Lower Expression of <i>CFTR</i> Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer
Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (<i>CFTR)</i>, have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/3/989 |
| _version_ | 1797624978213961728 |
|---|---|
| author | Patricia Scott Shuo Wang Guillaume Onyeaghala Nathan Pankratz Timothy Starr Anna E. Prizment |
| author_facet | Patricia Scott Shuo Wang Guillaume Onyeaghala Nathan Pankratz Timothy Starr Anna E. Prizment |
| author_sort | Patricia Scott |
| collection | DOAJ |
| description | Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (<i>CFTR)</i>, have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of tumoral <i>CFTR</i> mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced <i>CFTR</i> expression in this population, we investigated association of tumoral <i>CFTR</i> expression with overall and disease-specific mortality in CRC patients. <i>CFTR</i> mRNA expression, clinical factors and survival data from 1177 CRC patients reported in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus studies GSE39582 and GSE17538 were included. Log-transformed and z-normalized [mean = 0, standard deviation (SD) = 1] <i>CFTR</i> expression values were modeled as quartiles or dichotomized at the median. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and disease-specific mortality in individual studies and meta-analyses. Analyses of each of the three individual datasets showed a robust association of decreased <i>CFTR</i> expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, <i>CFTR</i> expression was inversely associated with risk of overall death [pooled HR (95% CI): 0.70 (0.57–0.86)] and disease-specific death [pooled HR (95% CI): 0.68 (0.47–0.99)]. Associations did not differ by stage at diagnosis, age, or sex. Meta-analysis of overall death stratified by microsatellite instable (MSI) versus microsatellite stable (MSS) status indicated potential interaction between MSI/MSS status and <i>CFTR</i> expression, (<i>p</i>-interaction: 0.06). The findings from these three datasets support the hypothesis that low <i>CFTR</i> expression is associated with increased CRC mortality. |
| first_indexed | 2024-03-11T09:50:19Z |
| format | Article |
| id | doaj.art-a6f4d50464c34ff6a86abfb083ed6e3b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:50:19Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a6f4d50464c34ff6a86abfb083ed6e3b2023-11-16T16:20:05ZengMDPI AGCancers2072-66942023-02-0115398910.3390/cancers15030989Lower Expression of <i>CFTR</i> Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal CancerPatricia Scott0Shuo Wang1Guillaume Onyeaghala2Nathan Pankratz3Timothy Starr4Anna E. Prizment5Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USADivision of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 55455, USADivision of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 55455, USADepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USADepartment of Obstetrics, Gynecology and Women’s Health, University of Minnesota Medical School, Minneapolis, MN 55455, USADivision of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN 55455, USAIndividuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (<i>CFTR)</i>, have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of tumoral <i>CFTR</i> mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced <i>CFTR</i> expression in this population, we investigated association of tumoral <i>CFTR</i> expression with overall and disease-specific mortality in CRC patients. <i>CFTR</i> mRNA expression, clinical factors and survival data from 1177 CRC patients reported in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus studies GSE39582 and GSE17538 were included. Log-transformed and z-normalized [mean = 0, standard deviation (SD) = 1] <i>CFTR</i> expression values were modeled as quartiles or dichotomized at the median. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and disease-specific mortality in individual studies and meta-analyses. Analyses of each of the three individual datasets showed a robust association of decreased <i>CFTR</i> expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, <i>CFTR</i> expression was inversely associated with risk of overall death [pooled HR (95% CI): 0.70 (0.57–0.86)] and disease-specific death [pooled HR (95% CI): 0.68 (0.47–0.99)]. Associations did not differ by stage at diagnosis, age, or sex. Meta-analysis of overall death stratified by microsatellite instable (MSI) versus microsatellite stable (MSS) status indicated potential interaction between MSI/MSS status and <i>CFTR</i> expression, (<i>p</i>-interaction: 0.06). The findings from these three datasets support the hypothesis that low <i>CFTR</i> expression is associated with increased CRC mortality.https://www.mdpi.com/2072-6694/15/3/989colorectal cancerCFTRsurvivalmortalityCox proportional hazards regressionTCGA COADREAD |
| spellingShingle | Patricia Scott Shuo Wang Guillaume Onyeaghala Nathan Pankratz Timothy Starr Anna E. Prizment Lower Expression of <i>CFTR</i> Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer Cancers colorectal cancer CFTR survival mortality Cox proportional hazards regression TCGA COADREAD |
| title | Lower Expression of <i>CFTR</i> Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer |
| title_full | Lower Expression of <i>CFTR</i> Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer |
| title_fullStr | Lower Expression of <i>CFTR</i> Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer |
| title_full_unstemmed | Lower Expression of <i>CFTR</i> Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer |
| title_short | Lower Expression of <i>CFTR</i> Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer |
| title_sort | lower expression of i cftr i is associated with higher mortality in a meta analysis of individuals with colorectal cancer |
| topic | colorectal cancer CFTR survival mortality Cox proportional hazards regression TCGA COADREAD |
| url | https://www.mdpi.com/2072-6694/15/3/989 |
| work_keys_str_mv | AT patriciascott lowerexpressionoficftriisassociatedwithhighermortalityinametaanalysisofindividualswithcolorectalcancer AT shuowang lowerexpressionoficftriisassociatedwithhighermortalityinametaanalysisofindividualswithcolorectalcancer AT guillaumeonyeaghala lowerexpressionoficftriisassociatedwithhighermortalityinametaanalysisofindividualswithcolorectalcancer AT nathanpankratz lowerexpressionoficftriisassociatedwithhighermortalityinametaanalysisofindividualswithcolorectalcancer AT timothystarr lowerexpressionoficftriisassociatedwithhighermortalityinametaanalysisofindividualswithcolorectalcancer AT annaeprizment lowerexpressionoficftriisassociatedwithhighermortalityinametaanalysisofindividualswithcolorectalcancer |