JMIR Publications

ABSTRACT

Background:

Pancreatic ductal adenocarcinoma (PDAC) incidence is rising on an unprecedented scale in women, with the highest increases in younger and minority populations in the last two decades. GABRA3, an X-linked GABA-A receptor subunit, is biallelically expressed in females under X-inactivation escape. Wild-type GABRA3 drives Akt-dependent invasion and metastasis in PDAC and triple-negative breast cancer, whereas ADAR1-mediated A-to-I editing has been shown to elicit protective effects in aggressive malignancies. How protection translates into chronic metabolic stress in the pancreas under diabetes mellitus has yet to be elucidated.

Objective:

To obtain a genetic profile of female diabetic patients at risk or with pancreatic cancer and explore the relationship between structural variants of ADAR-1, lncXIST, and GABRA3 wild-type versus edited versions in tissue and blood samples for early risk detection of aggressive pancreatic ductal adenocarcinoma through existing datasets.

Methods:

Proposed method for upcoming research study using preexisting data sets across cBioPortal, NCBI GEO and TCGA includes: (1) quantify wild-type and A-to-I edited GABRA3 in pancreatic tissue, blood samples from diabetic women, healthy control, panINs and positive pancreatic status samples using targeted single cell and bulk RNA-sequencing, (2) observe any structural or isoforms of ADAR1 that reflect A-to-I editing functions, and characterize XIST variants against GABRA3 edits; and (3) assess whether changes in editing status of isoleucine to methionine predict risk or TNM stage of pancreatic cancer, or that has altered protection of GABRA3 functioning in reducing aggressive, metastatic forms of PDAC.

Results:

Preliminary results have examined studies from 2012 to 2026 on genetic mutations, copy number alterations, and structural variants in ADAR, GABA components, and X-chromosome-residing GABA components. Specialty genome database curation for pancreatic tissue and blood samples across normal human pancreatic tissue, diabetic control tissues, as well as blood samples, RNA-seq data for the largest cohort to exceed N=500 to meet Pancreatic Cancer Consortium 2018 recommendations.

Conclusions:

Further computational work and methods will be delivered with the final results based on the curated database sample size. A GABRA3 editing–based risk score would identify diabetic women at the highest PDAC risk in a population poorly served by CA 19-9, CEA, and other validated markers that are detected late to end stage, while further investigation of miR-92b, that down regulates GABRA3, as a sex-stratified therapeutic candidate in reducing the more aggressive forms of pancreatic ductal adenocarcinoma. Further investigations of Editing Inducer Element, EIE in editing wild-type GABRA3 to be investigated for potential therapeutic methods in reducing metastasis in pancreatic ductal adenocarcinoma. Clinical Trial: None.