Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions.
Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions.
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DOI：
10.1136/gutjnl-2020-321217
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发表时间：
2021-05
期刊：
影响因子：
24.5
通讯作者：
Wood LD
中科院分区：
文献类型：
--
作者：
Fujikura K;Hosoda W;Felsenstein M;Song Q;Reiter JG;Zheng L;Beleva Guthrie V;Rincon N;Dal Molin M;Dudley J;Cohen JD;Wang P;Fischer CG;Braxton AM;Noë M;Jongepier M;Fernández-Del Castillo C;Mino-Kenudson M;Schmidt CM;Yip-Schneider MT;Lawlor RT;Salvia R;Roberts NJ;Thompson ED;Karchin R;Lennon AM;Jiao Y;Wood LD
导管内乳头状粘液性肿瘤（IPMN）是一种非侵入性前驱病变，可进展为侵袭性胰腺癌，并根据肿瘤上皮的形态分为低级别或高级别。我们的目的是比较同一IPMN的低级别和高级别区域的遗传改变，以确定肿瘤进展背后的分子改变。我们对来自17个具有低度和高度异型增生的IPMN的组织样本进行了多区域全外显子组测序（76个IPMN区域，包括49个低度异型增生和27个高度异型增生）。我们重建了每个病例的遗传学，并评估了63个IPMN囊液样本的独立队列中新驱动基因的突变。我们的多区域全外显子组测序鉴定了KLF4，一种先前未报道的IPMN肿瘤发生的遗传驱动因子，在>50%的分析的IPMN中鉴定出两个密码子之一的热点突变。在我们测序的病例中，KLF4突变在低级别区域中明显更普遍。全外显子组测序数据的系统发育分析表明IPMN起始和进展的不同模式。在IPMN囊液样本的独立队列中也发现了KLF4的热点突变，同样在低级别IPMN中具有显著较高的患病率。KLF4的热点突变在IPMN中发生率很高。KLF 4突变在胰腺驱动基因中是独一无二的，在低级IPMNs中富集。这些数据突出了低级别和高级别异型增生的不同分子特征，并表明通过IPMN途径通向高级别异型增生的多种途径。
Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression. We performed multi-region whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples. Our multi-region whole exome sequencing identified KLF4, a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs. Hotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.
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影响因子：
7.3
作者：
Amato, Eliana;dal Molin, Marco;Mafficini, Andrea;Yu, Jun;Malleo, Giuseppe;Rusev, Borislav;Fassan, Matteo;Antonello, Davide;Sadakari, Yoshihiko;Castelli, Paola;Zamboni, Giuseppe;Maitra, Anirban;Salvia, Roberto;Hruban, Ralph H.;Bassi, Claudio;Capelli, Paola;Lawlor, Rita T.;Goggins, Michael;Scarpa, Aldo
通讯作者：
Scarpa, Aldo
影响因子：
24.5
作者：
Felsenstein, Matthaus;Noe, Michael;Masica, David L.;Hosoda, Waki;Chianchiano, Peter;Fischer, Catherine G.;Lionheart, Gemma;Brosens, Lodewijk A. A.;Pea, Antonio;Yu, Jun;Gemenetzis, Georgios;Groot, Vincent P.;Makary, Martin A.;He, Jin;Weiss, Matthew J.;Cameron, John L.;Wolfgang, Christopher L.;Hruban, Ralph H.;Roberts, Nicholas J.;Karchin, Rachel;Goggins, Michael G.;Wood, Laura D.
通讯作者：
Wood, Laura D.
影响因子：
30.8
作者：
Makohon-Moore AP;Zhang M;Reiter JG;Bozic I;Allen B;Kundu D;Chatterjee K;Wong F;Jiao Y;Kohutek ZA;Hong J;Attiyeh M;Javier B;Wood LD;Hruban RH;Nowak MA;Papadopoulos N;Kinzler KW;Vogelstein B;Iacobuzio-Donahue CA
通讯作者：
Iacobuzio-Donahue CA
影响因子：
11.1
作者：
Myant KB;Cammareri P;Hodder MC;Wills J;Von Kriegsheim A;Győrffy B;Rashid M;Polo S;Maspero E;Vaughan L;Gurung B;Barry E;Malliri A;Camargo F;Adams DJ;Iavarone A;Lasorella A;Sansom OJ
通讯作者：
Sansom OJ
DOI：
10.2214/ajr.07.3340
发表时间：
2008-09
期刊：
AJR. American journal of roentgenology
影响因子：
--
作者：
Laffan TA;Horton KM;Klein AP;Berlanstein B;Siegelman SS;Kawamoto S;Johnson PT;Fishman EK;Hruban RH
通讯作者：
Hruban RH