Comprehensive Assessment of Diet Quality and Risk of Precursors of Early-Onset Colorectal Cancer

Xiaobin Zheng, MD, PhD; Jinhee Hur, PhD; Long H. Nguyen, MD, MS; Jie Liu, MD; Mingyang Song, MD, ScD; Kana Wu, MD, PhD; Stephanie A. Smith-Warner, PhD; Shuji Ogino, MD, MS, PhD; Walter C. Willett, MD, DrPH; Andrew T. Chan, MD, MPH; Edward Giovannucci, MD, ScD; Yin Cao, MPH, ScD


J Natl Cancer Inst. 2021;113(5):543-552. 

In This Article

Abstract and Introduction


Background: The role of poor diet quality in the rising incidence of colorectal cancer (CRC) diagnosed younger than age 50 years has not been explored. Based on molecular features of early-onset CRC, early-onset adenomas are emerging surrogate endpoints.

Methods: In a prospective cohort study (Nurses' Health Study II), we evaluated 2 empirical dietary patterns (Western and prudent) and 3 recommendation-based indexes (Dietary Approaches to Stop Hypertension DASH, Alternative Mediterranean Diet [AMED], and Alternative Healthy Eating Index [AHEI]-2010) with risk of early-onset adenoma overall and by malignant potential (high-risk: ≥1 cm, tubulovillous or villous histology, high-grade dysplasia, or ≥3 adenomas), among 29 474 women with 1 or more lower endoscopy before age 50 years (1991–2011). Multivariable logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: We documented 1157 early-onset adenomas with 375 at high risk. Western diet was positively associated, whereas prudent diet, DASH, AMED, and AHEI-2010 were inversely associated with risk of early-onset adenoma. The associations were largely confined to high-risk adenomas (the highest vs lowest quintile: Western, OR = 1.67, 95% CI = 1.18 to 2.37; prudent, OR = 0.69, 95% CI = 0.48 to 0.98; DASH, OR = 0.65, 95% CI = 0.45 to 0.93; AMED, OR = 0.55, 95% CI = 0.38 to 0.79; AHEI-2010, OR = 0.71, 95% CI = 0.51 to 1.01; all P trend ≤ .03), driven by those identified in the distal colon and rectum (all P trend ≤ .04, except AMED: P trend = .14).

Conclusion: Poor diet quality was associated with an increased risk of early-onset distal and rectal adenomas of high malignant potential. These findings provide preliminary but strong support to the role of diet in early-onset CRC.


Despite falling sharply or leveling off in older adults,[1] colorectal cancer (CRC) has increased among young adults aged younger than 50 years (early-onset) in 9 high-income countries over the past 2 decades, including the United States. Largely driven by the rise in distal colon and rectal tumors,[1,2] early-onset CRCs are diagnosed at more advanced stages with more aggressive clinicopathological characteristics compared with CRC diagnosed at older ages.[3] In contrast to the vast accumulated evidence on the etiopathogenesis of older-onset CRC,[4] risk factors for early-onset CRC remain largely unknown.

Poor diet quality has been linked to elevated risk of older-onset CRC.[5–8] Increasing evidence points to hyperinsulinemia,[9] chronic inflammation,[10] and gut dysbiosis[11–13] as the plausible mechanisms linking diet and CRC. Prior evidence on obesity and sedentary behaviors has indirectly implicated the role of lifestyle factors, likely tied to unhealthy diet, in the etiology of early-onset CRC.[14,15] In the United States, diet quality declined steadily between 1985 and 2006[16] and has remained stable thereafter. Further, diet quality among younger adults is consistently poorer compared with the older population.[17] Based on data from the National Health and Nutrition Examination Survey 1999–2016, the estimated overall diet quality of younger individuals in the United States showed modest improvement, but more than half of youth still had poor-quality diets.[18] Yet, the health impact of poorer diet among the younger population, including its role in early-onset colorectal neoplasia, has not been well examined, in part because of the lack of cohort studies that followed younger adults for an extensive period of time with validated dietary assessment.

The majority (approximately 80%) of early-onset CRCs exhibits microsatellite stable (MSS) phenotypes,[19,20] leading to the postulation that adenomas but not serrated polyps are the precursors of early-onset CRC. In a recent analysis from the Genetics and Epidemiology of Colorectal Cancer Consortium,[21] compared with CRC diagnosed after age 65 years, early-onset CRC was more likely to present with a molecular subtype (MSS or microsatellite instability low, non-CpG island methylator phenotype, BRAF and KRAS wild type) arising from the adenoma-carcinoma sequence.[22] These findings lend additional support to the etiological relevance of adenomas, particularly those of high-malignant potential,[23] in understanding the etiology of early-onset CRC.

We therefore conducted a comprehensive analysis in the Nurses' Health Study II (NHSII) to elucidate the role of diet quality, as measured by empirical dietary patterns as well as recommendation-based indexes, in early-onset CRC using early-onset adenoma and that of high-malignant potential as surrogate endpoints. The NHSII, a well-established, large, ongoing prospective cohort of young women with detailed documentation of endoscopic history and indications and family history, as well as validated assessment of dietary intake and lifestyle factors, provides a unique opportunity to address these knowledge gaps.