Genetic predisposition to colorectal cancer: Where we stand and future perspectives

Table 1 Hereditary colorectal cancer genes, major associated syndromes, modes of inheritance, types of mutations identified and specific molecular characteristics of associated tumors

Gene	Syndrome	Inheritance	Mutations reported	Tumor molecular features
MLH1	Lynch syndrome	Autosomal dominant	Point mutations1	MMR deficiency (MSI)
			Large rearrangements
			CpG island methylation
MSH2	Lynch syndrome	Autosomal dominant	Point mutations	MMR deficiency (MSI)
			Large rearrangements
			CpG island methylation2
MSH6	Lynch syndrome	Autosomal dominant	Point mutations	MMR deficiency (MSI)
			Large rearrangements
PMS2	Lynch syndrome	Autosomal dominant	Point mutations	MMR deficiency (MSI)
			Large rearrangements
EPCAM	Lynch syndrome	Autosomal dominant	Large rearrangements2	MMR deficiency (MSI)
APC	(Attenuated) familial adenomatous polyposis	Autosomal dominant	Point mutations	-
		De novo mutations	Large rearrangements
		Mosaicisms	ASE (deep-intronic and promoter mutations)
MUTYH	MUTYH-associated polyposis	Recessive	Point mutations	Base excision repair deficiency: KRAS c.34G>T
			Large rearrangements
POLE	Polymerase proofreading-associated polyposis	Autosomal dominant	Point mutations (exonuclease domain)	Hypermutated: excess of G:C>T:A transversions
POLD1	Polymerase proofreading-associated polyposis	Autosomal dominant	Point mutations (exonuclease domain)	Hypermutated: excess of G:C>T:A transversions
GREM1	Hereditary mixed polyposis	Autosomal dominant	40-kb upstream duplication3	-
SMAD4	Juvenile polyposis	Autosomal dominant	Point mutations	-
			Large rearrangements
BMPR1A	Juvenile polyposis	Autosomal dominant	Point mutations	-
			Large rearrangements
STK11	Peutz-Jeghers	Autosomal dominant	Point mutations	-
			Large rearrangements
PTEN	PTEN hamartoma tumor4	Autosomal dominant	Point mutations	-
			Large rearrangements
			Promoter

¹Point mutations include missense, non-sense, frameshift and splice-site mutations and small intragenic deletions/insertions;

²MSH2 germline CpG island methylation occurs secondary to EPCAM deletions;

³Founder Ashkenazi mutation;

⁴PTEN hamartoma tumor syndrome includes Cowden, Bannayan-Riley-Ruvalcaba, PTEN-related Proteus and Proteus-like syndromes. ASE: Allele-specific expression; MMR: DNA mismatch repair; MSI: Microsatellite instability.