Aberration of ARID1A Is Associated With the Tumorigenesis and Prognosis of Sporadic Nonfunctional Pancreatic Neuroendocrine Tumors

Abstract

Objective The genetic aberrations that underlie chromatin remodeling in sporadic nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) remain largely unknown. Here, we investigated the dysregulation of the switch/sucrose nonfermentable (SWI/SNF) component ARID1A and its correlation with clinicopathological features and prognosis. Methods We sequenced the exomes of sporadic NF-pNETs. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to determine messenger RNA level and protein expression. Results The sporadic NF-pNETs harbored 264 somatic mutations in 228 different genes, most commonly affecting the SWI/SNF components ARID1B (57.1%) and ARID1A (42.9%). The expression of ARID1A was remarkably downregulated in NF-pNETs and corresponding liver metastases compared with that in normal pancreatic islet tissue. Reduced expression of ARID1A was associated with malignant clinicopathological features (P < 0.05). The loss of ARID1A was related to a high Ki-67 index (P < 0.05). Patients with ARID1A-negative expression had a significantly worse overall survival rate than those with ARID1A-positive expression (P < 0.05). The ARID1A status was an independent predictor of overall survival, and a nomogram integrating ARID1A with clinicopathological features was proposed. Conclusions The loss of SWI/SNF components ARID1A may be associated with malignant behaviors and an unfavorable prognosis. Aberrations of ARID1A may contribute to tumorigenesis and metastasis in sporadic NF-pNETs.

Characterization of Hepatitis B Virus Integrations Identified in Hepatocellular Carcinoma Genomes

“…We identified HBV integrations with high integration allele fraction seven non-recurrent cancer-related genes, including GAS7 [74,75], NS [77,78], NRG1 [79], PRDM16 [80], ARID1B [81], and AFF1 [82]. GAS7 has be directly regulated by P53 and is part of a critical mechanism that mediate metastasis [74]; NRG1 fusions were identified as drivers for lung adenoc…”

“…We identified HBV integrations with high integration allele fractions in tumors in seven non-recurrent cancer-related genes, including GAS7 [74,75], NSP [76], RSPO2 [77,78], NRG1 [79], PRDM16 [80], ARID1B [81], and AFF1 [82]. GAS7 has been shown to be directly regulated by P53 and is part of a critical mechanism that mediates breast cancer metastasis [74]; NRG1 fusions were identified as drivers for lung adenocarcinoma [79]; And the involvement of PRDM16 in leukemia [80], ARID1B in ovarian cancer [81], and AFF1 in leukemia [82] has also been reported; It has been demonstrated that a GAS7-mediated pathway suppressed proliferation of HCC cells following treatment with oxaliplatin, an alkylating anti-neoplastic agent, and the inhibition of GAS7 negated the beneficial effects of the drug [83]. Similarly, NRG1 is associated with promoting metastasis of HCC cells by increasing epithelial-mesenchymal transition, thus increasing migratory behavior of the cancer cells [84] (genetic variants in NRG1 have also been associated with schizophrenia [85]).…”

Molecular profile of pancreatic neuroendocrine neoplasms (PanNENs): Opportunities for personalized therapies

“…It has been demonstrated that increasing numbers of molecular pathways are involved in the biology and clinical behavior of panNENs (Table 1). 6,12‐15 A 2003 study by Maitra et al 16 in well differentiated panNETs identified approximately 200 differentially expressed genes. The results of the International Cancer Genome Consortium effort on panNENs identified 4 pathways: DNA damage repair, chromatin remodeling, telomere alteration, and PI3K/mTOR signaling 17 …”

“…The role of MMR deficiency and microsatellite instability in the carcinogenesis of panNENs and treatment selection is less well studied 33,34 . A recent study suggested that the frequently downregulated ARID1A in panNENs was associated with a worse prognosis 14 …”

Effect of ARID1A mutation and expression on prognosis of hepatocellular carcinoma and cholangiocarcinoma: a meta-analysis

“…Thus, ARID1A was considered as a broad tumor suppressor [8]. Mutations and abnormal expression of ARID1A have been found in a variety of cancers, such as urothelial bladder tumors [9], colorectal cancer [10], nonfunctional pancreatic neuroendocrine tumors [11], invasive micropapillary carcinomas of the breast [12], endometriosis and uterine endometrioid carcinoma [13,14].…”