Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
J Neurooncol. 2020 Apr;147(2):309-315. doi: 10.1007/s11060-020-03424-9. Epub 2020 Feb 13.
Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark.
Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2.
Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10), but none were statistically significant after adjusting for multiple testing (p < 5 × 10). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (OR = 1.59, p = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, OR = 3.76, p = 3.2 × 10) and rs79036813 (PTCH1, OR = 0.42, p = 2.6 × 10).
The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.
髓母细胞瘤是一种主要发生在儿童身上的小脑恶性胚胎肿瘤。为了寻找与髓母细胞瘤风险相关的种系遗传变异，我们对来自瑞典和丹麦的 244 例髓母细胞瘤病例和 247 例对照进行了全基因组关联研究（GWAS）。
使用 Illumina BeadChips 进行基因分型，使用 IMPUTE2 对未分型的变体进行推断。
在 11 个位点的 59 个变体与增加的髓母细胞瘤风险相关（p<1×10），但在调整多重检验后（p<5×10），没有一个具有统计学意义。其中 13 个变体进行了基因分型，而 46 个进行了推断。在一项包含 249 例髓母细胞瘤病例和 629 例对照的验证研究中进一步研究了基因分型的变体。在验证研究中，rs78021424（18p11.23，PTPRM）与髓母细胞瘤风险相关，与发现队列中的方向一致（OR=1.59，p=0.02）。我们还使用候选基因方法选择了七个髓母细胞瘤易感性基因进行研究：APC、BRCA2、PALB2、PTCH1、SUFU、TP53 和 GPR161。rs201458864（PALB2，OR=3.76，p=3.2×10）和 rs79036813（PTCH1，OR=0.42，p=2.6×10）与关联的最强证据。
这项研究的结果，包括在 18p11.23 处的一个新的潜在髓母细胞瘤风险位点，具有提示性，但需要在独立队列中进一步验证。
