Morcrette Guillaume, Hirsch Theo Z, Badour Elise, Pilet Jill, Caruso Stefano, Calderaro Julien, Martin Yoann, Imbeaud Sandrine, Letouzé Eric, Rebouissou Sandra, Branchereau Sophie, Taque Sophie, Chardot Christophe, Guettier Catherine, Scoazec Jean-Yves, Fabre Monique, Brugières Laurence, Zucman-Rossi Jessica
Centre de Recherche des Cordeliers, Functional Genomics of Solid Tumors laboratory, Sorbonne Université, Inserm, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France.
Labex OncoImmunology, Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547. eCollection 2019.
Hepatoblastoma (HB) is the most common liver cancer in children. We aimed to characterize HB related to (Adenomatous Polyposis Coli) germline mutation (APC-HB). This French multicentric retrospective study included 12 APC-HB patients under 5 at diagnosis. Clinical features of APC-HB were compared to the French SIOPEL2-3 cohort of HB patients. Molecular and histopathological analyses of APC-HB were compared to 15 consecutive sporadic HB treated at Bicêtre hospital from 2013 to 2015 (non-APC-HB). APC-HB patients have a peculiar spectrum of germline mutations, with no events in the main hotspot of classical mutations at codon 1309 ( < .05). Compared to sporadic HB, they have similar clinical features including good prognosis since all patients are alive in complete remission at last follow-up. APC-HB are mostly well-limited tumors with fetal predominance and few mesenchymal components. All APC-HB have an activated Wnt/β-catenin pathway without mutation, confirming that germline and somatic mutations are mutually exclusive ( < .001). Pathological reviewing identified massive intratumor tertiary lymphoid structures (TLS) containing both lymphocytes and antigen-presenting cells in all 11 APC-HB cases who received cisplatin-based neoadjuvant chemotherapy but not in five pre-chemotherapy samples (four paired biopsies and one patient resected without chemotherapy), indicating that these TLS are induced by chemotherapy ( < .001). Conclusion: APC-HB show a good prognosis, they are all infiltrated by cisplatin-induced TLS, a feature only retrieved in a minority of non-APC-HB. This suggests that C inactivation can synergize with cisplatin to induce an immunogenic cell death that initiates an anti-tumor immune response.
肝母细胞瘤（HB）是儿童最常见的肝癌。我们旨在对与腺瘤性息肉病 coli（APC）种系突变相关的 HB（APC-HB）进行特征描述。这项法国多中心回顾性研究纳入了12例诊断时年龄小于5岁的APC-HB患者。将APC-HB的临床特征与法国SIOPEL2-3队列中的HB患者进行比较。将APC-HB的分子和组织病理学分析与2013年至2015年在比塞特尔医院接受治疗的15例连续散发性HB（非APC-HB）进行比较。APC-HB患者具有独特的种系突变谱，在密码子1309处经典突变的主要热点区域未发生突变（P<0.05）。与散发性HB相比，它们具有相似的临床特征，包括预后良好，因为所有患者在最后一次随访时均处于完全缓解状态且存活。APC-HB大多为边界清楚的肿瘤，以胎儿型为主，间充质成分较少。所有APC-HB均具有激活的Wnt/β-连环蛋白通路且无CTNNB1突变，证实种系CTNNB1和体细胞CTNNB1突变相互排斥（P<0.001）。病理检查发现，在接受基于顺铂的新辅助化疗的所有11例APC-HB病例中，肿瘤内存在大量包含淋巴细胞和抗原呈递细胞的三级淋巴样结构（TLS），但在5份化疗前样本（4份配对活检和1例未接受化疗而切除的患者）中未发现，表明这些TLS是由化疗诱导的（P<0.001）。结论：APC-HB预后良好，它们均被顺铂诱导的TLS浸润，这一特征仅在少数非APC-HB中发现。这表明CTNNB1失活可与顺铂协同作用，诱导免疫原性细胞死亡，从而引发抗肿瘤免疫反应。
