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.