BJC: Urine test may be used for screening liver cancer
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BJC: Urine test may be used for screening liver cancer
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BJC: Urine test may be used for screening liver cancer
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide [1, 2], and its prognosis depends on the stage of the tumor.
Early-stage HCC patients can be treated by resection or liver transplantation, and their 5-year survival rate is >70%, while the 5-year survival rate of advanced HCC patients is <10%. It can be seen that early diagnosis is particularly important.
Currently, the commonly accepted and used biomarker for HCC screening is serum alpha-fetoprotein (AFP), however, its sensitivity is moderate (40-60%), especially when screening for early HCC[1]; and AFP is elevated It has also been associated with high ALT levels in patients with viral hepatitis [3].
To improve early HCC screening methods, there is an urgent need to develop better biomarkers.
Recently, a research team led by Ying-Hsiu Su of the Baruch S. Blumberg Institute in the United States published important research results in the British Journal of Cancer [4].
The team developed a test panel based on urine ctDNA biomarkers, including mutated TP53, methylated RASSF1A and GSTP1 , and combined with AFP to establish a two-stage model for HCC detection and screening.
Compared with AFP test alone, the two-stage model test with urine ctDNA increased the number of detected cases by 30%, and the detection rate of Barcelona Liver Cancer Stage (BCLC) stage 0 HCC increased from 62% to 92%, BCLC stage A Increased from 40% to 77%.
Therefore, urine ctDNA-based detection has good diagnostic value for HCC patients, especially those with low AFP, and can be used as a potential non-invasive HCC screening method.
Screenshot of the paper’s homepage
HCC is a heterogeneous disease caused by multiple etiologies, and therefore there are multiple genetic alterations.
Previous studies have shown that urine contains some low molecular weight DNA or cell-free DNA [5]; in addition, the DNA in the urine of cancer patients such as HCC is also cancer-specific, such as gene mutation and abnormal DNA methylation [6].
To identify potential urinary DNA markers for HCC, the researchers tested eight markers using preserved urine DNA from patients with chronic liver disease, cirrhosis or HCC and found that they were significantly higher than those in non-HCC (hepatitis + cirrhosis) patients.
Compared with HCC patients, the levels of TP53 mutation at site 249 , methylated mRASSF1A and mGSTP1 were significantly increased in the urine of HCC patients, so these three markers were used as ctDNA detection group for subsequent analysis.
Scatter plot of the distribution of urine markers in each disease category
Next, we conducted a prospective, multicenter case-control analysis of 609 patients, including 186 with HCC, 144 with cirrhosis, and 279 with hepatitis B, whose urine DNA samples (at least 1 ng/mL) and quantified the urine ctDNA panel to analyze its performance in screening for HCC.
Research flow chart
First, the researchers analyzed the screening performance of serum AFP and urine ctDNA detection groups for HCC by constructing ROC curves.
The results showed that although the performance of the urine ctDNA test group (AUROC of 0.7440) was inferior to that of serum AFP (AUROC of 0.8546), the diagnostic cut-off value of serum AFP at 90% specificity was 5.8 ng/mL, which was significantly lower than the generally accepted The AFP value of ≥20 ng/mL [7].
ROC of Serum AFP and Urine ctDNA Detection Group
Considering that the AFP of patients with cirrhosis and chronic hepatitis is usually higher than 5.8 ng/mL [8], the researchers defined patients with AFP <20 ng/mL as “low AFP”, and further analyzed the urine ctDNA detection group in patients with low AFP. detection performance in .
The researchers found that of 186 HCC patients, 98 (53%) had low AFP, a rate consistent with previous studies [8].
In addition, when the specificity was 90%, among all HCC patients, 82 (44.1%) patients had positive urine ctDNA test; among the low AFP patients, 48 patients had positive urine ctDNA.
This data suggests that the detection performance of urinary ctDNA markers is independent of serum AFP .
Distribution of AFP and urine ctDNA detection groups in HCC patients
In order to better identify HCC patients from the low AFP population, the researchers proposed a two-stage model for identifying HCC with AFP ≥ 20 ng/mL as the cutoff value, and then established a logistic model combining AFP and ctDNA on the low AFP subgroup .
The results showed that the AUROC of the two-stage model was 0.9118, which was significantly higher than that of the AFP-only model; the model could identify an additional 60 (60%) HCC patients from the low-AFP population at a specificity of 90% .
ROC of the two-stage model and comparison with each other
Next, the researchers further analyzed the overall performance of AFP, urine ctDNA, and the two-stage model in different tumor stages by tumor stage (BCLC stage).
The results showed that with AFP≥20 ng/mL as the cut-off value, the sensitivity of using AFP only for the detection of BCLC stage 0, A, B, C and D patients was 62%, 40%, 57%, 52% and 29%, respectively. %; when the specificity of urine ctDNA detection was 90%, the results were 23%, 49%, 39%, 43%, and 71%, respectively; while the sensitivity of the two-stage model was significantly improved, with 92%, 77%, 78%, 81% and 86% .
Sensitivity of the three models in different HCC patient stages
Since early detection is key for screening tests, the researchers further focused their attention on BCLC 0 and stage A HCC.
The analysis showed that although urine ctDNA testing was less sensitive for screening BCLC stage 0, AFP was <20 ng/mL in all samples, so the two-stage model could increase the sensitivity to 92%; similarly, in BCLC A In the interim, the two-stage model sensitivity improved from 40% to 77% .
Finally, the researchers used ten-fold cross-validation to test the robustness of the model predictions.
The results show that the two-stage model is robust, its AUROC drops from 0.912 for training set to 0.902 for validation set, and at 90% specificity, its sensitivity only loses 1%, from 79.6% to 78.6%, with no significant difference.
Tenfold cross-validation to evaluate detection model performance
It is worth noting that the two-stage model requires further evaluation with blinded validation before it can be applied to clinical HCC screening.
In addition, this study was a cross-sectional study without serial collection of samples or additional imaging data.
These covariates may provide valuable information for future ctDNA applications, possibly in cases where lesions are too small to be detected by standard screening methods of patients with precancerous lesions or liver cancer.
Early screening and diagnosis of HCC is crucial for patient prognosis, and urine ctDNA detection as a new non-invasive detection method for HCC screening has shown good screening especially in patients with low AFP and early liver disease performance, with potential clinical application value.
references:
[1] Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358-380. doi:10.1002/hep.29086
[2] Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-E386. doi:10.1002/ijc.29210
[3] Yang JD, Dai J, Singal AG, et al. Improved Performance of Serum Alpha-Fetoprotein for Hepatocellular Carcinoma Diagnosis in HCV Cirrhosis with Normal Alanine Transaminase. Cancer Epidemiol Biomarkers Prev. 2017;26(7):1085-1092. doi:10.1158/1055-9965.EPI-16-0747
[4] Kim AK, Hamilton JP, Lin SY, et al. Urine DNA biomarkers for hepatocellular carcinoma screening [published online ahead of print, 2022 Jan 19]. Br J Cancer. 2022;10.1038/s41416-022-01706-9. doi:10.1038/s41416-022-01706-9
[5] Husain H, Melnikova VO, Kosco K, et al. Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine. Clin Cancer Res. 2017;23(16):4716-4723. doi:10.1158/1078-0432.CCR-17-0454
[6] Hann HW, Jain S, Park G, Steffen JD, Song W, Su YH. Detection of urine DNA markers for monitoring recurrent hepatocellular carcinoma. Hepatoma Res. 2017;3:105-111. doi:10.20517/2394-5079.2017.15
[7] European Association for the Study of the Liver. Electronic address: [email protected]; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma [published correction appears in J Hepatol. 2019 Apr;70(4):817]. J Hepatol. 2018;69(1):182-236. doi:10.1016/j.jhep.2018.03.019
[8] Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. Ann Intern Med. 2003;139(1):46-50. doi:10.7326/0003-4819-139-1-200307010-00012
BJC: Urine test may be used for screening liver cancer
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