Variant Ciz1 is a circulating biomarker for early-stage lung cancer.
There is an unmet need for circulating biomarkers that can detect early-stage lung cancer. Here we show that a variant form of the nuclear matrix-associated DNA replication factor Ciz1 is present in 34/35 lung tumors but not in adjacent tissue, giving rise to stable protein quantifiable by Western blot in less than a microliter of plasma from lung cancer patients. In two independent sets, with 170 and 160 samples, respectively, variant Ciz1 correctly identified patients who had stage 1 lung cancer with clinically useful accuracy. For set 1, mean variant Ciz1 level in individuals without diagnosed tumors established a threshold that correctly classified 98% of small cell lung cancers (SCLC) and non-SCLC patients [receiver operator characteristic area under the curve (AUC) 0.958]. Within set 2, comparison of patients with stage 1 non-SCLC with asymptomatic age-matched smokers or individuals with benign lung nodules correctly classified 95% of patients (AUCs 0.913 and 0.905), with overall specificity of 76% and 71%, respectively. Moreover, using the mean of controls in set 1, we achieved 95% sensitivity among patients with stage 1 non-SCLC patients in set 2 with 74% specificity, demonstrating the robustness of the classification. RNAi-mediated selective depletion of variant Ciz1 is sufficient to restrain the growth of tumor cells that express it, identifying variant Ciz1 as a functionally relevant driver of cell proliferation in vitro and in vivo. The data show that variant Ciz1 is a strong candidate for a cancer-specific single marker capable of identifying early-stage lung cancer within at-risk groups without resort to invasive procedures.
Cizzle Biotech, University of York, Yorkshire YO10 5DD, United Kingdom.
Gillian
G
Higgins
Katherine M
KM
Roper
Irene J
IJ
Watson
Fiona H
FH
Blackhall
William N
WN
Rom
Harvey I
HI
Pass
Justin F X
JF
Ainscough
Dawn
D
Coverley
D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000097:blood* / Q000235:genetics*; D012680:Sensitivity and Specificity
D014408:Biomarkers, Tumor; C400423:Ciz1 protein, human; D009687:Nuclear Proteins