Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.
Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.
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DOI：
10.1016/s1470-2045(18)30242-0
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发表时间：
2018-06
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通讯作者：
Pfister SM
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作者：
Waszak SM;Northcott PA;Buchhalter I;Robinson GW;Sutter C;Groebner S;Grund KB;Brugières L;Jones DTW;Pajtler KW;Morrissy AS;Kool M;Sturm D;Chavez L;Ernst A;Brabetz S;Hain M;Zichner T;Segura-Wang M;Weischenfeldt J;Rausch T;Mardin BR;Zhou X;Baciu C;Lawerenz C;Chan JA;Varlet P;Guerrini-Rousseau L;Fults DW;Grajkowska W;Hauser P;Jabado N;Ra YS;Zitterbart K;Shringarpure SS;De La Vega FM;Bustamante CD;Ng HK;Perry A;MacDonald TJ;Hernáiz Driever P;Bendel AE;Bowers DC;McCowage G;Chintagumpala MM;Cohn R;Hassall T;Fleischhack G;Eggen T;Wesenberg F;Feychting M;Lannering B;Schüz J;Johansen C;Andersen TV;Röösli M;Kuehni CE;Grotzer M;Kjaerheim K;Monoranu CM;Archer TC;Duke E;Pomeroy SL;Shelagh R;Frank S;Sumerauer D;Scheurlen W;Ryzhova MV;Milde T;Kratz CP;Samuel D;Zhang J;Solomon DA;Marra M;Eils R;Bartram CR;von Hoff K;Rutkowski S;Ramaswamy V;Gilbertson RJ;Korshunov A;Taylor MD;Lichter P;Malkin D;Gajjar A;Korbel JO;Pfister SM
髓母细胞瘤与罕见的遗传性癌症易感综合征有关；然而，一致的髓母细胞瘤易感基因尚未定义，也没有儿科患者遗传咨询和检测的筛选指南。我们的目标是评估和定义这些基因，为未来的筛查指南提供证据。在这项国际化的多中心研究中，我们分析了髓母细胞瘤患者，这些患者来自回顾性队列(国际癌症基因组联盟[ICGC]PedBrain、髓母细胞瘤高级基因组国际联盟[MAGIC]和Cefalo系列)和来自四项临床研究(SJMB03、SJMB12、SJYC07和I-HIT-MED)的前瞻性队列。对血液和肿瘤样本的全基因组序列和外显子组序列进行了分析，以寻找癌症易感基因中罕见的破坏性胚系突变。DNA甲基化分析以确定共有的分子亚群：WNT(MBWNT)、SHH(MBSHH)、第3组(MBGroup3)和第4组(MBGroup4)。髓母细胞瘤的易感基因是根据Exome Aggregation Consortium(ExAC)对没有癌症诊断的对照组进行的罕见的变异负荷试验预测的。使用先前定义的体细胞突变特征进一步将髓母细胞瘤基因组分成两组，钟状组(签名1和5)和同源重组修复缺陷组(签名3和8)，并使用先前建立的标准来研究嗜铬细胞症。对具有髓母细胞瘤遗传易感性的患者的无进展生存期和总生存期进行了建模。我们纳入了来自回顾队列(n=673)和四个前瞻性研究(n=349)的1022例髓母细胞瘤患者，其中血液样本(n=1022)和肿瘤样本(n=800)分析了110个癌症易感基因的胚系突变。在我们的罕见变异负荷分析中，我们将这些基因与来自ExAC的53个 105测序对照进行比较，根据我们的罕见变异负荷分析，确定APC、BRCA2、PALB2、PTCH1、SUFU和TP53为一致的髓母细胞瘤易感基因，并估计在回顾队列中，胚系突变占髓母细胞瘤诊断的6%。回顾队列中不同分子亚组的遗传易感性不同，MBSHH亚组患者的遗传易感性最高(在回顾队列中为20%)。这些估计在前瞻性临床队列中重复(胚系突变占髓母细胞瘤诊断的5%，在MBSHH亚组中患病率最高[14%])。具有胚系APC突变的患者发生MBWNT，并且占大多数(7例中的5例)无体细胞CTNNB1外显子3突变的MBWNT。SUFU和ptch1发生胚系突变的患者大多发生婴儿MBSHH。生殖系TP53突变只出现在MBSHH亚组中的儿童患者中，并解释了该亚组中超过一半(14例中的8例[57%])的嗜铬细胞症事件。在MBSHH、MBGroup3和MBGroup4分子亚群中观察到PALB2和BRCA2的胚系突变，并与典型的同源重组修复缺陷的突变特征有关。在具有髓母细胞瘤遗传易感性的患者中，5年无进展生存率为52%(95%可信区间40-69)，5年总生存率为65%(95%可信区间52-81)；这些生存估计在不同髓母细胞瘤易感基因种系突变的患者中存在显著差异。遗传咨询和检测应该被用作MBWNT和MBSHH患者的标准护理程序，因为这些患者在已知的癌症易感基因中具有最高的破坏性胚系突变的发生率。根据临床和分子肿瘤特征，我们提出了髓母细胞瘤患者常规基因筛查的标准。德国癌症援助；德国联邦教育和研究部；德国儿童癌症基金会；欧洲研究理事会；国家卫生研究院；加拿大卫生研究所；德国癌症研究中心；圣裘德综合癌症中心；美国黎巴嫩叙利亚协会慈善机构；瑞士国家科学基金会；欧洲分子生物学组织；英国癌症研究中心；赫蒂基金会；亚历山大和玛格丽特·斯图尔特信托基金；V癌症研究基金会；桑塔格基金会；音乐家抗击儿童癌症基金会；BC癌症基金会；瑞典健康、工作、生活和福利委员会；瑞典研究委员会；瑞典癌症协会；瑞典辐射防护管理局；丹麦战略研究委员会；瑞士联邦公共卫生办公室；参与该计划的机构有：瑞士移动通信研究基金会；Masaryk大学；捷克共和国卫生部；挪威研究委员会；加拿大基因组局；BC基因组公司；Terry Fox研究所；安大略省癌症研究所；安大略省儿科肿瘤学小组；凯瑟琳·洛雷特家族和克拉克·H·史密斯脑瘤中心；蒙特利尔儿童医院基金会；患病儿童医院：索尼娅和亚瑟·拉巴特脑瘤研究中心、癌症遗传学研究基金负责人、加伦家庭癌症中心、加伦家庭捐赠基金、BC儿童癌症家长协会；治愈搜索基金会；儿童脑瘤基金会；以及安大略省政府。
Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40–69) and 5-year overall survival was 65% (95% CI 52–81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Genetic 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. German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.