Medulloblastoma, SHH-activated and TP53-altered and medulloblastoma, SHH-activated and TP53-wild type

SHH tumors are medulloblastomas with aberrations in the SHH pathway and represent approximately 25% of medulloblastoma cases.[112] SHH medulloblastomas are characterized by chromosome 9q deletions; desmoplastic/nodular histology; and variants in SHH pathway genes, including PTCH1, PTCH2, SMO, SUFU, and GLI2.[116]

Heterozygous deleterious germline pathogenic variants in the GPR161 gene were identified in approximately 3% of cases of SHH medulloblastoma.[124] GPR161 is an inhibitor of SHH signaling. Median age at diagnosis for GPR161-altered cases was 1.5 years. Loss of heterozygosity (LOH) at the GPR161 locus was noted in all tumors, with tumors from five of six patients showing copy-neutral LOH of chromosome 1q (on which GPR161 resides).

Variants in the third nucleotide (r.3A>G) of the U1 spliceosomal small nuclear RNAs (snRNAs) are highly specific for SHH medulloblastoma.[125,126] U1 snRNA r.3A>G variants are observed in virtually all cases of SHH medulloblastoma in adults, in approximately one-third of cases in children and adolescents, and are absent in cases in infants.[126] U1 snRNA variants disrupt RNA splicing, leading to inactivation of tumor-suppressor genes (e.g., PTCH1) and activation of oncogenes (e.g., GLI2). The significance of U1 snRNA r.3A>G variants in specific SHH medulloblastoma subtypes is described below.

SHH medulloblastomas show a bimodal age distribution and are observed primarily in children younger than 3 years and in older adolescence/adulthood. The tumors are believed to emanate from the external granular layer of the cerebellum. The heterogeneity in age at presentation maps to distinctive subsets identified by further molecular characterization, as follows:

The outcome for patients with nonmetastatic SHH medulloblastoma is relatively favorable for children younger than 3 years and for adults.[112] Young children with the MBEN histology have a particularly favorable prognosis.[131-135] Patients with SHH medulloblastoma at greatest risk of treatment failure are children older than 3 years whose tumors have TP53 variants, often with co-occurring GLI2 or MYCN amplification and large cell/anaplastic histology.[112,127,136]

Patients with unfavorable molecular findings have an unfavorable prognosis, with fewer than 50% of patients surviving after conventional treatment.[108,127,136-139]

The 2021 WHO classification identifies SHH medulloblastoma with a TP53 variant as a distinctive entity (medulloblastoma, SHH-activated and TP53-altered).[1,78] Approximately 25% of SHH-activated medulloblastoma cases have TP53 variants, with a high percentage of these cases also showing a TP53 germline pathogenic variant (9 of 20 in one study). These patients are commonly between the ages of 5 years and 18 years and have a worse outcome (5-year overall survival rate, <30%).[138] The tumors often show large cell anaplastic histology.[138] A larger retrospective study has confirmed the poor prognosis of these patients.[128]