revealed that both smoking and opium use dramatically increase the risk of gastrointestinal cancers, but that cessation can significantly reduce this risk 7 .
| Substance Use Status | Risk of Oesophageal Cancer (Hazard Ratio) |
|---|---|
| Smoking | |
| Current/Recent Quitters | 1.53 (1.14-2.07) |
| Long-Term Quitters (>5 years) | 0.68 (0.47-0.99) |
| Opium Use | |
| Current/Recent Quitters | 1.50 (1.20-1.88) |
| Long-Term Quitters (>5 years) | 0.33 (0.12-0.90) |
The data shows that while current users and recent quitters face elevated cancer risks, long-term quitters of both substances experience substantial risk reductions 7 . For opium users who quit for more than five years, the risk of oesophageal cancer was reduced by a remarkable 67%.
A separate 2023 analysis calculated the population attributable fractions—the proportion of cancers caused by these substances. The findings were striking: using opium and/or cigarettes was estimated to cause 13% of all cancers in this population, with the combined exposure having the greatest impact on cancers of the larynx, pharynx, lung, and bladder .
While analyses are ongoing, the study continues to investigate the role of dietary patterns, oral health, genetic predisposition, and other environmental factors in oesophageal cancer development 1 . The rich dataset and biospecimen collection continue to enable new discoveries, including a 2020 metabolomics study that identified specific biochemical perturbations in opium users that may contribute to cancer development 4 .
The Golestan Cohort Study employed a multifaceted approach to uncover these findings. Below are some of the essential "tools" that have made this research possible.
| Research Component | Function and Application |
|---|---|
| Structured Questionnaires | Comprehensive interviews covering demographics, medical history, lifestyle factors (tobacco, opium, alcohol use), and tea drinking habits, including temperature measurement 1 2 . |
| Food Frequency Questionnaire (FFQ) | A validated dietary assessment tool covering 116 food items specific to the local cuisine, used to evaluate nutritional patterns 1 . |
| Biospecimen Collection | Blood, urine, hair, and nail samples processed and stored at ultra-low temperatures (-80°C) for molecular and genetic analyses 1 4 . |
| Cancer Registry Linkage | Monthly reviews of the Golestan Cancer Registry and Atrak Clinic databases to identify new cancer cases among participants 1 9 . |
| Active Follow-up Procedures | Annual follow-up with participants via phone or home visits to track health status, hospitalizations, and new disease diagnoses 1 9 . |
| Metabolomics Analysis | Advanced techniques using UPLC-MS and NMR spectroscopy to identify biochemical perturbations associated with risk factors like opium use 4 . |
Blood, urine, hair, and nail samples stored at -80°C for analysis.
Comprehensive interviews covering lifestyle and medical history.
Monthly reviews to identify new cancer cases among participants.
While initially focused on oesophageal cancer, the Golestan Cohort has evolved into a valuable resource for studying a range of health conditions. A 2025 publication used the cohort data to assess risk factors for lung cancer, confirming that smoking, opium consumption, and use of non-gas fuels for heating and cooking are significant risk factors 9 . The study found the age and sex-adjusted incidence rate of lung cancer was 18.78 per 100,000 person-years, with markedly higher rates in males (32.19) than females (9.42) 9 .
The cohort has also contributed to our understanding of the metabolic consequences of opium use. A 2020 study analyzing urine samples from 218 opium users and 80 non-users revealed that opium consumption disrupts multiple biochemical pathways, including those involving vitamins and co-factors, neurotransmission, Krebs cycle, and purine metabolism 4 .
The Golestan Cohort Study represents more than just a cancer investigation—it provides a model for population-based studies in countries undergoing economic and social transition 1 . Its success demonstrates the power of collaboration between local health workers, local health authorities, national research centres, and international institutions 1 .
The study has also influenced cancer screening and prevention. Recent clinical trials are now testing less invasive screening methods, such as the EsoGuard test—a balloon-based cell collection device that could make esophageal cancer screening more accessible 8 . These advances build upon the risk factor identification made possible by the Golestan Cohort.
As the study continues, with participants being followed for a minimum of 10 years (and now well beyond that), its database continues to yield insights 1 . Each year of follow-up adds statistical power to detect smaller effects and rarer outcomes, ensuring that this long-term investment in population health will continue to pay dividends for years to come.
The Golestan Cohort stands as a testament to the power of persistent, methodical science to solve complex health mysteries—and to the potential of international collaboration to address health challenges that transcend borders.