Kumari Niraj, Singh Rajneesh K, Mishra Shravan K, Krishnani Narendra, Mohindra Samir, L Raghvendra
Departments of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Department of Pathology & Lab Medicine, All India Institute of Medical Sciences, Raebareli, India.
J Pathol Transl Med. 2021 May;55(3):192-201. doi: 10.4132/jptm.2021.01.23. Epub 2021 Mar 9.
The genetic landscape of intestinal (INT) and pancreatobiliary (PB) type ampullary cancer (AC) has been evolving with distinct as well as overlapping molecular profiles.
We performed whole-exome sequencing in 37 cases of AC to identify the targetable molecular profiles of INT and PB tumors. Paired tumor-normal sequencing was performed on the HiSeq 2500 Illumina platform.
There were 22 INT, 13 PB, and two cases of mixed differentiation of AC that exhibited a total of 1,263 somatic variants in 112 genes (2-257 variants/case) with 183 somatic deleterious variants. INT showed variations in 78 genes (1-31/case), while PB showed variations in 51 genes (1-29/case). Targetable mutations involving one or more major pathways were found in 86.5% of all ACs. Mutations in APC, CTNNB1, SMAD4, KMT2, EPHA, ERBB, and Notch genes were more frequent in INT tumors, while chromatin remodeling complex mutations were frequent in PB tumors. In the major signaling pathways, the phosphoinositide 3-kinase (PI3)/AKT and RAS/mitogen-activated protein kinase (MAPK) pathways were significantly mutated in 70% of cases (82% INT, 46% PB, p = .023), with PI3/AKT mutation being more frequent in INT and RAS/MAPK in PB tumors. Tumor mutation burden was low in both differentiation types, with 1.6/Mb in INT and 0.8/Mb in PB types (p =.217).
The exome data suggest that INT types are genetically more unstable than PB and involve mutations in tumor suppressors, oncogenes, transcription factors, and chromatin remodeling genes. The spectra of the genetic profiles of INT and PB types suggested primary targeting of PI3/AKT in INT and RAS/RAF and PI3/AKT pathways in PB carcinomas.
肠型（INT）和胰胆管型（PB）壶腹癌（AC）的基因图谱一直在演变，具有不同但又重叠的分子特征。
我们对37例AC进行了全外显子组测序，以确定INT和PB肿瘤的可靶向分子特征。在Illumina HiSeq 2500平台上进行配对肿瘤-正常测序。
有22例INT、13例PB以及2例AC混合分化病例，共在112个基因中发现1263个体细胞变异（2 - 257个变异/病例），其中有183个体细胞有害变异。INT在78个基因中显示变异（1 - 31个/病例），而PB在51个基因中显示变异（1 - 29个/病例）。在所有AC中，86.5%发现涉及一个或多个主要通路的可靶向突变。APC、CTNNB1、SMAD4、KMT2、EPHA、ERBB和Notch基因的突变在INT肿瘤中更常见，而染色质重塑复合体突变在PB肿瘤中更常见。在主要信号通路中，磷酸肌醇3激酶（PI3）/AKT和RAS/丝裂原活化蛋白激酶（MAPK）通路在70%的病例中发生显著突变（INT为82%，PB为46%，p = 0.023），PI3/AKT突变在INT中更常见，而RAS/MAPK在PB肿瘤中更常见。两种分化类型的肿瘤突变负担都较低，INT型为1.6/Mb，PB型为0.8/Mb（p = 0.217）。
外显子组数据表明，INT型在基因上比PB型更不稳定，且涉及肿瘤抑制基因、癌基因、转录因子和染色质重塑基因的突变。INT和PB型的基因图谱谱表明，INT中PI3/AKT以及PB癌中RAS/RAF和PI3/AKT通路为主要靶向目标。
