Dietary Polyunsaturated Fat Intake in Relation to Head and Neck, Esophageal, and Gastric Cancer Incidence in the National Institutes of Health–AARP Diet and Health Study

Shawn A. Zamani; Kathleen M. McClain; Barry I. Graubard; Linda M. Liao; Christian C. Abnet; Michael B. Cook; Jessica L. Petrick


Am J Epidemiol. 2020;189(10):1096-1113. 

In This Article

Abstract and Introduction


Recent epidemiologic studies have examined the association of fish consumption with upper gastrointestinal cancer risk, but the associations with n-3 and n-6 polyunsaturated fatty acid (PUFA) subtypes remain unclear. Using the National Institutes of Health–AARP Diet and Health Study (United States, 1995–2011), we prospectively investigated the associations of PUFA subtypes, ratios, and fish with the incidence of head and neck cancer (HNC; n = 2,453), esophageal adenocarcinoma (EA; n = 855), esophageal squamous cell carcinoma (n = 267), and gastric cancer (cardia: n = 603; noncardia: n = 631) among 468,952 participants (median follow-up, 15.5 years). A food frequency questionnaire assessed diet. Multivariable-adjusted hazard ratios were estimated using Cox proportional hazards regression. A Benjamini-Hochberg (BH) procedure was used for false-discovery control. Long-chain n-3 PUFAs were associated with a 20% decreased HNC and EA risk (for HNC, quintile5 vs. 1 hazard ratio = 0.81, 95% confidence interval: 0.71, 0.92, and BH-adjusted P trend = 0.001; and for EA, quintile5 vs. 1 hazard ratio = 0.79, 95% confidence interval: 0.64, 0.98, and BH-adjusted P trend = 0.1). Similar associations were observed for nonfried fish but only for high intake. Further, the ratio of long-chain n-3:n-6 was associated with a decreased HNC and EA risk. No consistent associations were observed for gastric cancer. Our results indicate that dietary long-chain n-3 PUFA and nonfried fish intake are associated with lower HNC and EA risk.


Polyunsaturated fatty acids (PUFAs) are fatty acids containing more than 1 double bond. Fish and other marine meats are rich sources of n-3 PUFAs, which have antiinflammatory properties and suppress tumor progression for several cancer types.[1–4] In contrast, n-6 PUFAs, which are primarily found in nonmarine oil-rich diets, exhibit carcinogenic properties.[5] The n-3 PUFAs can competitively inhibit n-6 PUFAs, which results in modulation of inflammation, cellular proliferation, apoptosis, angiogenesis, and metastasis.[6] Thus, a higher n-3:n-6 PUFA ratio might be associated with a reduced risk of developing cancer.

Upper gastrointestinal (UGI) cancers represent an etiologically diverse group of cancers and can be divided by histologic classifications (i.e., squamous cell carcinoma or adenocarcinoma). Head and neck cancers (HNCs) are squamous cell carcinomas that occur in the oral cavity, pharynx, or larynx.[7] Primary risk factors for HNCs include tobacco use and alcohol consumption.[8–11] Esophageal cancer includes squamous cell carcinoma (ESCC), which can occur throughout the esophagus, and adenocarcinoma (EA), which typically develops near the gastroesophageal junction.[12,13] As with HNCs, the primary risk factors for ESCC are tobacco use and alcohol consumption.[14] In addition to tobacco use,[15] gastroesophageal reflux disease[16] and obesity[17] are the primary risk factors for EA. Gastric cancers are categorized into cardia and noncardia adenocarcinomas (GCA and NCGA, respectively).[18] Risk factors for GCA are similar to EA,[15–17] while primary risk factors for NCGA include Helicobacter pylori infection[18] and tobacco use.[14] Worldwide, ESCC and NCGA account for most types of esophageal and gastric cancer. In the United States and other Western countries, incidence of EA and GCA cases has rapidly increased.[12,13] However, prognosis remains poor for all of these cancers.[19,20]

Recent epidemiologic studies have examined the association of fish, total PUFAs, and n-3 fatty acid intake with risk of UGI cancers,[21–23] but the associations with n-3 and n-6 fatty acid subtypes (e.g., α-linolenic acid and linoleic acid), PUFA intake ratio (i.e., n-3:n-6), or fish high in n-3 versus n-6 fatty acids remain unclear. Clarifying these associations might elucidate the underlying etiology. Thus, we prospectively investigated the association of dietary PUFA subtypes, ratios, and fish with the incidence of head and neck, esophageal, and gastric cancers using the National Institutes of Health (NIH)-AARP Diet and Health Study.