Dataset Information

Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer.

ABSTRACT:

Purpose

To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS).

Experimental design

A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes.

Results

One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE.

Conclusions

Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.

SUBMITTER: Fasching PA

PROVIDER: S-EPMC9357161 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer.

Fasching Peter A PA Liu Duan D Scully Steve S Ingle James N JN Lyra Paulo C PC Rack Brigitte B Hein Alexander A Ekici Arif B AB Reis Andre A Schneeweiss Andreas A Tesch Hans H Fehm Tanja N TN Heinrich Georg G Beckmann Matthias W MW Ruebner Matthias M Huebner Hanna H Lambrechts Diether D Madden Ebony E Shen Jess J Romm Jane J Doheny Kim K Jenkins Gregory D GD Carlson Erin E EE Li Liang L Fridley Brooke L BL Cunningham Julie M JM Janni Wolfgang W Monteiro Alvaro N A ANA Schaid Daniel J DJ Häberle Lothar L Weinshilboum Richard M RM Wang Liewei L

Clinical cancer research : an official journal of the American Association for Cancer Research 20220801 15

<h4>Purpose</h4>To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS).<h4>Experimental design</h4>A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated wit ...[more]

PMID: 35653140

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Project description:BackgroundThe most common toxic side effect after chemotherapy, one of the main treatments for colorectal cancer (CRC), is myelosuppression.ObjectiveTo analyze the correlation between gut microbiota and leukopenia after chemotherapy in CRC patients.MethodsStool samples were collected from 56 healthy individuals and 55 CRC patients. According to the leukocytes levels in peripheral blood, the CRC patients were divided into hypoleukocytes group (n = 13) and normal leukocytes group (n = 42). Shannon index, Simpson index, Ace index, Chao index and Coverage index were used to analyze the diversity of gut microbiota. LDA and Student's t-test(St test) were used for analysis of differences. Six machine learning algorithms, including logistic regression (LR) algorithm, random forest (RF) algorithm, neural network (NN) algorithm, support vector machine (SVM) algorithm, catboost algorithm and gradient boosting tree algorithm, were used to construct the prediction model of gut microbiota with leukopenia after chemotherapy for CRC.ResultsCompared with healthy group, the microbiota alpha diversity of CRC patients was significantly decreased (p < 0.05). After analyzing the gut microbiota differences of the two groups, 15 differential bacteria, such as Bacteroides, Faecalibacterium and Streptococcus, were screened. RF prediction model had the highest accuracy, and the gut microbiota with the highest predictive value were Peptostreptococcus, Faecalibacterium, and norank_f__Ruminococcaceae, respectively. Compared with normal leukocytes group, the microbiota alpha diversity of hypoleukocytes group was significantly decreased (p < 0.05). The proportion of Escherichia-Shigella was significantly decreased in the hypoleukocytes group. After analyzing the gut microbiota differences of the two groups, 9 differential bacteria, such as Escherichia-Shigella, Fusicatenibacter and Cetobacterium, were screened. RF prediction model had the highest accuracy, and the gut microbiota with the highest predictive value were Fusicatenibacte, Cetobacterium, and Paraeggerthella.ConclusionGut microbiota is related to leukopenia after chemotherapy. The gut microbiota may provide a novel method for predicting myelosuppression after chemotherapy in CRC patients.

Project description:BackgroundBreast cancer is one of the most common cancers and a major cause of death in women worldwide. Chemotherapy is mainly used to treat and control the progression of breast cancer. Leukopenia is the most common side effect of chemotherapy which may decrease immune function and further lead to serious fatal infections. The purpose of this study was to evaluate the effect of acupuncture on regulating hematopoietic function in chemotherapy-induced leukopenia among patients with breast cancer.MethodsPubMed, Embase, Cochrane Library, CINAHL Plus, Web of Science, and Chinese articles in the Airiti Library and China National Knowledge Infrastructure (CNKI) databases were searched to August 2021 for papers to include in a systematic review and meta-analysis. A random-effects model was applied. The effect size was calculated by Hedges' g. Heterogeneity was determined using Cochran's Q test. Moderator analyses were performed to examine potential sources of heterogeneity. A trial sequential analysis (TSA) was conducted to determine whether the current sample size was sufficient.ResultsTen randomized controlled trials involving 650 participants were eligible for inclusion. Analysis by the random-effects model showed a significant effect by acupuncture of ameliorating leukopenia during chemotherapy. Levels of white blood cells (WBCs) were increased (Hedges' g = 0.70, P < .001, I2 = 34%), neutrophil counts (Hedges' g = 0.80, P < .001, I2 = 0%) were significantly enhanced. Moreover, regardless of the manner through which acupuncture was applied, overall values of WBCs increased.ConclusionsThe current meta-analysis supports acupuncture possibly ameliorating chemotherapy-induced leukopenia, as WBC and neutrophil values significantly increased after acupuncture in patients undergoing chemotherapy. Additionally, regardless of the type of acupuncture, values of WBCs increased. These findings are actionable and support both the clinical use of acupuncture to relieve chemotherapy-induced leukopenia and further research regarding the use of acupuncture in patients experiencing immunosuppression when undergoing chemotherapy.Trial Registration: PROSPERO-CRD42020215759.

Dataset Information

Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer.

Purpose

Experimental design

Results

Conclusions

Publications

Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer.

Similar Datasets

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