Common variation in a long non-coding RNA gene modulates variation of circulating TGF-β2 levels in metastatic colorectal cancer patients (Alliance).

Autor: Quintanilha JCF; UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Sibley AB; Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA., Liu Y; Department of Medicine, Duke University Medical Center, Durham, NC, USA., Niedzwiecki D; Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.; Alliance Statistics and Data Management Center, Duke University, Durham, NC, USA., Halabi S; Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.; Alliance Statistics and Data Management Center, Duke University, Durham, NC, USA., Rogers L; Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA., O'Neil B; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA., Kindler H; Department of Medicine, The University of Chicago, Chicago, IL, USA., Kelly W; Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Venook A; Department of Medicine, University of California at San Francisco, San Francisco, CA, USA., McLeod HL; University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Utah Tech University, St George, UT, USA., Ratain MJ; Department of Medicine, The University of Chicago, Chicago, IL, USA., Nixon AB; Department of Medicine, Duke University Medical Center, Durham, NC, USA., Innocenti F; Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Owzar K; Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA. kouros.owzar@duke.edu.; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA. kouros.owzar@duke.edu.; Alliance Statistics and Data Management Center, Duke University, Durham, NC, USA. kouros.owzar@duke.edu.
Jazyk: angličtina
Zdroj: BMC genomics [BMC Genomics] 2024 May 14; Vol. 25 (1), pp. 473. Date of Electronic Publication: 2024 May 14.
DOI: 10.1186/s12864-024-10354-7
Abstrakt: Background: Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC). The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms. The abundance of protein markers was quantified using a multiplex enzyme-linked immunosorbent assay from plasma derived from peripheral venous blood collected at baseline. A robust rank-based method was used to assess the statistical significance of each variant and protein pair against a strict genome-wide level. A given pQTL was tested for validation in two external datasets of prostate (CALGB 90401) and pancreatic cancer (CALGB 80303) patients. Bioinformatics analyses were conducted to further establish biological bases for these findings.
Results: The final analysis was carried out based on data from 540,021 common typed genetic variants and 23 protein markers from 869 genetically estimated European patients with mCRC. Correcting for multiple testing, the analysis discovered a novel cis-pQTL in LINC02869, a long non-coding RNA gene, for circulating TGF-β2 levels (rs11118119; AAF = 0.11; P-value < 1.4e-14). This finding was validated in a cohort of 538 prostate cancer patients from CALGB 90401 (AAF = 0.10, P-value < 3.3e-25). The analysis also validated a cis-pQTL we had previously reported for VEGF-A in advanced pancreatic cancer, and additionally identified trans-pQTLs for VEGF-R3, and cis-pQTLs for CD73.
Conclusions: This study has provided evidence of a novel cis germline genetic variant that regulates circulating TGF-β2 levels in plasma of patients with advanced mCRC and prostate cancer. Moreover, the validation of previously identified pQTLs for VEGF-A, CD73, and VEGF-R3, potentiates the validity of these associations.
(© 2024. The Author(s).)
Databáze: MEDLINE
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