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.

Table 2 Clinico-pathological characteristics of Lynch syndrome

Clinico-pathological characteristics
The onset of colorectal cancer (CRC) occurs at an early age (average 45 yr)
Predilection to develop proximal (right-sided) colon cancer
High risk of multiple primary colorectal tumors (synchronous or metachronous)
Specific pathological features of lynch syndrome-related colorectal tumors:
Poorly differentiated
Mucinous
Signet-cell features
Crohn’s-like lymphocytic reaction
Excess of tumor-infiltrating lymphocytes
Increased survival (in patients with CRC)
Accelerated carcinogenesis
Increased risk of cancer at extracolonic sites:
Endometrium
Ovary
Stomach
Small bowel
Hepatobiliary tract
Pancreas
Upper uroepithelial tract
Brain (Turcot’s syndrome)
Sebaceous adenomas, carcinomas and keratoacanthomas (Muir-Torre syndrome)

Table 3 Clinical characteristics of familial adenomatous polyposis

Clinical characteristics
Hundreds to thousands of colonic adenomatous polyps (on average beginning at age 16 yr)1
Colorectal cancer (100% penetrance if not treated; average age 39 yr)1
Other gastrointestinal polyps and malignant lesions:
Fundic gland polyps in the stomach
Adenomatous polyps in the stomach and small bowel
Periampullary carcinoma
Duodenal cancer
Congenital hypertrophy of the retinal pigmented epithelium (CHRPE)
Other less common manifestations:
Embryonal tumors (hepatoblastoma and medulloblastoma)
Pancreatobiliary carcinoma
Papillary thyroid carcinoma (especially cribriform-morular variant)
Adrenal cortical tumors
Gardner syndrome subtype (specific characteristics):
Colonic adenomatous polyposis
Desmoid tumors
Epithelial inclusion cysts
Osteoid osteomas
Supernumerary and/or impacted teeth
CHRPE
Turcot syndrome subtype (specific characteristics):
Colonic adenomatous polyposis
Tumors of the central nervous system (medulloblastoma)

¹AFAP: Patients have 10-100 colorectal adenomas. Polyps develop preferentially in the proximal colon, and the onset of colorectal cancer (CRC) occurs 10-15 years later than in patients with classic familial adenomatous polyposis. The cumulative risk of CRC by age 80 years is estimated to be approximately 70%.

Table 4 Clinical characteristics of individuals with suspected MUYTH-associated polyposis

Clinical characteristics
One to ten colonic adenomas before 40 yr of age
Tens to hundreds of colonic adenomas and/or hyperplastic polyps
Colonic polyposis (i.e., > 100 colonic polyps) in the absence of a germline APC mutation
Colorectal cancer with the somatic KRAS mutation c.34G>T in codon 12
Family history of colon cancer (with or without polyps) consistent with autosomal recessive inheritance

The definitive diagnosis is confirmed by the presence of a biallelic MUTYH mutation. APC: Adenomatous polyposis coli.

Table 5 Clinical characteristics of the PTEN hamartoma tumor syndrome

Clinical characteristics
Benign neoplasia
Dermatologic
Palmoplantar keratoses
Trichilemmomas
Lipomas
Fibromas
Freckling of the glans penis
Vascular anomalies/hemangiomas
Lhermitte-Duclos (dysplastic gangliocytoma of the cerebellum)
Genitourinary tumors/malformations
Colorectal polyposis
Mucosal lesions
Thyroid goiter/nodules
Proliferative breast changes
Malignant neoplasia
Breast cancer
Non-medullary thyroid cancer
Renal cancer
Endometrial cancer
Colorectal cancer
Melanoma
Central nervous system
Macrocephaly
Autism/developmental delay
Dysmorphic characteristics
Dolichocephaly
Postaxial polydactyly

Table 6 Genetic variants identified using candidate-gene association studies

Gene	Variant	Frequency in controls	OR (95%CI)	Cumulative evidence of association	Ethnicity
MUTYH	Biallelic mutation	0.01%	10.19 (5.0-22.0)	Strong	Caucasian
MUTYH	G382D (rs36053993)	0.00%	6.49 (2.6-10.4)	Strong	Caucasian
MUTYH	Y165C (rs34612342)	0.01%	3.32 (1.1-9.8)	Strong	Caucasian
APC	I1307K (rs1801155)	6.80%	1.96 (1.4-2.8)	Strong	Ashkenazi
CHEK2	1100delC	0.71%	1.88 (1.3-2.7)	Strong	Caucasian
CHEK2	I157T (rs17879961)	3.91%	1.56 (1.3-1.8)	Strong	Caucasian
MLH1	rs1800734 (promoter)	21.11%	1.51 (1.3-1.7)	Strong	Caucasian
DNMT3B	rs1569686 (promoter)	16.99%	0.57 (0.5-0.7)	Strong	All
GSTM1	Present/null	50.64%	1.10 (1.0-1.2)	Moderate	All
TERT	rs2736100 (intron 2)	49.34%	1.07 (1.0-1.1)	Moderate	Caucasian

Genetic variants identified using candidate-gene association studies, significantly associated with a risk of colorectal cancer in meta-analyses and showing strong and moderate cumulative evidence of association according to Venice criteria and false-positive report probability tests[189].

Table 7 Clinical criteria established for the identification of serrated polyposis

Clinical criteria
At least five serrated polyps proximal to the sigmoid colon, two of which are larger than 10 mm in diameter
Any number of serrated polyps occurring proximally to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis
More than 20 serrated polyps of any size distributed throughout the colon

Diagnosis is made when one of the criteria is fulfilled.