Turcot Syndrome Molecular Basis of Disease

Turcot syndrome is a rare complex genetic disorder that results in primary colonic neoplasms and concurrent primary malignant tumors of the central nervous system. This syndrome has been reported as a dominant and a recessive disorder as homozygous and compound heterozygous mutations in APC, MLH1, MSH2, and PMS2 have been described. MSH6 also may be involved, as one individual with homozygous MSH6 mutations was reported with Turcot syndrome.11

Turcot syndrome represents an intricate interplay between the characteristics of the germline mutation and additional somatic events in target tissues. Central nervous system tumors associated with this syndrome are typically either a medulloblastoma or a glioblastoma multiforme. Turcot syndrome was at one time thought to be a separate disease entity, but now it is known that two thirds of the cases are associated with mutations in the APC gene, while one third are associated with mutations in the mismatch repair genes, MLH1, MSH2, MSH6, or PMS2.

Individuals with Turcot syndrome who present with a medulloblastoma, astrocytoma, or ependymoma tend to have a germline mutation in the APC gene.12 Polyposis and extracolonic manifestations are often present. Approximately 80% of families with Turcot syndrome and polypo-sis will have a detectable APC mutation. Polyposis may be identified before or after the manifestation of the brain tumor. The age of onset and type of brain tumor may differ greatly even between affected family members. The medul-loblastomas and colorectal cancers in these families do not exhibit microsatellite instability. As is the case with FAP, the APC mutations encode protein products that are truncated. Analysis of individuals with FAP and brain tumors suggests that mutations in codons 457 to 1309 of the APC gene may account for the majority of cases.12,13 It is not understood why some individuals will develop brain tumors and others will not when the mutations in the APC gene are similar. The lifetime relative risk for those affected with FAP to develop medulloblastoma is estimated to be 92 times that of the general population, but the absolute lifetime risk remains below 1%.12

Individuals who present with glioblastomas and col-orectal tumors likely have mismatch repair gene germline mutations in MLH1, MSH2,or PMS2. Café au lait spots also may be seen. Both the glioblastomas and colorectal tumors may exhibit microsatellite instability that characterizes HNPCC (see chapter 19). This phenomenon is characteristic of an inability to repair interstrand mismatch errors during DNA replication and often is associated with defects in the mismatch repair genes. Microsatellite instability is more prevalent or present to a greater degree in colorectal cancers than in central nervous system cancers.12,14 Examination of repetitive sequences of coding and 5' upstream regions of several loci revealed frequent alterations that increase in prevalence with the advancement of colorectal cancer according to Dukes categories.15 The colorectal adenomas in patients with MLH1, MSH2, or PMS2 mutations may not be clinically distinguishable from those resulting from an APC mutation. Large numbers of colorectal adenomas may be present, and these individuals may not meet the clinical criteria for HNPCC.

The tumorigenic pathway leading to colorectal cancer and glioblastomas in mismatch repair genes that are associated Turcot syndrome has been shown to be somewhat heterogeneous. Leung et al. reported that colorectal carcinomas frequently contained somatic frameshift mutations of TGFBRII, while glioblastomas did not.14 Microsatellite instability-high glioblastomas overexpress the TP53 protein, whereas colorectal carcinomas had normal TP53 levels. Glioblastomas exhibit chromosomal instability with aneuploid DNA content, but colorectal tumors are diploid or contain near-diploid DNA content.14 Loss of 9p is frequently observed in glioblastomas, but 9p is not commonly lost in colorectal cancers. These differences suggest that the underlying germline mutation present in mismatch repair genes may facilitate malignant processes in the central nervous system that are divergent from those in the colon.14

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