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Lincp21-RNA As Predictive Response Marker for Preoperative Chemoradiotherapy in Rectal Cancer

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Lincp21-RNA As Predictive Response Marker for Preoperative Chemoradiotherapy in Rectal Cancer Journal of Personalized Medicine Article Lincp21-RNA as Predictive Response Marker for Preoperative Chemoradiotherapy in Rectal Cancer Jose Carlos Benitez 1,2,†, Marc Campayo 2,*,†, Tania Díaz 3, Carme Ferrer 4, Melissa Acosta-Plasencia 3 , Mariano Monzo 3, Luis Cirera 2, Benjamin Besse 1,5 and Alfons Navarro 3,* 1 Department of Cancer Medicine, Gustave Roussy Cancer Center, 94805 Villejuif, France; [email protected] (J.C.B.); [email protected] (B.B.) 2 Department of Medical Oncology, Mutua Terrassa University Hospital, University of Barcelona, 08221 Terrassa, Spain; [email protected] 3 Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, Faculty of Medicine and Health Sciences, University of Barcelona, IDIBAPS, 08036 Barcelona, Spain; [email protected] (T.D.); [email protected] (M.A.-P.); [email protected] (M.M.) 4 Department of Pathology, Mutua Terrassa University Hospital, University of Barcelona, 08221 Terrassa, Barcelona, Spain; [email protected] 5 Faculty of Science, Orsay Campus, Paris-Saclay University, 91400 Orsay, France * Correspondence: [email protected] (M.C.); [email protected] (A.N.) † These two authors contributed equally to this work. Abstract: Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (RC) patients, but its use in non-responders can be associated with increased toxicities and resection delay. LincRNA-p21 is a long non-coding RNA involved in the p53 pathway and angiogenesis regulation. We aimed to study whether lincRNA-p21 expression levels can act as a Citation: Benitez, J.C.; Campayo, M.; predictive biomarker for neoadjuvant CRT response. We analyzed RNAs from pretreatment biopsies Díaz, T.; Ferrer, C.; Acosta-Plasencia, from 70 RC patients treated with preoperative CRT. Pathological response was classified according to M.; Monzo, M.; Cirera, L.; Besse, B.; the tumor regression grade (TRG) Dworak classification. LincRNA-p21 expression was determined Navarro, A. Lincp21-RNA as Predictive Response Marker for by RTqPCR. The results showed that lincRNA-p21 was upregulated in stage III tumors (p = 0.007) Preoperative Chemoradiotherapy in and in tumors with the worst response regarding TRG (p = 0.027) and downstaging (p = 0.016). ROC Rectal Cancer. J. Pers. Med. 2021, 11, curve analysis showed that lincRNA-p21 expression had the capacity to distinguish a complete 420. https://doi.org/10.3390/ response from others (AUC:0.696; p = 0.014). LincRNA-p21 was shown as an independent marker jpm11050420 of preoperative CRT response (p = 0.047) and for time to relapse (TTR) (p = 0.048). In conclusion, lincRNA-p21 is a marker of advanced disease, worse response to neoadjuvant CRT, and shorter TTR Academic Editor: James Meehan in locally advanced RC patients. The study of lincRNA-p21 may be of value in the individualization of pre-operative CRT in RC. Received: 22 April 2021 Accepted: 12 May 2021 Keywords: lincRNA-p21; rectal cancer; chemoradiotherapy; colorectal cancer; long non-coding RNA; Published: 16 May 2021 p53; predictive biomarker Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Rectal cancer (RC) accounts for approximately one-third of all colorectal tumors (CRC) and remains the third most common cancer worldwide and the second leading cause of cancer-related death in the world [1]. RC differs in etiologies and risk factors due to odd environmental exposures [2,3] and may have unique genetics and epigenetics factors [4]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. However, during the past decade, reduction in mortality for RC has slowed [1] owing This article is an open access article to a high rate of distant metastasis (29–39%) [5,6]. Long-term analysis has shown that distributed under the terms and preoperative chemoradiotherapy (CRT) followed by surgery of primary tumor results in conditions of the Creative Commons persistent local control [5] and has become the standard of care for locally advanced tumors Attribution (CC BY) license (https:// (T3-T4 or N+) [7]. The most frequently used chemotherapy agent is 5-fluorouracil in combi- creativecommons.org/licenses/by/ nation with concurrent fractionation radiotherapy [7]. Preoperative CRT achieves a higher 4.0/). radiosensitivity of tissues before surgery, a lower rate of toxicities, and a higher probability J. Pers. Med. 2021, 11, 420. https://doi.org/10.3390/jpm11050420 https://www.mdpi.com/journal/jpm J. Pers. Med. 2021, 11, 420 2 of 10 of sphincter preservation due to tumor downstaging [8]. Of note, the rate of pathological response after neoadjuvant treatment has been associated with prognosis [8,9]. Patho- logical complete response (pCR; ypT0N0), which occurs in 15–25% of patients, has been linked with lower rates of local recurrences [9,10]. Indeed, to achieve a complete response after preoperative CRT has been associated with better disease-free survival (DFS) and overall survival (OS) rates [9]. Nonetheless, survival outcomes of patients with an assessed pCR compared to those without have not been properly compared; therefore, selection of patients to avoid unnecessary toxicities and to perform suitable management remains uncertain. Furthermore, despite the adoption of adjuvant postoperative chemotherapy, patients are more than twice as likely to present with a distant recurrence rather than tumor regrowth at the primary site [5,6]. This situation emphasizes the urgency of devising upfront treatment strategies aimed at controlling obscure micro-metastases. Identifying patients who will not respond to treatment is crucial to avoid unnecessary treatment, potential toxicities, and a delay of surgery. Biomarkers to identify patients at high risk of relapse or lack of response are needed to guide treatment options and improve survival rates [11], and non-coding RNAs are promising candidates [12,13]. Non-coding RNAs comprise 97% of the transcriptome, while protein-coding messen- ger RNAs (mRNA) account for only 3% [14]. Long non-coding RNAs (lncRNAs) have been related to the main hallmarks of cancer [15] and have been described as key in the tumorigenesis of different solid tumors, including RC [16,17]. Indeed, lncRNAs have been shown to be highly tissue specific [18,19], being able to discriminate between tumor and normal cells [20]. The long intergenic non-coding RNA p21 (lincRNA-p21) acts as a regu- lator for p53-mediated apoptosis [21], angiogenesis [22], and HIF1A-mediated response to hypoxia in cancer cells [23]. However, the role of lincRNA-p21 in RC remains poorly understood and explored only in vitro or using small cohorts of patients [24,25]. In this setting, lncRNAs, and especially lincRNA-p21, could serve as predictive biomarkers to select the most optimal treatment in each case in order to individualize therapy. We aimed to evaluate whether lincRNA-p21 can act as a predictive biomarker for CRT response in a 70-patient cohort of RC treated before resection. 2. Materials and Methods 2.1. Study Population Seventy patients diagnosed from December 2006 to October 2016, with RC and avail- able baseline endoscopy biopsy from Mutua Terrassa University Hospital, were included in the present study. All selected patients suffered with rectal adenocarcinoma in a clinical stage II or III (uT3-T4 and/or uN+) and were consecutively treated at Mutua Terrassa University Hospital. Although the study population was collected in Barcelona (Europe), ethnical information was not considered for patient inclusion within the study. All samples were stored as paraffin-embedded blocks until use. All patients had received neoadjuvant chemotherapy with 5-fluorouracil 225 mg/m2/day × 7 days in continuous infusion and in combination with pelvic locoregional radiotherapy (45–50 Gy). Six to eight weeks after completion, all patients underwent surgery. All surgical specimens were evaluated and classified according to TNM 7th edition, and the pathological response was graded ac- cording to the tumor regression grade (TRG) Dworak classification [26]. Approval for the study was obtained from the Institutional Review Board of the Mutua Terrassa University Hospital, Barcelona, Spain. 2.2. RNA Extraction and lincRNA-p21 Quantification Total RNA was extracted from formalin-fixed, paraffin-embedded, tumor tissues from pretreatment endoscopy biopsies using a RecoverAll Total Nucleic Acid Isolation Kit (Ambion, ThermoFisher Scientific, Waltham, MA, USA) as previously reported [27] and quantified using a NanoDrop ND-1000 Spectrophotometer (NanoDrop Technologies, Wilmington, DE). Total cDNA was obtained from 250 ng of RNA using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA). LincRNA- J. Pers. Med. 2021, 11, 420 3 of 10 p21 expression was determined as previously described [22]. LincRNA-p21 expression was calculated using 2−DDCt using B2M (beta-2-microglobulin) (Hs99999907_m1) (Applied Biosystems) as endogenous control. 2.3. Statistical Methods Assumptions of distributional normality were tested using the Shapiro–Wilk test and quantile–quantile plot. Continuous data were tested with the T-test (two groups) or ANOVA (more than two groups) when normally distributed and the Mann–Whitney U-test or Kruskal–Wallis test when not normally distributed. ROC curves were calculated using R package pROC [28]. The multivariate analysis for treatment response was performed by using binary logistic regression. Time
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