Medulloblastomas with ELP1 pathogenic variants: A weakly penetrant syndrome with a restricted spectrum in a limited age window

Abstract

Background: ELP1 pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome.

Methods: We retrospectively reviewed clinical and genetic data of a French series of 29 ELP1-mutated MB.

Results: All patients developed SHH-MB, with a biallelic inactivation of PTCH1 found in 24 tumors. Other recurrent alterations encompassed the TP53 pathway and activation of MYCN/MYCL signaling. The median age at diagnosis was 7.3 years (range: 3-14). ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y - OS = 86%); no unusual side effect of treatments was noticed. Remarkably, a germline ELP1 PV was identified in all patients with available constitutional DNA (n = 26); moreover, all tested familial trio (n = 11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with ELP1 PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms.

Conclusions: The low penetrance, the "at risk' age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with SHH-MB, depending on the parents" request.

Keywords: ELP1; cancer predisposition syndrome; medulloblastoma; pathogenic variant.

Figure 1.

Molecular features of ELP1-mutated MB. (A) Summary and gene localization of all pathogenic variants (PV) found in our series of 29 MB. Black color refers to truncating variants, green color to missense variants, and orange color to splice site variants. (B) Oncoprint on the 28 MB samples for which next-generation sequencing was performed: each column refers to a sample, each line to 1 gene; genes are ranked according to the frequency of genetic alterations occurring in the pathway they are involved in. Only ELP1-Fr3 could not be analyzed (sample not available).

Figure 2.

Clinical features of ELP1-mutated MB. (A) Repartition of the various histological types (local diagnosis, no central review): large cell/anaplasia containing MB (LCA), classic MB (CLA), and nodular desmoplastic/extensive nodularity MB (DNMB); MB with no available histological type (NA). (B) Repartition of metastatic status within the cohort; M0 to localized disease, and M+ to metastatic cases. NA refers to cas with unknown status. (C) Box-plot showing the distribution of ages of patients, in years, at the time of diagnosis; each dot corresponds to 1 patient’s age. (D) Various treatments administered to patients; in the external circle, conventional chemotherapy (CONV) and high-dose chemotherapy containing regimen (HD); in the internal circle, PNET5 refers to treatment based on the PNET5 SIOPE protocol; PNET HR + 5 refers to treatments based on the French SFCE PNET HR + 5 protocol, HIT-SKK refers to treatments based on the HIT SKK treatment; VC+IRR refers to Vincristine and Irradiation only; VC+BT  refers to VP16-Carboplatin followed by Busulfan-Thiotepa strategy; NA refer to unspecified treatment.

Figure 3.

Patient outcomes assessed by the Kaplan–Meier method. (A) Overall survival of the entire cohort of patients affected by MB: x axis refers to the time from diagnosis in years, and y axis refers to the actualized percentage of alive patients. (B) Relapse-free survival in the entire cohort. (C) Overall surviving according to risk factors, HR refers to the high-risk in thin line (group 1, including LCA, M+, TP53 mutated, or MYCN amplified MB), and SR refers to low to intermediate risk in thick line (group 0, all others). Numbers at risk are specified below the x axis.

Figure 4.

Pedigrees of familial cases. (A) Pedigree of the family of patients ELP1-Fr5 and ELP1-Fr6. (B) Pedigree of the family of patient MB15_12. (C) Pedigree of the Dutch family. The index case is pointed to by an arrow; black box refers to MB; wt: wild-type; PV: pathogenic variant; NA: not assessed.