Oncotarget. 2017;8(30):49796-49806.

DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors.

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제1저자 박주경, 백우현 · 교신저자 류지곤

PMID 28591701 PMC5564808 DOI 10.18632/oncotarget.17964 IF 5.168 소화기내과

소속 (3)

Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Department of Internal Medicine and Liver Research Institutute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Abstract

BACKGROUND PanNETs shows heterogeneous biological behaviors. The aim was to investigate prognostic markers based on most frequently mutated genes in PanNETs.

RESULTS There was a total of 76 patients (M: 39, F: 37) with pathologically proven PanNETs. ATRX/DAXX and MEN1 protein expression was detected in 16 (21%) and 31 (41%) patients, respectively. The mean OS of the total study patients was 16 years, and DFS was 17 years among the 68 patients with curative resections. PanNETs presented with distant metastasis or loss of ATRX/DAXX protein expression was the independent prognostic factors associated with poor OS. In curative resected PanNETs, there was no significant difference in the mean DFS according to ATRX/DAXX or MEN1 protein. However, there was statistically significant difference in survival after the recurrence according to the expression of ATRX/DAXX protein; Y/N: 10 vs. 15 years, p < 0.001. In metastatic PanNETs, we could find out OS was significantly longer in negative protein expression of ATRX/DAXX and MEN1 groups; 7 vs. 1 years, p < 0.001, 6 vs. 2 years, p = 0.02, respectively.

MATERIALS AND METHODS The histologically proven PanNETs were enrolled and the clinicopathologic and genetic alterations were evaluated.

CONCLUSIONS Protein expression of MEN1 and DAXX/ATRX can be prognostic markers for PanNETs. Further investigation in genetic alterations of PanNETs may give us insights understanding the behavior of PanNETs.

Keywords

DAXX/ATRXMENneuroendocrine tumor

Figures

**Figure 1** Immunohistochemical staining of MEN1 (A)(D)(G), ATRX (B)(E)(H), and DAXX (C)(F)(I) (A–C) Positive nuclear staining of MEN1, ATRX, and DAXX (D–F) Positive cytoplasmic staining of MEN1, ATRX, and DAXX (G–I) Negative staining of MEN1, ATRX, and DAXX (all pictures x200) (J) Expression status of MEN1 and ATRX/DAXX according to the immunohistochemical staining.

**Figure 2** Kaplan-Meier curve of overall survival and DFS of the study patients (A) OS of the total of 76 study patients (B) DFS of the patients who underwent curative resection.

**Figure 3** Univariate analyses of OS according to the clinicopathologic factors (A) No distant metastasis vs. metastatic PanNETs at the time of diagnosis (mean OS 3.0 yrs vs. 16.9 yrs, p < 0.001) (B) Lymph node positive vs. negative at the time of diagnosis (mean OS 8.8 yrs vs. 16.0 yrs, p = 0.025) (C) Whether curative intent surgery was done or not (mean OS 16.7 yrs vs. 2.9 yrs, p < 0.001) (D) WHO grade (mean OS G1 16.4 yrs vs. G2 15.4 yrs vs. G3 0.6 yrs, p < 0.001) and (E) Negative for ATRX/DAXX protein expression (N/Y: mean OS 15.3 yrs vs. 10.8 yrs, p < 0.001) were statistically significant factors associated with OS among the study patients.

**Figure 4** Prognostic factors affecting survival in patients with curatively resected PanNETs (A) Kaplan-Meier curves of DFS for ATRX/DAXX protein expression (N/Y: 15.4 yrs vs. 17.1 yrs, p = 0.77) and MEN1 protein expression (N/Y: 16.0 yrs vs. 16.4 yrs, p = 0.47) (B) Kaplan-Meier curves of OS after the recurrence for ATRX/DAXX protein expression (N/Y: 15.3 yrs vs. 9.7 yrs, p < 0.001) and MEN1 protein expression (N/Y: 16.4 yrs vs. 12.4 yrs, p = 0.08).

**Figure 5** Prognostic factors affecting survival in patients with metastatic PanNETs (A) Kaplan-Meier curves of OS according to the protein expression of ATRX/DAXX (N/Y: 6.5 yrs vs. 1.1 years, p < 0.001) (B) Kaplan-Meier curves of OS according to the protein expression of MEN1 (N/Y: 6.2 yrs vs. 1.5 yrs, p = 0.03).

**Figure 6** Flow chart of study patients

그림 출처: PubMed Central 공개 논문 (PMC5564808)

Conflict of interest statement

CONFLICTS OF INTEREST. None.

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