Genetic predisposition to medulloblastomas: just follow the tumour genome
Authors: Franck Bourdeaut, Olivier Delattre
Journal: The Lancet Oncology (2018)

The actual contribution of germline mutations to paediatric cancers has been a major concern for paediatricians, basic researchers, geneticists, epidemiologists, and parents for a long time. Next-generation sequencing approaches run on large cohorts of tumours offer a substantial contribution to helping to progressively disentangle this pending issue. The first notable piece of work1Zhang J Walsh MF Wu G et al.Germline mutations in predisposition genes in pediatric cancer.N Engl J Med. 2015; 373: 2336-2346Crossref PubMed Scopus (707) Google Scholar in this field was produced by researchers from the St Jude Research Hospital (Memphis, TN, USA), evaluating the number of germline variants in known cancer genes, assessed using constitutional DNA from more than 1000 paediatric patients. The overall proportion of predisposing mutations defined across a total of 565 genes was not much higher (8·5%) than the expected values. By use of a similar approach, Sebastian M Waszak and colleagues2Waszak SM Northcott PA Buchhalter I et al.Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.Lancet Oncol. 2018; (published online May 8.)http://dx.doi.org/10.1016/S1470-2045(18)30242-0Summary Full Text Full Text PDF Scopus (196) Google Scholar report the results of germline mutation analyses in 110 cancer genes on 1022 patients with medulloblastomas. The study by Waszak and colleagues is novel in two ways. First, by use of the largest retrospective cohort constituted and validating it on prospectively collected DNAs, it aimed to unbiasedly assess the actual incidence of cancer predisposition syndromes in patients with medulloblastoma. The authors identified six genes with a significant excess of damaging germline mutations for patients with medulloblastoma: APC, BRCA2, PALB2, PTCH1, SUFU, and TP53. Remarkably, the proportion of medulloblastoma cases attributable to these germline mutations did not differ between the retrospective cohort (6%) and prospective cohort (5%). The highest prevalence of genetic predisposition was recorded in patients with SHH medulloblastomas, in both the retrospective and prospective cohorts. This study confirms the high prevalence of SUFU and PTCH1 mutations in infants with SHH medulloblastomas,3Brugières L Remenieras A Pierron G et al.High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age.J Clin Oncol. 2012; 30: 2087-2093Crossref PubMed Scopus (100) Google Scholar, 4Smith MJ Beetz C Williams SG et al.Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations.J Clin Oncol. 2014; 32: 4155-4161Crossref PubMed Scopus (191) Google Scholar and also substantiates the overall higher risk for TP53 or PTCH1 germline mutations in SHH medulloblastomas, whatever the age at onset.5Kool M Jones DT Jäger N et al.Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.Cancer Cell. 2014; 25: 393-405Summary Full Text Full Text PDF PubMed Scopus (533) Google Scholar However, it also highlights that a familial history of cancer is often absent in these cases of SHH medulloblastoma. The study shows for the first time the phenotype of the rare (seven [1%] of 1022 patients) germline APC-related medulloblastomas (five of whom were children in the WNT subgroup who had excellent overall survival of 100% at 36 months) which, by contrast with SHH medulloblastomas, usually occur in a clear familial context, emphasising the need for a careful interview regarding familial history in children with WNT medulloblastomas. The second main finding was the refinement of the potential role of BRCA2 and PALB2 germline mutations in medulloblastoma, so far known only in the context of Fanconi anaemia.6Reid S Schindler D Hanenberg H et al.Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.Nat Genet. 2007; 39: 162-164Crossref PubMed Scopus (495) Google Scholar, 7Hirsch B Shimamura A Moreau L et al.Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.Blood. 2004; 103: 2554-2559Crossref PubMed Scopus (144) Google Scholar Germline heterozygous BRCA2 (seven [1%] of 1022 patients) and PALB2 (five [<1%] of 1022) variants might also be associated with an increased risk of medulloblastoma in childhood. The presence of loss of heterozygosity of the wildtype BRCA2 and PALB2 allele in some tumours or the tendency of corresponding tumours to present some signs of homologous recombination repair deficiency (HRD) might suggest pathogenicity. However, the very few BRCA2 and PALB2 mutated cases identified in the study preclude definitive conclusions. International collaboration to collect data from more families with BRCA2 and PALB2 mutations with precise evaluation of the frequency of medulloblastomas might help to decipher the actual involvement of these heterozygous mutations in predisposition to medulloblastoma. The clinical consequence in terms of genetic counselling also remains to be established. In that respect, because chromothripsis medulloblastoma indicates the presence of TP53 mutations and can subsequently induce familial screening,4Smith MJ Beetz C Williams SG et al.Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations.J Clin Oncol. 2014; 32: 4155-4161Crossref PubMed Scopus (191) Google Scholar finding insights for HRD and BRCA2 and PALB2 mutations in a child with medulloblastoma might eventually cause the initiation of tumour screening in the relatives. Since early cancer detection in unaffected individuals is one major goal of genetic counselling, possible familial consequences of broad genetic analyses on tumour DNA will need to be explicitly anticipated with parents; moreover, the medical benefit and psychological effects of such findings on families with no cancer history should be prospectively evaluated. Finally, the study does not identify any specific predisposing genes for group 3 and group 4 medulloblastomas, which shows that a young age at cancer onset (group 3) might not indicate a strong probability of predisposing syndrome per se. Alternatively, this outcome might also indicate that the predisposing genes for these groups lie outside the list of cancer genes that was assessed here. Moreover, although many studies have investigated this class of high-penetrance predisposition genes, the contribution of low-penetrance, high-frequency alleles remains unknown and still needs to be investigated through genome-wide association studies for medulloblastoma. The huge amount of germline data collected here, including non-coding sequences, might allow for a conclusion on this issue in the near future. Overall, this study emphasises the need for molecular analysis of medulloblastoma DNA. The study highlights the major interest of somatic molecular criteria, in addition to family history and potential malformative syndrome, to suggest genetic predisposition and hence lead to genetic counselling and germline genetic assessment with a clear prioritisation scheme depending on the type of medulloblastoma. We declare no competing interests. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohortGenetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. Full-Text PDF Open Access