Early-onset colorectal cancer: A separate subset of colorectal cancer

Table 1 Main pathways involved in the onset and development of colorectal cancer

	Chromosomal instability or “suppressor” pathway	Microsatellite instability or “mutator” pathway	CpG island methylator phenotype or “serrated” pathway
Percentage of CRC	80%-85%	10%-15%	40%
Clinical characteristics	Predominant location of tumor in the distal colon	Predominant location of tumor in the right colon	Predominant location of tumor in the right colon
		Better prognosis	Female sex
Histopathologic characteristics	No lymphocytic reactions	Lymphocytic reactions	Low-grade tumor differentiation
	No mucinous features	Mucinous features
	Good differentiation	Signet ring cells
		Low-grade tumor differentiation
Molecular characteristics	Aneuploidy, polyploidy, loss of heterozygosity	Diploidy, MSI	Methylation of CpG islands
Main genes involved	APC, P53, KRAS, C-MYC, DCC/SMAD4, TGFBR, PIK3CA	MLH1, MSH2,	BRAF, MSI
		MSH6, PMS2,
		TGF-βRII, IGFIIR,
		MSH3 and BAX
Hereditary syndromes	Familial adenomatous polyposis	Lynch syndrome

CRC: Colorectal cancer; MSI: Microsatellite instability.

Table 2 Main features of molecular classification

Category	CRC	Characteristics
		Molecular	Histopathologic	Clinical
MSI/CIMP-high	10%	MLH1 methylation	Poor differentation	Predominant location of tumor in right colon
		BRAF mutations	Lymphocytic reaction	Elderly females
			Mucinous/signet ring cells	Sporadic MSI
MSI/CIMP-low/0	5%	MMR	Lymphocytic reaction	LS
		Negative for BRAF mutations	Mucinous features
			No signet ring cells
			Good or moderate differentation
MSS/CIMP-high	5%-10%	BRAF mutations and methylation of multiple other genes	Poor differentation	Predominant location of tumor in right colon
			Signet ring cell	Elderly females
MSS/CIMP-low/0	75%-80%	CIN	Well differentiated	Predominant location of tumor in distal colon
		KRAS mutations	Heterogeneous	Male sex

CIMP: CpG island methylator phenotype; CIN: Chromosomal instability; CRC: Colorectal cancer; LS: Lynch syndrome; MMR: Mismatch repair; MSI: Microsatellite instability; MSS: Microsatellite stability

Table 3 Proportion of microsatellite instability in early-onset colorectal cancers series and their age of onset

Study	Age of CRC onset, yr	Population	MSI, n (%)
Losi et al[9]	≤ 45	Unselected CRC surgical patients	71 (19.7)
Liang et al[10]	≤ 40	Unselected CRC surgical patients	138 (40.5)
Perea et al[11]	≤ 45	Unselected CRC surgical patients	88 (13.6)
Jasperson et al[50]	< 36	Hereditary cancer registries	96 (29.1)
Durno et al[51]	< 25	Familial cancer registry	16 (72.7)
Farrington et al[52]	< 30	Cancer registries	50 (47.5)
Antelo et al[66]	< 50	Cancer registry	118 (22.9)

CRC: Colorectal cancer; MSI: Microsatellite instability.