Turcot syndrome

This genetic disease is characterized by an increased incidence of colorectal adenomas and brain tumours and was first described in 1959 by the Canadian surgeon Jacques Turcot. The tumors are detected by means of colonoscopies or MRI examinations. The therapy depends on the individual findings.

Patients usually present with seemingly harmless symptoms such as headache, malaise and vomiting, which can be attributed to increased intracranial pressure [1]. It was found that patients with an APC gene mutation between codons 697 and 1224 have a 13-fold increased risk of developing medulloblastoma. The incidence of medulloblastoma is highest in patients with familial adenomatous polyposis coli before the age of 20 [2]. The histological classification of medulloblastomas includes the classic medulloblastoma and four other variants: Medulloblastoma with extensive nodularity, desmoplastic-nodular, anaplastic and large cell. The classic medulloblastoma is the most common form.

A study of 25 Turcot patients showed that the patients died on average at the age of 20.3 years. The main cause of death is a brain tumor in 76% of cases and colorectal cancer in 16% [3]. The Turcot-associated cerebral tumors are 61% gliomas of any dignity and 25% medulloblastomas. Lymphomas, meningiomas, pituitary adenomas and craniopharyngiomas have also been described [4]. Brain tumors usually manifest themselves in the second decade of a patient’s life (average age 15 years) and are associated with a high mortality rate [5]. As a result, many brain tumor patients die before other symptoms of Turcot syndrome, such as the development of colorectal carcinoma, can become clinically relevant.

Molecular genetics

The inheritance pattern in Turcot syndrome is very complex [5]. Both autosomal dominant and autosomal recessive cases are described in the literature [8,9]. In terms of molecular genetics, Turcot syndrome can be divided into two groups [4]:

Group 1: Mutations in the tumor suppressor gene APC are detectable (analogous to familial adenomatous polyposis, FAP).

Group 2: Mutations in mismatch repair genes are detectable (analogous to hereditary non-polyposis colorectal carcinoma, HNPCC).

The therapeutic approach for medulloblastoma is a combination of chemotherapy, surgical resection and radiotherapy [1]. The five-year overall survival rate with standard treatment is 70-85%. Of the subgroups, classical histology has an event-free 5-year survival of 84%, desmoplastic tumors 77% and large cell anaplastic tumors 57% [6]. The oncogenes MYC and MYCN are prognostically unfavorable factors and as such correlate with a poorer prognosis in group 3 (MYC) and “sonic hedgehog” (MYCN) [7].

Mutations in the APC gene can be detected in up to 75% of Turcot’s disease patients, leading to medulloblastomas, particularly in children. In the remaining cases, mutations in MMR genes are predominantly associated with gliomas [10]. While Turcot patients with APC mutations are heterozygous, Turcot patients with MMR defects mainly have homozygous or mixed heterozygous defects.

Targeted treatment modalities can be considered, particularly for highly aggressive forms of medulloblastoma.

Literature:

Waller A, Findeis S, Lee MJ: Familial Adenomatous Polyposis. J Pediatr Genet 2016; 5(2): 78-83.
Attard TM, et al: Brain tumors in individuals with familial adenomatous polyposis: a cancer registry experience and pooled case report analysis. Cancer 2007; 109(4): 761-766.
Matsui T, et al: A father and son with Turcot’s syndrome: evidence for autosomal dominant inheritance: report of two cases. Dis Colon Rectum 1998; 41: 797-801.
Paraf F, Jothy S, Van Meir EG: Brain tumor-polyposis syndrome: two genetic diseases? J Clin Oncol 1997; 15: 2744-2758.
“Dysfunction of DNA repair genes as a risk factor for the development of hereditary colorectal carcinomas”, https://opus.bibliothek.uni-wuerzburg.de/opus4-wuerzburg/frontdoor/deliver/index/docId/4176/file/MuenchAndreadiss.pdf,(last accessed 05.04.2024)
Gajjar A, et al: Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 2006; 7(10): 813-820.
Kool M, et al: Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 2012; 123(4): 473-484.
Hamilton SR, et al: The molecular basis of Turcot’s syndrome. New Eng J Med 1995; 332: 839-847.
De Rosa M, et al: Evidence for a recessive inheritance of Turcot’s syndrome caused by compound heterozygous mutations within the PMS2 gene. Oncogene 2000; 19: 1719-1723.
Hedge MR, et al: A homozygous mutation in MSH6 causes Turcot syndrome. Clin Cancer Res 2005; 11: 4689-4693.