Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas

Abstract

Background Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description. Methods We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae. Results Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1–28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series. Conclusions Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.

Medulloblastoma and familial adenomatous polyposis: Good prognosis and good quality of life in the long‐term?

“…By examining these patients’ diagnostic and treatment data, we aimed to: (a) describe their progression‐free survival and overall survival; (b) confirm the favorable prognosis reported in the recent literature, 15 and describe the potential (clinical, therapeutic, pathological, and molecular) prognostic factors associated with successful treatment; and (c) examine in‐depth the complex hereditary genetic mechanism behind the onset and course of MBL in these patients.…”

“…What we are still lacking, however, is therapeutic guidelines that take into account both the good outcomes reported in a handful of more recent papers 15 and the genetic fragility of these patients. They spontaneously develop many different types of tumors and are obviously more susceptible to secondary tumors after adjuvant treatment for MBL.…”

“…They spontaneously develop many different types of tumors and are obviously more susceptible to secondary tumors after adjuvant treatment for MBL. It is sadly remarkable that the only death of a patient, in the series recently reported by a cooperative French group, 15 was due to a triton tumor 14 years after MBL had been diagnosed.…”

Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy

“…The most common somatic mutations in the WNT subgroup occur in exon 3 of CTNNB1 encoding β-catenin and can be identified by direct sequencing or nuclear immunopositivity for β-catenin. The 10% of WNT tumors without CTNNB1 mutations usually harbor germline mutations in the adenomatous polyposis coli (APC) gene [82][83][84][85]. Approximately 80% have a deletion of one copy of chromosome 6 (monosomy 6) [86].…”

Genetic predisposition in pediatric oncology

“…Patients with GS are also at increased risk for extracolonic malignancies: thyroid cancer, pancreatic adenocarcinoma, gastric adenocarcinoma. Of particular interest for pediatric oncology is the increased risk for hepatoblastoma and medulloblastoma in patients with GS [ 89 , 90 ].…”