Turcot syndrome

Identity

Other names	Malignant tumors of the central nervous system associated with familial polyposis of the colon
Atlas_Id	10026
Genes implicated in	APC  MLH1  MHS6  MSH2  PMS2
Note	Turcot syndrome (TS) is characterized by the association of colonic polyps and central nervous system tumors. The relative risk of cerebral tumor in patients with familial adenomatous polyposis is considered 92 times more that found in the general population. The predominant brain tumors are medulloblastoma and gliomas.
Inheritance	Both autosomal dominant and autosomal recessive modes of inheritance have been described, based on the analysis of familial segregation of the disease and the results of molecular studies. Nevertheless, considering the low penetrance and rarity of TS, the involvement of a major gene in association with a second locus containing a modifier gene or of environmenmtal factors has been suggested.

Clinics

Neoplastic risk

Cardinal findings in TS are colonic polyps with tendency to colorectal cancer and malignant central nervous system tumors. Colonic polyps: Three types of polyposis coli are described to occur in TS: 1) Type 1 is characterized by multiple colonic polyps numbering between 20 and 100, some of which may exceed 3 cm in diameter; 2) Type 2 is characterizd by a small number of colonic polyps, usually less than 10; 3) Type 3 is characterized by numerous small colonic polyps similar to those of classical familial polyposys coli. Based on molecular entities, two groups can differentiated: the one due to mutation in the APC gene (see below), characterized by colonic polyps, the second one due to mutations in the DNA mismatch repair (MMR) genes (see below) and characterized by colorectal adenomas without polyposis. Colorectal cancer: the polyps frequently show malignant transformation in the second and third decades of life. Central nervous system tumors: Two major types of TS are distinguished based on different types of central nervous system tumors. The first one is characterized by childhood cerebellar medullobastoma and the second by gliomas, particularly glioblastoma multiforme, arising in both children and adult. The two different types are related to different molecular pathogenesis. In fact, the first type is caused by mutations in the APC gene (see below), whereas the second type is related to MMR genes mutations (see below). Other: In some instances, patients with TS have additional symptoms characteristic of other genetic conditions with familial polyposis of the coli, including pigmented ocular fundus lesions, epidermal inclusion cysts, osteosclerotic jaw lesions, cafe-au-lait spots or lipomas.

Cytogenetics

Note	Chromosome analysis is generally normal in patients with TS

Genes involved and Proteins

Gene Name	APC (Adenomatous Popyposis of the Colon)
Location	5q21
Note	The APC locus consists of 15 exons

Gene Name	MLH1
Location	3p21.3
Note	The MLH1 locus encompasses approximately 100 kb and consists of 19 exons

Gene Name	PMS2
Location	7p22
Note	The PMS2 locus encompasses 16 kb and consists of 15 exons

Protein

Function

APC: APC seems to be invoved in cell adhesion with a role in the beta-catenin-APC interaction. It is possible that the APC complex regulates transmission of the contact inhibition signal into the cells, since APC mutations are associated with the development of hyperplasia, an early event in tumorigenesis. Alternatively, it is possible that the APC-catenin complex regulates adhesions, since loss of cadherin-mediated adhesion can contribute to metastasis MMR genes: MLH1 and PMS2 are involved in DNA mismatch repair, and neoplasms of affected patients show DNA replication errros.

Mutations

Note

Germline APC mutations are detectable in 2/3 of patients with TS. In the remaining patients, germline mutations in MMR genes can be found. Molecular analysis have shown that heterozygous, homozygous or compound heterozygous mutations may be implicated in TS. TS caused by APC mutations is associated with childhood cerebellar medulloblastoma and colonic polyps, while TS related to MMR genes is associated with glioma and colorectal adenomas without polyposis. Nevertheless, there is a wide clinical heterogeneity among carriers of mutations in the same gene, and even among pedigrees segregating for the same molecular defect. Such variations could be accounted for by genetic or environmental modifiers. PMS2 mutations have been identified in a few families so far, and a very severe phenotype has been described in most of the cases.

Bibliography

The glioma-polyposis syndrome.

Baughman FA Jr, List CF, Williams JR, Muldoon JP, Segarra JM, Volkel JS

The New England journal of medicine. 1969 ; 281 (24) : 1345-1346.

PMID 4311244

Germline hMSH2 and differential somatic mutations in patients with Turcot's syndrome.

Chan TL, Yuen ST, Chung LP, Ho JW, Kwan K, Fan YW, Chan AS, Leung SY

Genes, chromosomes & cancer. 1999 ; 25 (2) : 75-81.

PMID 10337989

Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.

De Rosa M, Fasano C, Panariello L, Scarano MI, Belli G, Iannelli A, Ciciliano F, Izzo P

Oncogene. 2000 ; 19 (13) : 1719-1723.

PMID 10763829

Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.

De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT

American journal of human genetics. 2004 ; 74 (5) : 954-964.

PMID 15077197

The molecular basis of Turcot's syndrome.

Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B

The New England journal of medicine. 1995 ; 332 (13) : 839-847.

PMID 7661930

Turcot syndrome and its characteristic colonic manifestations.

Itoh H, Ohsato K

Diseases of the colon and rectum. 1985 ; 28 (6) : 399-402.

PMID 4006635

Turcot's syndrome: evidence for linkage to the adenomatous polyposis coli (APC) locus.

Lasser DM, DeVivo DC, Garvin J, Wilhelmsen KC

Neurology. 1994 ; 44 (6) : 1083-1086.

PMID 8208405

Turcot's syndrome. Evidence for autosomal dominant inheritance.

Lewis JH, Ginsberg AL, Toomey KE

Cancer. 1983 ; 51 (3) : 524-528.

PMID 6821830

Hereditary nonpolyposis colorectal cancer and related conditions.

Lucci-Cordisco E, Zito I, Gensini F, Genuardi M

American journal of medical genetics. Part A. 2003 ; 122 (4) : 325-334.

PMID 14518071

Drastic genetic instability of tumors and normal tissues in Turcot syndrome.

Miyaki M, Nishio J, Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Nagato M, Chong JM, Koike M, Terada T, Kawahara Y, Fukutome A, Tomiyama J, Chuganji Y, Momoi M, Utsunomiya J

Oncogene. 1997 ; 15 (23) : 2877-2881.

PMID 9419979

Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases.

TURCOT J, DESPRES JP, ST PIERRE F

Diseases of the colon and rectum. 1959 ; 2 : 465-468.

PMID 13839882

Citation

This paper should be referenced as such :

Digilio, MC

Turcot syndrome

Atlas Genet Cytogenet Oncol Haematol. 2006;10(1):38-39.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/TurcotID10026.html

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Fri Jun 30 11:24:39 CEST 2017

For comments and suggestions or contributions, please contact us