Journal of Shanghai Jiao Tong University (Medical Science) >

2025 , Vol. 45 >Issue 10: 1342 - 1352

DOI: https://doi.org/10.3969/j.issn.1674-8115.2025.10.009

Clinical research

Identification and evaluation of COL12A1 as a novel serological diagnostic marker in pancreatic ductal adenocarcinoma

  • LIU Jia ,
  • REN Lingjie ,
  • SHI Minmin ,
  • TANG Xiaomei ,
  • MA Fangfang ,
  • QIN Jiejie
Expand
  • 1.Institute of Pancreas Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    2.Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
QIN Jiejie, E-mail: qinjie2007@126.com.

Received date: 2025-03-25

  Accepted date: 2025-09-18

  Online published: 2025-10-23

Supported by

National Natural Science Foundation of China(82304212)

Fold

Abstract

Objective ·To identify and evaluate novel and reliable non-invasive serological biomarkers for detecting pancreatic ductal adenocarcinoma (PDAC). Methods ·Sixty-seven PDAC patients (Ruijin cohort Ⅰ) were recruited at Pancreatic Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, from May 2018 to December 2019. Global proteome profiling of 67 PDAC tumor tissues and 67 matched adjacent normal tissues was performed using mass spectrum. Bioinformatics analysis on the proteomics data was conducted to identify new biomarkers, and receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to evaluate their value of detecting PDAC. The proteomic and mRNA sequencing data were further downloaded and analysed from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) cohort for validation. In addition, the Ruijin Cohort Ⅱ, consisting of 47 PDAC patients and 75 healthy individuals, was recruited for a case-control study from June 2021 to June 2022. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression level of new biomarkers in the serum of patients and healthy individuals to evaluate the serological diagnostic values of them. Results ·Collagen type Ⅻ α1 chain (COL12A1) was identified as a candidate biomarker for PDAC diagnosis based on differential expression analysis on the proteomic data and was validated to be higher in tumor tissues than in adjacent normal tissues in the CPTAC cohort. In addition, COL12A1 protein levels were significantly higher in the sera of PDAC patients than in those of healthy controls, showing good diagnostic performance with an AUC of 0.82, a sensitivity of 81%, and a specificity of 83%. ROC analysis revealed that COL12A1 improved the performance of carbohydrate antigen 199 (CA199) in distinguishing PDAC patients from healthy individuals (AUCCA199=0.91 vs AUCCA199 +COL12A1=0.95, P<0.05). Furthermore, COL12A1 also showed excellent ability to distinguish early-stage PDAC patients (stage Ⅰ‒Ⅱ) from healthy individuals (AUCCOL12A1=0.83), and significantly improved the AUC of CA199 in early-stage PDAC patients (AUCCA199=0.92 vs AUCCA199+COL12A1=0.97, P<0.05). Conclusion ·COL12A1 is a potential serological diagnostic marker that complements CA199 in detecting early-stage PDAC.

Key words： pancreatic ductal adenocarcinoma (PDAC); collagen type Ⅻ α1 chain (COL12A1); carbohydrate antigen 199 (CA199); diagnosis; proteome

Cite this article

LIU Jia , REN Lingjie , SHI Minmin , TANG Xiaomei , MA Fangfang , QIN Jiejie . Identification and evaluation of COL12A1 as a novel serological diagnostic marker in pancreatic ductal adenocarcinoma[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025 , 45(10) : 1342 -1352 . DOI: 10.3969/j.issn.1674-8115.2025.10.009

References

[1] SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[2] RYAN D P, HONG T S, BARDEESY N. Pancreatic adenocarcinoma[J]. N Engl J Med, 2014, 371(11): 1039-1049.
[3] 佟陈昀颢. 中国大陆地区胰腺癌回顾性临床流行病学研究[D]. 北京: 北京协和医学院, 2024.
  TONG C Y H. A retrospective clinical epidemiology study of pancreatic cancer in mainland China[D]. Beijing: Peking Union Medical College, 2024.
[4] MIZRAHI J D, SURANA R, VALLE J W, et al. Pancreatic cancer[J]. Lancet, 2020, 395(10242): 2008-2020.
[5] 胡斌, 宋少莉. 胰腺癌的治疗进展[J]. 上海交通大学学报(医学版), 2015, 35(3): 445-449.
  HU B, Song S L. Progresses of treatment of pancreatic cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2015, 35(3): 445-449.
[6] LUO G P, JIN K Z, DENG S M, et al. Roles of CA19-9 in pancreatic cancer: biomarker, predictor and promoter[J]. Biochim Biophys Acta Rev Cancer, 2021, 1875(2): 188409.
[7] BOYD L N C, ALI M, COMANDATORE A, et al. Prediction model for early-stage pancreatic cancer using routinely measured blood biomarkers[J]. JAMA Netw Open, 2023, 6(8): e2331197.
[8] HICKS D, FARSANI G T, LAVAL S, et al. Mutations in the collagen Ⅻ gene define a new form of extracellular matrix-related myopathy[J]. Hum Mol Genet, 2014, 23(9): 2353-2363.
[9] ZHANG Y P, WANG H X, GAO Z C, et al. COL12A1 promotes osteosarcoma progression via the FAK/PI3K/AKT/mTOR pathway[J]. Curr Mol Med, 2024. DOI:10.2174/0115665240322280240903111159.
[10] YAN Y L, LIANG Q J, LIU Y H, et al. COL12A1 as a prognostic biomarker links immunotherapy response in breast cancer[J]. Endocr Relat Cancer, 2023, 30(5): e230012.
[11] 张文姣. COL12A1在胰腺癌中的表达与临床病理特征及预后的关系[D]. 青岛: 青岛大学, 2024.
  ZHANG W J. The expression of COL12A1 in pancreatic cancer and its relationship with clinicopathological features and prognosis[D]. Qingdao: Qingdao University, 2024.
[12] KRUG K, JAEHNIG E J, SATPATHY S, et al. Proteogenomic landscape of breast cancer tumorigenesis and targeted therapy[J]. Cell, 2020, 183(5): 1436-1456.e31.
[13] JIANG L X, QIN J J, DAI Y T, et al. Prospective observational study on biomarkers of response in pancreatic ductal adenocarcinoma[J]. Nat Med, 2024, 30(3): 749-761.
[14] RITCHIE M E, PHIPSON B, WU D, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies[J]. Nucleic Acids Res, 2015, 43(7): e47.
[15] FANG H, KNEZEVIC B, BURNHAM K L, et al. XGR software for enhanced interpretation of genomic summary data, illustrated by application to immunological traits[J]. Genome Med, 2016, 8(1): 129.
[16] DELONG E R, DELONG D M, CLARKE-PEARSON D L. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach[J]. Biometrics, 1988, 44(3): 837-845.
[17] CAO L W, HUANG C, ZHOU D C, et al. Proteogenomic characterization of pancreatic ductal adenocarcinoma[J]. Cell, 2021, 184(19): 5031-5052.e26.
[18] AMIN M B, EDGE S, GREENE F L. AJCC cancer staging manual[M]. 8th ed. New York: Springer, 2017: 327-335.
[19] DOU Y C, KATSNELSON L, GRITSENKO M A, et al. Proteogenomic insights suggest druggable pathways in endometrial carcinoma[J]. Cancer Cell, 2023, 41(9): 1586-1605.e15.
[20] 李宝宝. 基于蛋白质组学技术筛选脑膜瘤诊断的血清学潜在生物标志物的研究[D]. 延安: 延安大学, 2022.
  LI B B. Screening serological diagnosis of meningioma based on proteomic techniques studies on potential biomarkers[D]. Yan'an: Yan'an University, 2022.
[21] GERECKE D R, OLSON P F, KOCH M, et al. Complete primary structure of two splice variants of collagen Ⅻ, and assignment of alpha 1 (Ⅻ) collagen (COL12A1), alpha 1 (Ⅸ) collagen (COL9A1), and alpha 1 (ⅩⅨ) collagen (COL19A1) to human chromosome 6q12-q13[J]. Genomics, 1997, 41(2): 236-242.
[22] XU S S, XU H X, WANG W Q, et al. The role of collagen in cancer: from bench to bedside[J]. J Transl Med, 2019, 17(1): 309.
[23] TIAN C X, HUANG Y, CLAUSER K R, et al. Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells[J]. Nat Commun, 2021, 12(1): 2328.
[24] GELSE K, P?SCHL E, AIGNER T. Collagens: structure, function, and biosynthesis[J]. Adv Drug Deliv Rev, 2003, 55(12): 1531-1546.
[25] NISSEN N I, KARSDAL M, WILLUMSEN N. Collagens and cancer associated fibroblasts in the reactive stroma and its relation to cancer biology[J]. J Exp Clin Cancer Res, 2019, 38(1): 115.
[26] THORLACIUS-USSING J, JENSEN C, MADSEN E A, et al. Type ⅩⅩ collagen is elevated in circulation of patients with solid tumors[J]. Int J Mol Sci, 2022, 23(8): 4144.
[27] WILLUMSEN N, ALI S M, LEITZEL K, et al. Collagen fragments quantified in serum as measures of desmoplasia associate with survival outcome in patients with advanced pancreatic cancer[J]. Sci Rep, 2019, 9(1): 19761.
[28] SONG Y, WANG L, WANG K D, et al. COL12A1 acts as a novel prognosis biomarker and activates cancer-associated fibroblasts in pancreatic cancer through bioinformatics and experimental validation[J]. Cancers (Basel), 2023, 15(5): 1480.
[29] WERNER S, CHEN H D, TAO S, et al. Systematic review: serum autoantibodies in the early detection of gastric cancer[J]. Int J Cancer, 2015, 136(10): 2243-2252.
[30] PEPE M S, ETZIONI R, FENG Z, et al. Phases of biomarker development for early detection of cancer[J]. J Natl Cancer Inst, 2001, 93(14): 1054-1061.
[31] SONG J, SOKOLL L J, PASAY J J, et al. Identification of serum biomarker panels for the early detection of pancreatic cancer[J]. Cancer Epidemiol Biomarkers Prev, 2019, 28(1): 174-182.
[32] 李祥苏, 王冬冬, 吴旭东. 血清MUC5AC和CA199联合检测在胰腺癌诊断中的作用[J]. 现代肿瘤医学, 2022, 30(5): 852-855.
  LI X S, WANG D D, WU X D. Evaluation of serum MUC5AC in combination with CA199 for the diagnosis of pancreatic cancer[J]. Journal of Modern Oncology, 2022, 30(5): 852-855.
[33] KIM J, BAMLET W R, OBERG A L, et al. Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers[J]. Sci Transl Med, 2017, 9(398): eaah5583.
[34] LEI X F, JIA S Z, YE J, et al. Application values of detection of serum CA199, CA242 and CA50 in the diagnosis of pancreatic cancer[J]. J Biol Regul Homeost Agents, 2017, 31(2): 383-388.
[35] DONG D, JIA L, ZHANG L F, et al. Periostin and CA242 as potential diagnostic serum biomarkers complementing CA19.9 in detecting pancreatic cancer[J]. Cancer Sci, 2018, 109(9): 2841-2851.
[36] HUANG B W, HUANG H R, ZHANG S T, et al. Artificial intelligence in pancreatic cancer[J]. Theranostics, 2022, 12(16): 6931-6954.
Options
Outlines

/

〈 〉