Since the 1990s, the incidence of early-onset colorectal cancer (at <50 years of age) in the US has increased by more than 50%; similar increases have also been observed internationally. These increases are found particularly among individuals born during and after the 1960s, raising the possibility that the increased rates of early-onset colorectal cancer are attributable to changes in risk-factor patterns throughout successive generations. The reasons for these alarming epidemiologic patterns for early-onset colorectal cancer worldwide are only recently being investigated and major gaps in our knowledge remain. In the current issue of this journal, Arif and colleagues differentiated characteristics and outcomes of early-onset colorectal cancer in patients with the predisposing conditions of inflammatory bowel disease or hereditary genetic syndromes, compared with patients who have sporadic disease. Also, in this issue, Schumacher and colleagues investigated risk factors for early-onset colorectal adenocarcinoma in a nested case-control study among Kaiser Permanente Southern California (KPSC) health plan members. The research presented on characteristics and outcomes points to the importance of sporadic disease in the rise of early-onset colorectal cancer, while the research presented on risk factors points to the importance of obesity as a potential explanatory factor for this rise.

See related articles by Arif et al., p. 1785 and by Schumacher et al., p. 1792

Since the 1990s, the incidence of colorectal cancer in the United States has decreased overall by more than 35%, at a similar rate across all racial groups, largely due to the success of early detection. By contrast, clinically-diagnosed colorectal cancer incidence rates at less than 50 years of age (early-onset colorectal cancer) increased by more than 50% (1). Early-onset colorectal cancer typically exhibits higher pathologic grade and a greater risk of recurrence and metastatic disease (2); although, these differentials may largely be due to diagnostic delay (3), with evidence suggesting that survival is better than for older cases, when stage at diagnosis is considered (4). Initially, increasing trends of early-onset colorectal cancer were largely limited to cancers of the rectum; however, recent data from 2012 to 2016 show 1.8% annual increases for tumors in the proximal and distal colon as well, contributing to the current overall 2.2% annual increase in the U.S. in early-onset colorectal cancer (5).

Racial and ethnic disparities are prominent in early-onset colorectal cancer (6). U.S. blacks overall have a 20% higher incidence of colorectal cancer and experience 40% greater mortality (5). The recent trend of increasing incidence of early-onset colorectal cancer is greater, however, for non-Hispanic whites (2% per year) than for blacks and Asian/Pacific Islanders (0.5% per year, mostly due to rectal cancer). The result of these trends is that early-onset colorectal cancer incidence rates are now equivalent in blacks and non-Hispanic whites, despite the 40% higher incidence rates in young blacks during 1995 to 1996. Furthermore, young American Indians/Alaskan Natives also are experiencing increases in colorectal cancer, similar to non-Hispanic whites.

Beyond the United States, there are at least 8 other high-income countries across North America, Europe, and Oceania where rates of colorectal cancer in young adults are increasing while rates in older adults are stable or declining (7). The pattern of increasing rates internationally for early-onset colorectal cancer has been observed particularly among individuals born during and after the 1960s, suggesting that the differential rates over time may be attributable to changes in risk-factor patterns throughout successive generations. Provocatively, 2011 to 2016 U.S. data now show rising trends for distal colon and rectal cancer at 50 to 64 years of age, consistent with a promotion of the early-onset disease pattern to intermediate ages, as the birth cohorts beginning in the 1960s progress through the life course (5).

The reasons for these alarming epidemiologic patterns for early-onset colorectal cancer worldwide are under intense study, yet major gaps in our knowledge remain. As reported in this issue of Cancer Epidemiology, Biomarkers and Prevention, Arif and colleagues differentiated characteristics and outcomes of early-onset colorectal cancer in patients with the predisposing conditions of inflammatory bowel disease (IBD; 4.1%) or hereditary genetic syndromes (6.8%), in contrast to patients with sporadic disease (89.1%), in a population-based cohort of 2,135 patients with early-onset colorectal cancer in British Columbia. Predisposing conditions were most common in the youngest cases (≤29 years, 34.3%). Compared with sporadic disease, patients with IBD presented more often with synchronous metastatic disease and experienced poorer survival, while patients with genetic syndromes had metastatic disease less often and experienced better survival, particularly among those with the hereditary Lynch syndrome. The study revealed a particularly poor prognosis for early-onset IBD-related tumors, in contrast to the experience previously reported with later-onset IBD-related tumors, which tend to have a clinical course similar to that of sporadic disease (8). In comparison with early-onset colorectal cancer related to predisposing conditions, Arif and colleagues found that sporadic cases occurred more often at older ages, were more likely female, and more often exhibited increased body mass index.

The findings by Arif and colleagues in British Columbia on early-onset colorectal cancer related to high-risk predisposing conditions are largely in agreement with earlier research (9, 10). The strength of the Arif and colleagues study is its comprehensive, population-based inclusion of a large series of more than 2,100 early-onset colorectal cancer cases that were diagnosed province-wide between 1990 and 2016, encompassing the period of overall increase in early-onset colorectal cancer in several high-income countries, including Canada (11). Genetic syndromes (12) and common genetic variants (13) are more strongly associated with early-onset than late-onset colorectal cancer, but temporal trends in these population traits are unlikely to account for the rapid secular changes being observed in the incidence of early-onset colorectal cancer. There is evidence that IBD is increasing worldwide (14); however, the relative proportion of early-onset colorectal cancer linked to IBD remains small and is also unlikely to contribute substantially to the observed increases in early-onset disease. This contribution by Arif and colleagues helps focus our attention on the majority sporadic cases and temporal trends in environmental exposures as a possible explanation for the rise in early-onset colorectal cancer.

Also reported in this issue, Schumacher and colleagues investigated risk factors for early-onset colorectal adenocarcinoma in a nested case-control study among Kaiser Permanente Southern California (KPSC) health plan members (ages 15–49, 2008–2018), using data from the KPSC cancer registry and electronic health records. KPSC is an integrated health care delivery system serving over 4.4 million members broadly representative of the diverse population of southern California. The study included 1,032 early-onset cases and 5-fold matched controls. Subjects with IBD were excluded, and genetic syndromes were not specifically evaluated. The risk of early-onset colorectal adenocarcinoma was significantly associated with obesity (as also found by Arif and colleagues for sporadic compared with predisposition-related cases), but not with diabetes, hypertension, or dyslipidemia. Stratified by tumor location, obesity was significantly associated with risk of colon adenocarcinoma, but its association with rectal adenocarcinoma was less clear.

Obesity has also been related to early-onset colorectal cancer in meta-analysis (15); some inconsistent results, particularly in case-control studies (16), might be driven by reverse causality resulting from weight loss prior to colorectal-cancer diagnosis. The prevalence of obesity among US adults began to rise dramatically in the 1980s to a degree paralleling the temporal rise by successive birth cohorts in occurrence of early-onset colorectal cancer. Obesity increases have impacted all racial groups in the United States, with evidence that the increase in some obesity measures have recently plateaued among blacks (17). Worldwide increases in obesity are potentially related to increased sedentary behavior, higher consumption of calorie-rich foods and suboptimal diet quality, insufficient sleep, environmental exposure to endocrine disrupting chemicals, as well as multilevel social and environmental factors (17).

Understanding the scope, clinical consequences, and underlying causes of early-onset colorectal cancer is critical for colorectal cancer control. The research presented in this issue on characteristics and outcomes points to the importance of sporadic disease in the rise of early-onset colorectal cancer, while the research presented on risk factors points to the importance of obesity as a potential explanatory factor for this rise. Of course, colorectal cancer is multifactorial, and we already have indication from a first wave of epidemiologic studies that early-onset colorectal cancer could be linked (in addition to obesity) to sedentary lifestyle, poor diet, including elevated consumption of red and processed meat and sugar-sweetened beverages and reduced consumption of vegetables and citrus fruit, as well as to greater alcohol use, smoking, reduced aspirin use, metabolic factors, and diabetes mellitus (16, 18–26).

Perhaps there is a single key-factor that accounts for the rise in early-onset colorectal cancer, and worldwide increases in obesity could be that “smoking gun.” It could also be that parallel changes in several components of the multifactorial risk profile are operative, without any single-causal agent dominating. We also need to consider factors, particularly at an early age, that have yet received little attention in epidemiologic study of early-onset colorectal cancer, such as novel exposure to endocrine disrupters and other recently-introduced environmental chemicals, early exposure to antibiotics and other bioactive drugs, broad environmental influences on the gut microbiome, and the potential role of genetic and epigenetic interrelationships.

Further research, including in international consortia (16, 23) over the life-course and in diverse populations, promises to provide deeper understanding of the causes of early-onset colorectal cancer and the reasons for its recent rise. Improved understanding of these risks will be critical for primary prevention and could improve strategies for early detection (27) of the potentially large pool of preclinical colorectal cancer (and premalignant disease) in people younger than 50 years of age (28, 29).

R.B. Hayes reports grants from NCI during the conduct of the study; and grants from NCI outside the submitted work. No other disclosures were reported.

This work was supported by grants from NCI (to R.B. Hayes).

1.
Stoffel
EM
,
Murphy
CC
. 
Epidemiology and mechanisms of the increasing incidence of colon and rectal cancers in young adults
.
Gastroenterology
2020
;
158
:
341
53
.
2.
Yeo
H
,
Betel
D
,
Abelson
JS
,
Zheng
XE
,
Yantiss
R
,
Shah
MA
. 
Early-onset colorectal cancer is distinct from traditional colorectal cancer
.
Clin Colorectal Cancer
2017
;
16
:
293
9
.
3.
Dharwadkar
P
,
Greenan
G
,
Singal
AG
,
Murphy
CC
. 
Is colorectal cancer in patients younger than 50 years of age the same disease as in older patients?
Clin Gastroenterol Hepatol
2021
;
19
:
192
-+.
4.
Cheng
E
,
Blackburn
HN
,
Ng
K
,
Spiegelman
D
,
Irwin
ML
,
Ma
X
, et al
Analysis of survival among adults with early-onset colorectal cancer in the National Cancer Database
.
JAMA Netw Open
2021
;
4
:
e2112539
.
5.
Siegel
RL
,
Miller
KD
,
Goding Sauer
A
,
Fedewa
SA
,
Butterly
LF
,
Anderson
JC
, et al
Colorectal cancer statistics, 2020
.
CA Cancer J Clin
2020
;
70
:
145
64
.
6.
Acuna-Villaorduna
AR
,
Lin
J
,
Kim
M
,
Goel
S
. 
Racial/ethnic disparities in early-onset colorectal cancer: implications for a racial/ethnic-specific screening strategy
.
Cancer Med
2021
;
10
:
2080
7
.
7.
Siegel
RL
,
Torre
LA
,
Soerjomataram
I
,
Hayes
RB
,
Bray
F
,
Weber
TK
, et al
Global patterns and trends in colorectal cancer incidence in young adults
.
Gut
2019
;
68
:
2179
85
.
8.
Reynolds
IS
,
O'Toole
A
,
Deasy
J
,
McNamara
DA
,
Burke
JP
. 
A meta-analysis of the clinicopathological characteristics and survival outcomes of inflammatory bowel disease associated colorectal cancer
.
Int J Colorectal Dis
2017
;
32
:
443
51
.
9.
Bogach
J
,
Pond
G
,
Eskicioglu
C
,
Seow
H
. 
Age-related survival differences in patients with inflammatory bowel disease-associated colorectal cancer: a population-based cohort study
.
Inflamm Bowel Dis
2019
;
25
:
1957
65
.
10.
Dominguez-Valentin
M
,
Sampson
JR
,
Seppala
TT
,
ten Broeke
SW
,
Plazzer
JP
,
Nakken
S
, et al
Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database
.
Genet Med
2020
;
22
:
15
25
.
11.
O'Sullivan
DE
,
Hilsden
RJ
,
Ruan
Y
,
Forbes
N
,
Heitman
SJ
,
Brenner
DR
. 
The incidence of young-onset colorectal cancer in Canada continues to increase
.
Cancer Epidemiol
2020
;
69
:
101828
.
12.
Stigliano
V
,
Sanchez-Mete
L
,
Martayan
A
,
Anti
M
. 
Early-onset colorectal cancer: a sporadic or inherited disease?
World J Gastroenterol
2014
;
20
:
12420
30
.
13.
Archambault
AN
,
Su
YR
,
Jeon
J
,
Thomas
M
,
Lin
Y
,
Conti
DV
, et al
Cumulative burden of colorectal cancer associated genetic variants is more strongly associated with early-onset vs late-onset cancer
.
Gastroenterology
2020
;
158
:
1274
86
.
14.
Wark
G
,
Samocha-Bonet
D
,
Ghaly
S
,
Danta
M
. 
The role of diet in the pathogenesis and management of inflammatory bowel disease: a review
.
Nutrients
2020
;
13
:
135
.
15.
O'Sullivan
DE
,
Sutherland
RL
,
Town
S
,
Chow
K
,
Fan
J
,
Forbes
N
, et al
Risk factors for early-onset colorectal cancer: a systematic review and meta-analysis
.
Clin Gastroenterol Hepatol
2021
;
29
:
S1542
3565
.
16.
Archambault
AN
,
Lin
Y
,
Jeon
J
,
Harrison
TA
,
Bishop
DT
,
Brenner
H
, et al
Nongenetic determinants of risk for early-onset colorectal cancer
.
JNCI Cancer Spectr
2021
;
5
:
pkab029
.
17.
Liu
B
,
Du
Y
,
Wu
Y
,
Snetselaar
LG
,
Wallace
RB
,
Bao
W
. 
Trends in obesity and adiposity measures by race or ethnicity among adults in the United States 2011–18: population based study
.
BMJ
2021
;
372
:
n365
.
18.
Brockway-Lunardi
L
,
Nelson
S
,
Pandiri
AR
,
Tricoli
JV
,
Umar
A
,
Wali
A
, et al
Early-onset colorectal cancer research: gaps and opportunities
.
Colorectal Cancer
2020
;
9
.
19.
Burnett-Hartman
AN
,
Lee
JK
,
Demb
J
,
Gupta
S
. 
An update on the epidemiology, molecular characterization, diagnosis, and screening strategies for early-onset colorectal cancer
.
Gastroenterology
2021
;
160
:
1041
9
.
20.
Chen
H
,
Zheng
X
,
Zong
X
,
Li
Z
,
Li
N
,
Hur
J
, et al
Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer
.
Gut
2021
;
70
:
1147
54
.
21.
Holowatyj
AN
,
Perea
J
,
Lieu
CH
. 
Gut instinct: a call to study the biology of early-onset colorectal cancer disparities
.
Nat Rev Cancer
2021
;
21
:
339
40
.
22.
Hur
J
,
Otegbeye
E
,
Joh
HK
,
Nimptsch
K
,
Ng
K
,
Ogino
S
, et al
Sugar-sweetened beverage intake in adulthood and adolescence and risk of early-onset colorectal cancer among women
.
Gut
2021 May 6 [Epub ahead of print]
.
23.
Murphy
N
,
Campbell
PT
,
Gunter
MJ
. 
Unraveling the etiology of early-onset colorectal cancer
.
J Natl Cancer Inst
2021
;
113
:
505
6
.
24.
Yue
Y
,
Hur
J
,
Cao
Y
,
Tabung
FK
,
Wang
M
,
Wu
K
, et al
Prospective evaluation of dietary and lifestyle pattern indices with risk of colorectal cancer in a cohort of younger women
.
Ann Oncol
2021
;
32
:
778
86
.
25.
Otegbeye
EE
,
Colditz
GA
,
Cao
Y
. 
Prevention of early-onset colorectal cancer: not one size fits all
.
JNCI Cancer Spectr
2021
;
5
:
pkab030
.
26.
Zaborowski
AM
,
Abdile
A
,
Adamina
M
,
Aigner
F
,
d'Allens
L
,
Allmer
C
, et al
Characteristics of early-onset vs late-onset colorectal cancer: a review
.
JAMA Surg
2021
Jun 30 [Epub ahead of print]
.
27.
Knudsen
AB
,
Rutter
CM
,
Peterse
EFP
,
Lietz
AP
,
Seguin
CL
,
Meester
RGS
, et al
Colorectal cancer screening: an updated modeling study for the US Preventive Services Task Force
.
JAMA
2021
;
325
:
1998
2011
.
28.
Abualkhair
WH
,
Zhou
M
,
Ahnen
D
,
Yu
Q
,
Wu
XC
,
Karlitz
JJ
. 
Trends in incidence of early-onset colorectal cancer in the United States among those approaching screening age
.
JAMA Netw Open
2020
;
3
:
e1920407
.
29.
Kolb
JM
,
Hu
J
,
DeSanto
K
,
Gao
D
,
Singh
S
,
Imperiale
T
, et al
Early-age onset colorectal neoplasia in average risk individuals undergoing screening colonoscopy: a systematic review and meta-analysis
.
Gastroenterology
2021
Jun 10 [Epub ahead of print]
.