Characterization and Identification of Colorectal Cancer in Persons younger than 50 Years

Introduction:

The proportion of colorectal cancer (CRC) in persons under 50, early-onset CRC (EOCRC), has increased from 6% to 11% over the past 25 years, while the incidence of CRC has fallen in persons ≥50, or late-onset CRC (LOCRC) in the United States¹. It is not known if EOCRC is caused by the same factors that cause LOCRC or whether there are unique causes that alter the clinical features². This study was designed to analyze the clinical and genetic characteristics of EOCRC as presented at a community hospital.

Methods:

This is an observational Institutional Review Board-approved study of patients with CRC, ages 18–49 years, diagnosed between January 2006 and May 2017, taken from the registry of the Scripps Green Hospital in La Jolla, CA. Details of the methods and the comparative cohorts have been previously reported³. Evaluation of tumor tissue for defective DNA mismatch repair (MMR) activity was by immunohistochemistry (IHC) and/or microsatellite instability (MSI) and, if positive, by testing for germline mutations in DNA MMR genes.

Results:

The registry contained 127 cases with EOCRC, and 18 were excluded. The ages ranged from 20–49 (mean, 42.8, median 44); 53% were women; 81% Caucasians, 16% Asians, and 4% African-Americans. Family history (FH) of CRC was positive in 38 (35%); 15 (14%) had ≥1 first degree relative (FDR) with CRC, 23 (21%) had ≥1 second degree relative (SDR); one (0.9%) was positive for both 1 FDR and 2 SDRs (Table 1). Ten of 99 tested had defective DNA MMR activity (10%). Eight underwent germline testing; a deleterious mutation in a DNA MMR gene indicating Lynch syndrome was confirmed in 5 (2 in MLH1, and 1 each in MSH2, MSH6 and PMS2); 3 had suspected deleterious mutations (2 in MSH2 and 1 in PMS2); 2 did not have detectable germline mutations. BMI indicated 31 (28%) were overweight and 33 (30%) were obese. Twelve (11%) were active smokers, 13 (12%) past-smokers; six reported moderate to excessive drinking; seven were diabetic.

Table 1.

Comparison of characteristics between persons with early-onset versus late-onset, screen-detected and late-onset, symptom-detected colorectal cancer.

	Early-onset (N=109)	Late-onset* screen-detected (N=66)	p-value†	Late-onset* symptom-detected (N=351)	p-value‡
Age	42.8 ± 5.2	62.7 ± 9.6	--	71.3 ± 11.0	--
Sex			0.015		0.669
Male	47.2%	66.2%		49.6%
Female	52.8%	33.8%		50.4%
Body mass index (kg/m2)§			0.098
Ideal (≤24)	41.7%	25.8%		--	--
Overweight (25–29)	27.8%	37.9%		--	--
Obese (≥30)	30.6%	36.4%		--	--
Race			0.117		0.005
Caucasian	80.7%	92.3%		91.4%
Asian	15.6%	6.2%		7.8%
African American	3.7%	1.5%		0.9%
Family historyǁ			0.296		0.917
Yes	13.8%	8.3%		14.2%
No	86.2%	91.7%		85.8%
Cancer location			<0.001		<0.001
Proximal colon	22.0%	51.5%		47.3%
Distal colon	78.0%	48.5%		52.7%
Stage of disease¶			<0.001		0.182
Early	36.7%	69.7%		43.9%
Late	63.3%	30.3%		56.1%

Data presented as mean ± standard deviation or percentage.

^*Data for the two late-onset colorectal cancer cohorts taken from reference 13.

^†p-value for comparison between early-onset and late-onset, screen-detected cohort

^‡p-value for comparison between early-onset and late-onset, symptom-detected cohort

^§Body mass index for late-onset cases only available for screen-detected persons (n=66).

^ǁFamily history defined as having one or more 1^st degree relatives diagnosed with colorectal cancer

^¶Stage of disease defined as early (stage 0-2A) and late (stage 2B-4)

The dominant indicator leading to diagnosis was rectal bleeding in 67 (61%), moderate-to-severe abdominal pain in 29 (27%), iron-deficiency anemia in 6 (6%), persistent change in bowel habit in 5 (5%), and positive FH in 2 (2%). Of 67 persons presenting with bleeding, 63 (94%) had a distal cancer. The location of CRC was distal for 86 (79%), including 48 (44%) in the rectum.

Stage of disease was early in 40 (37%) and late in 69 (63%), and 30 (28%) were diagnosed with stage IV disease. Median duration of symptoms in early versus late-stage CRC was 5.0 months and 4.0 months with mean (and range) of 6.7 (0.1–36) months and 9.4 (0.1– 120) months, respectively.

The features of EOCRC were compared to the 2 cohorts of LOCRC; significant differences were noted for more distal cancer location (p < 0.001 versus both cohorts), increased late-stage disease (p< 0.001 versus the screen-detected LOCRC cohort), more women (p=0.015 versus the screen-detected LOCRC cohort), and more non-Caucasians (p=0.038 and p=0.002 versus the screen-detected and symptom-detected LOCRC cohorts, respectively (Table 1).

In a logistic regression model, distal location and non-Caucasian race predicted EOCRC; persons with a distal cancer were 3.4 times more likely to be diagnosed with EOCRC compared to persons with a proximal tumor (p<0.001); non-Caucasians were 2.9 times more likely to be diagnosed with EOCRC than Caucasians (p=0.001).

Discussion:

The incidence and mortality of EOCRC is steadily rising as the incidence in persons ≥50 is falling. A critical question is whether EOCRC is part of the continuum of CRC in younger people, or whether it includes cancers that are biologically different from LOCRC. It has been repeatedly shown that no more than 15–20% of EOCRC tumors have defective DNA MMR activity, reflecting Lynch syndrome or Lynch-like syndrome, compared to 10–15% overall^{4, 5}. EOCRC has distinctive clinical features including bleeding and abdominal pain in 86–98%, distal location, presentation at advanced stages, shorter interval from the onset of symptoms to diagnosis for advanced stages, and worse overall survival⁶.

Studies using multigene panels have demonstrated the range of germline mutations in CRC^{7, 8}. In EOCRC, about 10–20% of the tumors have defective DNA MMR activity; about half are Lynch syndrome, and the other half have double somatic mutations in MMR genes (Lynch-like syndrome). Another 2–3% are linked to FAP and its variants, and ~2–3% to other hereditary cancer genes^{7, 8}. The causes for the remaining 80% of cases of EOCRC are not known.

In May 2018, the American Cancer Society initiated a qualified recommendation for average-risk adults to begin screening at age 45 years². It remains to be seen whether the number of patients needed to screen to prevent one CRC death will be acceptable and whether this approach will save lives.