Open AccessPrinciples of tumorigenesis and emerging molecular drivers of SHH ‐activated medulloblastomas
Author(s) -
Menyhárt Otília,
Győrffy Balázs
Publication year - 2019
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.762
Subject(s) - medicine , carcinogenesis , cancer research , cancer
SHH ‐activated medulloblastomas ( SHH ‐ MB ) account for 25–30% of all medulloblastomas ( MB ) and occur with a bimodal age distribution, encompassing many infant and adult, but fewer childhood cases. Different age groups are characterized by distinct survival outcomes and age‐specific alterations of regulatory pathways. Here, we review SHH ‐specific genetic aberrations and signaling pathways. Over 95% of SHH ‐ MB s contain at least one driver event – the activating mutations frequently affect sonic hedgehog signaling ( PTCH 1, SMO , SUFU ), genome maintenance ( TP 53), and chromatin modulation ( KMT 2D, KMT 2C, HAT complexes), while genes responsible for transcriptional regulation ( MYCN ) are recurrently amplified. SHH ‐ MB s have the highest prevalence of damaging germline mutations among all MB s. TP 53‐mutant MB s are enriched among older children and have the worst prognosis among all SHH ‐ MB s. Numerous genetic aberrations, including mutations of TERT , DDX 3X, and the PI 3K/ AKT / mTOR pathway are almost exclusive to adult patients. We elaborate on the newest development within the evolution of molecular subclassification, and compare proposed risk categories across emerging classification systems. We discuss discoveries based on preclinical models and elaborate on the applicability of potential new therapies, including BET bromodomain inhibitors, statins, inhibitors of SMO , AURK , PLK , cMET , targeting stem‐like cells, and emerging immunotherapeutic strategies. An enormous amount of data on the genetic background of SHH ‐ MB have accumulated, nevertheless, subgroup affiliation does not provide reliable prediction about response to therapy. Emerging subtypes within SHH ‐ MB offer more layered risk stratifications. Rational clinical trial designs with the incorporation of available molecular knowledge are inevitable. Improved collaboration across the scientific community will be imperative for therapeutic breakthroughs.