Date Published: July 5, 2017
Publisher: Public Library of Science
Author(s): Cielito C. Reyes-Gibby, Stephanie C. Melkonian, Jian Wang, Robert K. Yu, Samuel A. Shelburne, Charles Lu, Gary Brandon Gunn, Mark S. Chambers, Ehab Y. Hanna, Sai-Ching J. Yeung, Sanjay Shete, Sunil K. Ahuja.
Mucositis is a complex, dose-limiting toxicity of chemotherapy or radiotherapy that leads to painful mouth ulcers, difficulty eating or swallowing, gastrointestinal distress, and reduced quality of life for patients with cancer. Mucositis is most common for those undergoing high-dose chemotherapy and hematopoietic stem cell transplantation and for those being treated for malignancies of the head and neck. Treatment and management of mucositis remain challenging. It is expected that multiple genes are involved in the formation, severity, and persistence of mucositis. We used Ingenuity Pathway Analysis (IPA), a novel network-based approach that integrates complex intracellular and intercellular interactions involved in diseases, to systematically explore the molecular complexity of mucositis. As a first step, we searched the literature to identify genes that harbor or are close to the genetic variants significantly associated with mucositis. Our literature review identified 27 candidate genes, of which ERCC1, XRCC1, and MTHFR were the most frequently studied for mucositis. On the basis of this 27-gene list, we used IPA to generate gene networks for mucositis. The most biologically significant novel molecules identified through IPA analyses included TP53, CTNNB1, MYC, RB1, P38 MAPK, and EP300. Additionally, uracil degradation II (reductive) and thymine degradation pathways (p = 1.06−08) were most significant. Finally, utilizing 66 SNPs within the 8 most connected IPA-derived candidate molecules, we conducted a genetic association study for oral mucositis in the head and neck cancer patients who were treated using chemotherapy and/or radiation therapy (186 head and neck cancer patients with oral mucositis vs. 699 head and neck cancer patients without oral mucositis). The top ranked gene identified through this association analysis was RB1 (rs2227311, p-value = 0.034, odds ratio = 0.67). In conclusion, gene network analysis identified novel molecules and biological processes, including pathways related to inflammation and oxidative stress, that are relevant to mucositis development, thus providing the basis for future studies to improve the management and treatment of mucositis in patients with cancer.
Mucositis is a toxicity (inflammation/ulceration) of the alimentary tract resulting from chemotherapeutic agents or radiation [1–3]. Mucositis represents a major complication for patients undergoing cancer treatment [4, 5]: oral and gastrointestinal mucositis are most commonly found in nearly 100% of patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation  and in 60%–80% of patients being treated for malignancies of the head and neck . Complications of mucositis include painful mouth ulcers, difficulty eating or swallowing, and gastrointestinal distress (including diarrhea), which can result in unplanned hospitalizations, poorer clinical outcomes, and reduced quality of life [2, 7]. Current treatment focuses on pain control, rehydration, and basic oral/bowel care, but these have not been shown to meaningfully influence the trajectory of mucositis . Clinical factors such as dose, duration, and intensity of radiation and chemotherapy , and patient factors such as age, sex, and body mass index [7–10], have been found to be associated with the development of mucositis, yet these explain only some of the variation observed in the risk for, severity of, and persistence of this condition. Therefore, a better understanding of the potential biological mechanisms underlying mucositis development, severity, and persistence may have significant clinical impact.
We first conducted a literature search on genetic studies of mucositis, as described below. Second, using genes pooled from the literature as a starting point, we used IPA to generate gene networks for mucositis and identified additional molecules that are functionally related to the genes obtained from the literature search.
In this study, we performed a comprehensive literature review with the aim of identifying genes that were previously associated with treatment-related mucositis in cancer patients. We then used IPA bioinformatic tools to conduct a comprehensive pathway and network analysis of the genes identified in the literature. From the review of the literature, we found that genes associated with the cell cycle and DNA repair were studied most frequently. Among the focus genes in our study, the genes most commonly assessed for their association with mucositis were ERCC1, XRCC1, and MTHFR. The results of the IPA suggest that the top focus genes, in terms of the number of connections, in mucositis were CDKN1A (p21) and BRCA1; the novel molecules identified through the IPA were TP53, CTNNB1, MYC, RB1, P38 MAPK, and EP300.