ADAR1 Expression Level in Rectal Cancer

Total neoadjuvant therapy (TNT) is currently the standard treatment for locally/locally advanced rectal cancer due to better response and fewer distant metastases. In TNT, sequential chemotherapy (CT) and chemoradiotherapy (CRT) are planned and depending on the treatment response, either surgery is performed or a watch and wait approach is applied. Depending on tumor localization and patient performance status, CT is planned as induction or consolidation. Most of the time, mFOLFOX6 and CAPOX are preferred as CT regimen. In proximal rectal cancer, surgery can be performed without CRT and only after CT. In locally/locally advanced rectal cancer, the aim is to avoid surgery as much as possible or to perform sphincter-sparing surgery if possible. Colonoscopy and pelvic MR at the time of diagnosis are the most important steps in staging, treatment selection and decision making. These two diagnostic methods should be repeated especially for watch and wait decision and for response evaluation after TNT. ADAR 1 (Adenosine deaminase acting on RNA1) is an RNA editing enzyme that catalyzes the deamination of adenosine to inosine (A-to-I), a dynamic modification that can lead to a diverse transcriptome in a combinatorial manner. A defect in ADAR1-mediated RNA modification results in abnormal regulation of substrates that can affect phenotypic changes in cancer. This phenomenon of over-regulation is seen in many cancers such as colon, liver, lung, breast and esophageal cancers and in many cases promotes tumor progression. In studies, increased ADAR1 expression has been associated with lower survival and worse prognosis, especially in metastatic colon and gastric cancer. ADAR1 is also predicted to increase proliferation through both the AKT pathway and the mTOR pathway and therefore may be targeted in the near future. ADAR1 expression is monitored by RNA-based real time PCR. In order to demonstrate increased expression, biopsies should be taken from the malignant tissue and the intact tissue of the patient and the biopsy should be stored under -80 C conditions immediately after biopsy to prevent RNA degradation. The tissue will not come into contact with nitrogen or formaldehyde. In this study, sufficient biopsies from cancerous and intact tissue will be taken from patients with suspected rectal cancer, confirmed by pelvic MRI and consent for participation in the study, and fresh tissue will be stored at -80 C in the genetics laboratory. After the TNT plan is made by the investigators and the treatment is completed, both pelvic MRI and control rectoscopy will be performed for preoperative evaluation. Again, biopsies will be taken from diseased and healthy tissue and ADAR1 expression will be evaluated. The study is planned to include 50 participants and a period of one year is foreseen for tissue procurement/storage. The investigators' aim in this study will be to determine whether ADAR1 expression level changes after TNT, whether this predicts clinical and pathological response, whether responses change according to the selected CT, whether there is a difference between CT induction-consolidation/RT short or long course, and the relationship between tumor DNA mismatch repair enzyme status and ADAR1 level. The investigators primary endpoint will be the effect of the change in ADAR1 expression level on the response after TNT (ORR). Secondary endpoints will be quality of life, recurrence-free survival (RFS) and overall survival (OS).