Birth Cohort Colorectal Cancer (CRC): Implications for Research and Practice

Abstract

Colorectal cancer (CRC) epidemiology is changing due to a birth cohort effect, first recognized by increasing incidence of early onset CRC (EOCRC, age <50 years). In this paper, we define "birth cohort CRC" as the observed phenomenon, among individuals born 1960 and later, of increasing CRC risk across successive birth cohorts, rising EOCRC incidence, increasing incidence among individuals aged 50 to 54 years, and flattening of prior decreasing incidence among individuals aged 55 to 74 years. We demonstrate birth cohort CRC is associated with unique features, including increasing rectal cancer (greater than colon) and distant (greater than local) stage CRC diagnosis, and increasing EOCRC across all racial/ethnic groups. We review potential risk factors, etiologies, and mechanisms for birth cohort CRC, using EOCRC as a starting point and describing importance of viewing these through the lens of birth cohort. We also outline implications of birth cohort CRC for epidemiologic and translational research, as well as current clinical practice. We postulate that recognition of birth cohort CRC as an entity-including and extending beyond rising EOCRC-can advance understanding of risk factors, etiologies, and mechanisms, and address the public health consequences of changing CRC epidemiology.

Keywords: AAPI (Asian-American/Pacific Islander); Birth Cohort; Black/African-American; Colorectal Cancer; Diverse/Diversity; Early Onset Colorectal Cancer; Epidemiology; Equity; Hispanic/Latinx; Native American/Indigenous/American Indian; Race/Racial; Racial/Ethnic Disparities; Socioeconomic; White/Caucasian.

Figure 1.. Birth Cohort Colorectal Cancer (CRC).

Birth cohort CRC is defined as the observed phenomenon, among individuals born 1960 and later, of increasing CRC risk across successive birth cohorts, rising early onset CRC incidence, increasing incidence among individuals age 50–54 years, and flattening of prior decreasing incidence among individuals age 55–74 years. Birth cohort CRC is associated with unique features, including increasing rectal (> than colon) cancer and distant (> local) stage CRC diagnosis, and increasing early onset CRC across all racial/ethnic groups.

Figure 2.. Distribution of colorectal cancer cases by age and race/ethnicity in 1992 versus 2019.

Among CRC cases, distribution of age shifted to include more representation of individuals younger than age 60 between 1992 (Panel A) and 2019 (Panel B), and distribution of race/ethnicity shifted to include more representation of individuals from non-Hispanic Black, non-Hispanic Asian/Pacific Islander, non-Hispanic American Indian/Alaska Native, and Hispanic individuals between 1992 (Panel C) and 2019 (Panel D). Data are from the Surveillance Research Program, National Cancer Institute. SEER 12, 1992 – 2019.

Figure 3.. Modeled and observed incidence rates of colorectal cancer for age 50–59 years, overall (A) and by anatomic site (B), stage at diagnosis (C), race and ethnicity (D).

Modeled rate (illustrated with smooth line) estimated with joinpoint regression using Joinpoint Regression Program version 4.9.1 (Surveillance Research Program, National Cancer Institute). SEER 12, 1992 – 2019. Y-axis scale varied to illustrate trend.

Figure 4.. Conceptual framework for interaction between the exposomal and germline genetic factors on somatic alterations to determine colorectal cancer risk.

Exposomal factors such as diet and lifestyle (e.g., alcohol, Western diet), early-life exposures (e.g., mode of delivery, antibiotics), metabolic disorders (e.g., obesity, diabetes) and gut microbiome and metabolites are believed to initiate and/or promote somatic alterations leading to colorectal cancer. Germline genetic factors such as high-penetrance pathogenic variants (e.g., mismatch repair genes in Lynch syndrome) and moderate- to low-penetrance variants (e.g., single nucleotide polymorphisms or SNPs) also drive somatic alterations and carcinogenesis. Based on current evidence, we postulate exposomal factors, possibly mediated through changes in the microbiome, play a larger role than germline genetics in driving somatic alterations and CRC risk, and that gene-by-exposome interactions likely modify somatic alterations and cancer development. Figure created with BioRender.com CRC, colorectal cancer.