Introduction
APC (adenomatous polyposis coli) is a tumor suppressor gene that has multiple important functions. It encodes a protein that is an essential component of the WNT signaling pathway; together with axin and GSK-3beta, it regulates the intracellular localization and degradation of beta-catenin, influencing cell adhesion and migration capacity and it controls cell replication.
Sporadic (non-hereditary) somatic mutations or loss of APC gene function are early events leading to colon cancer1. Germline mutations in the APC gene are responsible instead for a form of hereditary predisposition to the onset of colic adenomas known as familial adenomatous polyposis (FAP). Patients with FAP characteristically develop numerous intestinal polyps (adenomas). According to the guidelines2-5 , they need intensive endoscopic surveillance from 10-14 years of age, and prophylactic total colectomy no later than the second decade of life to reduce the risk of colorectal carcinoma (CRC). The recommended options for prophylactic total colectomy in this setting are: total rectal preservation and ileorectal anastomosis (TC/IRA) or total proctocolectomy with ileoanal canal anastomosis (PC/IPAA). The choice is dictated mainly by the number and distribution of polyps in the rectum (≥ or <30).
Patients with FAP can also develop lesions outside the colon, including gastric and duodenal polyps, desmoid tumors, thyroid tumors, hepatoblastomas, epidermoid cysts, osteomas and congenital hypertrophy of the retinal pigment epithelium6.
The occurrence of brain tumors in FAP patients remains rare (in no more than 1% of cases), MBL being the most likely central nervous system tumor to be described in carriers of APC germline pathogenic variants, typically in pediatric age7. The molecular changes underlying MBL are the same as those involved in the morphogenesis of the cerebellum, i.e. the Sonic Hedgehog pathway (involved in controlling the normal proliferation of cerebellar granules) and the WNT pathway (including APC and beta-catenin)8. Some of the most significant insight on the biological pathways involved in the pathogenesis of MBL has come from investigating rare family syndromes that predispose to its onset. APC is an essential component of the physiological activation of the WNT/Wg pathway, necessary for the normal development of neural cells. Activation of this pathway identifies a unique molecular subgroup of MBL with distinct DNA methylation patterns, gene expression profiles, genomic anomalies, and clinical outcome9. In independent biological studies based on clinical trials10, this subgroup exhibits a particular behavior and has been found associated with a favorable clinical outcome (with an overall survival exceeding 90%). WNT-medulloblastomas lack a blood–brain barrier and this feature may explain why these tumors are highly susceptible to chemotherapy and radiotherapy11. The overall good prognosis of WNT-medulloblastoma has solicited a hypothesis for treatment de-escalation ongoing in many trials and concerning both total dose of craniospinal irradiation (CSI) and total duration of treatment with reduced number of adjuvant chemotherapy courses12-13.
Although WNT/Wg-positive MBL tend to have classical histological features in the vast majority of cases (or may rarely resemble large cell/anaplastic lesions) and arise in older children, they are hard to distinguish from other tumors with similar clinical and histological characteristics, and have to be identified at the molecular level.
The aim of the present study was to describe the outcome of patients with MBL and FAP with APC germline pathogenic mutations treated for both conditions at our institute in the last 10 years.