What question did this study set out to answer?

To identify consensus cancer predisposition genes and determine the prevalence of damaging germline mutations across molecular subgroups of pediatric medulloblastoma.

May 9, 2018The Lancet OncologyOpen Access

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort

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To identify consensus cancer predisposition genes and determine the prevalence of damaging germline mutations across molecular subgroups of pediatric medulloblastoma.
Analyzed whole-genome and exome sequences of blood (n=1022) and tumor samples (n=800) from 1022 patients across retrospective cohorts (n=673) and four prospective clinical trial cohorts (n=349).
Assigned molecular subgroups (WNT, SHH, Group 3, Group 4) using DNA methylation profiling and evaluated gene enrichment via rare variant burden tests against 53,105 non-cancer ExAC controls.
Identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus predisposition genes, which accounted for germline mutations in 6% of retrospective and 5% of prospective medulloblastoma cases.
Predisposition rates peaked in the SHH subgroup at 20% in retrospective and 14% in prospective cohorts, with germline TP53 mutations accounting for 57% (8/14) of SHH chromothripsis events.
Patients with genetic predisposition had a 5-year progression-free survival of 52% (95% CI 40–69) and a 5-year overall survival of 65% (95% CI 52–81), with survival differing significantly by gene.

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Implication

Multicenter cohort study uncovers damaging germline mutations in 5% to 6% of medulloblastoma cases, indicating routine genetic screening is essential for high-risk molecular subgroups.

Cite This Study

Waszak et al. (2018) studied this question.

synapsesocial.com/papers/6a7d4d482935e92dbc77617a https://doi.org/10.1016/s1470-2045(18)30242-0

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Implication

Multicenter cohort study uncovers damaging germline mutations in 5% to 6% of medulloblastoma cases, indicating routine genetic screening is essential for high-risk molecular subgroups.

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort

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Discussion

Implication

Cite This Study

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort

Key Points

Discussion

Implication

Cite This Study

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