Current status of familial gastrointestinal polyposis syndromes

Table 1 The molecular profile and geographic particularities of inherited gastrointestinal cancer-predisposing syndromes[1-36]

Name of the syndrome	Mutated genes	Type of mutation	Geographic particularities
FAP	APC: Exon 15 - first half (54% of patients with FAP)	Classic phenotype: mutations between codons 178 and 309, and between 409 and 1580 (exons 5-8 and 9-14)	NS
		Germline truncation (C > T), especially at codons 1309 and 1061:
		Nonsense mutations (28%)
		Small insertions (10%)
		Small deletions (46%)
	APC: Chromosome arms 5q, 8p, 17p and 18q	LOH	NS
	β-catenin: Exon 3 (15%)	NS	NS
	APC/β-catenin (28%)	NS	NS
	K-ras: Codon 12 (3%) - associated mutation	GGT to TGT/GTT	NS
Gardner syndrome	APC: Long arm of chromosome 5	Interstitial deletion	NS
	APC: Patients with congenital hypertrophy of the retinal pigment epithelium	Truncating mutations between codons 311 and 1465	NS
	APC: Patients with desmoid tumor	Downstream codon 1400 (1445-2011)	NS
	APC: Patients with gastro-duodenal adenomas	Mutations at the 3’ before codon 1395 and between codons 564 and 1493	NS
	APC: Patients with hepatoblastomas	Mutations at the 5’ to the mid region between codons 141 and 1751	NS
	APC: Patients with thyroid tumors	Mutations between codons 140 and 1309	NS
AFAP	APC	Somatic G:C→T:A	NS
	APC: Exons 3 and 4 (5’ end of the gene), exon 9, and the very 3’ end of the gene beyond codon 1595	Truncating mutation	NS
	APC: Variants	Missense mutations I1307 K N1026S E1317Q	I1307K: almost exclusively in Ashkenazi Jewish descendents - detected in 6% of all family members, with 10%-20% lifetime risk of developing CRC
			N1026S: Identified in one Spanish AFAP family (all members)
			E1317Q: NS
MUTYH-associated polyposis	MUTYH: Located on the chromosome 1p34.3-p32.1, contains 16 exons	Germline biallelic inactivation	Absent in Asia (Japan, Taiwan, South Korea)
		Missense mutations: p.Y179C - exon 7 (c.536A > G; p.Tyr179Cys ) p.G396D - exon 13 (c.1187g > A;p.Gly396Asp)	Specific for Eastern, Southern, and Central Europe, North America, European inhabitants from Canada, and Sephardi Jews Absent in Finland, India, Pakistan, Tunisia, Singapore, and Ashkenazi Jewish
		Missense mutation p.Ala385ProfsX23	Specific for Northern Europe
		p.E410GfsX43	Specific for Tunisia
		Missense mutation p.Y104X	Specific for Pakistan
		Missense mutation p.E480X	Specific for India
	MUTYH variants	Heterozygous mutations	Asia (Japan, Taiwan, South Korea): p.Arg19; p.Arg109Trp; p.Gly286Glu
			Southern Europe: p.Glu480del Pakistan: p.Tyr104 India: p.Glu480
	K-ras: Codon 12 - associated mutation (64%), usually in patients with sessile serrated adenomas	c.34G > T	NS
Juvenile polyposis syndrome (pure type)	MADH4/SMAD4/DPC4: Chromosome 18q21.1 (30%)	NS	NS
	BMPR1A: Chromosome 10q23 (20%-30%)	Large deletions	NS
	Other genes (49%)	NS	NS
	ENG: exons 11, 12
	PTEN: chromosome 10q23.3
Juvenile polyposis + hemorrhagic telangiectasia	MADH4/SMAD4/DPC4: Chromosome 18q21.1 STK11: Chromosome 19p13.3 or 19q13.4 (50%-94%)	NS	NS NS
		NS
Peutz-Jeghers syndrome	TGF-βPTEN: Chromosome 10q23.3	NS	NS
Peutz-Jeghers syndrome + primary pulmonary hypertension	ALK1/ACVRL1	NS	NS
		NS	NS
Cowden syndrome	PTEN: Chromosome 10q23.3 (13-85%)	Nonsense mutations missense mutations frameshift mutations Large deletions	NS
Bannayan-Riley-Ruvalcaba syndrome	PTEN: Chromosome 10q23.3 (60%-65%)	NS	NS
Hereditary mixed polyposis syndrome	BMPR1A: Chromosome 10q23	NS	NS
	GREM1	NS	NS
Li-Fraumeni syndrome – classic type	p53: Exons 4-9 (23%-50%)	NS	NS
Unclassified/unexplained polyposis syndromes (50%)	PTEN: Chromosome 10q23.3	Nonsense mutations missense mutations frameshift mutations	NS
	Other genes: BMPR2, ACRV1, SMAD1, SMAD2, SMAD3, SMAD5, SMAD7 (22%)	NS	NS

FAP: Familial adenomatous polyposis; BMPR: Bone morphogenetic protein receptor; CRC: Colorectal cancer; ENG: Endoglin; FAP: Familial adenomatous polyposis syndrome; LOH: Loss of heterozygosity; NS: Non-specified; TGF: Transforming growth factor.