Genomic Alterations of Adamantinomatous and Papillary Craniopharyngioma
Genomic Alterations of Adamantinomatous and Papillary Craniopharyngioma
复制标题
DOI：
10.1093/jnen/nlw116
复制
发表时间：
2017-02-01
影响因子：
3.2
通讯作者：
Pietsch, Torsten
中科院分区：
文献类型：
--
作者：
Goschzik, Tobias;Gessi, Marco;Pietsch, Torsten
颅咽管瘤是罕见的组织学良性肿瘤，但临床上具有挑战性。为了进一步了解颅咽管瘤的分子遗传学和生物学信息，我们分析了121例金刚瘤和16例乳头状颅咽管瘤（ACP， PCP）。我们从福尔马林固定石蜡包埋组织中提取DNA，并通过Sanger测序、下一代面板测序和焦磷酸测序测定CTNNB1、BRAF和DDX3X的突变状态。对16例颅咽管瘤进行分子倒置分析（MIP）；76.1%的ACP在编码β -连环蛋白的CTNNB1的外显子3上发生突变，并且在Thr41位点突变的病例有更差的无事件生存的趋势。26个ACP的下一代面板测序未检测到除CTNNB1突变外的任何复发突变。BRAF V600E突变在94%的PCP中发现，但在ACP中未发现。对MIP数据的GISTIC分析显示，没有明显的较大的染色体畸变，但一小部分ACP显示染色体物质的复发性局灶性增加，其他病例显示染色体区域Xq28的丢失，第三组和PCP具有稳定的基因组。总之，关键的发病事件似乎是ACP中WNT的激活，而PCP中BRAF V600E突变激活Ras/Raf/MEK/ERK通路。
Craniopharyngiomas are rare histologically benign but clinically challenging neoplasms. To obtain further information on the molecular genetics and biology of craniopharyngiomas, we analyzed a cohort of 121 adamantinomatous and 16 papillary craniopharyngiomas (ACP, PCP). We extracted DNA from formalin-fixed paraffin-embedded tissue and determined mutational status of CTNNB1, BRAF, and DDX3X by Sanger sequencing, next generation panel sequencing, and pyrosequencing. Sixteen craniopharyngiomas were further analyzed by molecular inversion profiling (MIP); 76.1% of the ACP were mutated in exon 3 of CTNNB1 encoding for beta-catenin and there was a trend towards a worse event-free survival in cases mutated at Thr41. Next generation panel sequencing of 26 ACP did not detect any recurrent mutations other than CTNNB1 mutations. BRAF V600E mutations were found in 94% of the PCP, but not in ACP. GISTIC analysis of MIP data showed no significant larger chromosomal aberrations but a fraction of ACP showed recurrent focal gains of chromosomal material, other cases showed loss in the chromosomal region Xq28, and a third group and the PCP had stable genomes. In conclusion, the crucial pathogenetic event appears to be WNT activation in ACP, whereas it appears to be activation of the Ras/Raf/MEK/ERK pathway by BRAF V600E mutations in PCP.