Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome
ONCOTARGET
Authors: Lykkegaard, Christen; Nielsen, Helene Myrtue; Kristensen, Lasse Sommer; Sogaard, Alexandra; Vikesa, Jonas; Jonson, Lars; Nielsen, Finn Cilius; Hasselbalch, Hans; Bjerrum, Ole Weis; Punj, Vasu; Gronbaek, Kirsten
Abstract
A thorough understanding of the idiopathic hypereosinophilic syndrome (IHES) and further optimization of diagnostic work-up procedures are warranted. We analyzed purified eosinophils from patients with IHES by next-generation whole-exome sequencing and compared DNA methylation profiles from reactive eosinophilic conditions to known clonal and suspected clonal eosinophilia. Somatic missense mutations in cancer-related genes were detected in three IHES patients. These included the spliceosome gene PUF60 and the cadherin gene CDH17. Furthermore, reactive eosinophilia samples could be differentiated from known-and suspected clonal eosinophilia samples based on 285 differentially methylated CpG sites corresponding to 128 differentially methylated genes. Using Ingenuity pathway analysis, we found that differentially methylated genes were highly enriched in functional pathways such as cancer, cell death and survival, and hematological disease. Our data show that a subset of IHES may be of clonal origin not related to the classical molecular aberrations of FGFR, PDGFRA/B, or T-cells, and that the initiating hits could be point mutations in a variety of genes, including spliceosome mutations or hypermethylated tumor suppressor genes. In addition, we identified a DNA methylation signature that is relevant for distinguishing clonal and suspected clonal eosinophilia from reactive eosinophilia per se, which may be useful in daily clinical work.
Combination of cadherin-17 and SATB homeobox 2 serves as potential optimal makers for the differential diagnosis of pulmonary enteric adenocarcinoma and metastatic colorectal adenocarcinoma
ONCOTARGET
Authors: Bian, Tingting; Zhao, Jinli; Feng, Jia; Zhang, Qing; Qian, Li; Liu, Jian; Jiang, Daishan; Liu, Yifei; Zhang, Jianguo
Abstract
Background: Pulmonary enteric adenocarcinoma (PEAC), a rare type of non-small cell lung cancer, has similar histological and immunohistochemical morphology to colorectal adenocarcinoma. Cadherin-17 (CDH17) and SATB homeobox 2 (SATB2) immunoexpression have recently been demonstrated in colorectal adenocarcinoma. In this study, we evaluated the value of CDH17 and SATB2 in the diagnosis of pulmonary enteric adenocarcinoma and metastatic colorectal adenocarcinoma. Methods: A total of 13 PEAC cases and 27 metastatic colorectal adenocarcinoma cases were enrolled in our cohort study. We analyzed the expressions of CK7, CK20, CDX-2, villin, cadherin-17 (CDH17), and SATB homeobox 2 (SATB2) using immunohistochemistry. Staining intensity and percentage of positive-staining cells were recorded. Sensitivity and specificity values for immunostains, individually and in combination, were computed and compared. Results: Combining CDH17 and SATB2 resulted in high sensitivity (76.92%) and specificity (100%). In our study, the use of CK7+, napsin A+,TTF-1+, napsin A+ TTF-1+ in combination with CDH17-/SATB2- had a higher area under the curve compared to the combination CDH17-/SATB2-. However, no significant differences were observed between the combination CDH17-/SATB2- and other combinations (P>0.05). Conclusions: In combination, CDH17 and SATB2 serve as potential optimal markers for the differential diagnosis of PEAC and metastatic colorectal adenocarcinoma.