Myeloproliferative neoplasms and thrombosis

Blood ◽  
2013 ◽  
Vol 122 (13) ◽  
pp. 2176-2184 ◽  
Author(s):  
Tiziano Barbui ◽  
Guido Finazzi ◽  
Anna Falanga
Keyword(s):  
High Risk ◽  
Myeloproliferative Neoplasms ◽  
Low Risk ◽  
Related Factors ◽  
Hematopoietic Stem ◽  
Clonal Proliferation ◽  
Mutational Status ◽  
Novel Drugs ◽  
Risk Patients ◽  
Quantitative Changes

Abstract Major causes of morbidity and mortality in myeloproliferative neoplasms are represented by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. The pathogenesis of thrombosis results from a complex interplay of clinical and disease-related factors. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells involve not only quantitative changes but also qualitative modifications that characterize the switch of these cells from a resting to a procoagulant phenotype. According to age and previous thrombosis, patients are classified in a “high risk” or “low risk”. Novel disease-related determinants such as leukocytosis and JAK2V617F mutational status and/or mutational burden are now under active investigation. In low-risk polycythemia vera patients, only phlebotomy and primary antithrombotic prophylaxis with aspirin is recommended, while in high-risk patients cytotoxic therapy is considered. Whether novel drugs targeting the constitutively active JAK2/STAT pathway will improve the management of thrombosis is a challenge for future studies.

Select High Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy with Fludarabine and Rituximab in Chronic Lymphocytic Leukemia (CLL): Preliminary Justification for Risk-Adapted Therapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 476-476 ◽  
Author(s):  
John C. Byrd ◽  
John G. Gribben ◽  
Bercedis Peterson ◽  
Michael R. Grever ◽  
Gerard Lozanski ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Hierarchical Classification ◽  
P53 Mutation ◽  
Low Risk ◽  
P Value ◽  
P53 Mutations ◽  
Cytogenetic Abnormalities ◽  
Mutational Status ◽  
Risk Patients

Abstract Several prognostic factors in CLL including un-mutated VH mutational status, select interphase cytogenetic abnormalities [del(11q22.3), del(17p13.1)], and p53 mutations have been associated with decreased time from diagnosis to symptomatic disease requiring treatment as well as shortened progression-free survival (PFS) and overall survival (OS). To date, the impacts of these prognostic factors on treatment outcome with fludarabine and rituximab combination treatments have not been explored. The Cancer and Leukemia Group B recently reported results of a randomized phase II study (CALGB 9712) that added rituximab concurrently or sequentially to fludarabine as initial therapy for symptomatic, untreated CLL (Blood2003; 101:6). After a recently updated median follow-up of 43 months, PFS and OS are still similar in both arms. Of the 104 patients enrolled, we studied 88 patients for whom pre-treatment samples were available to examine the impact of VH mutational status (≥97% defined as un-mutated), common cytogenetic abnormalities, and p53 mutational status on outcome relative to CR (complete remission) and PFS. OS was not examined because only 13 deaths have occurred to date. A total of 46 out of 75 (61%) patients were VH un-mutated CLL. Fifteen (52%) of 29 mutated and 20 (43%) of 46 un-mutated patients achieved a CR (p= 0.49). The median PFS among the VH mutated patients was 46 months [95% CI (40, 54)] whereas for un-mutated it was 32 months [95% CI (22, 42)] (p= 0.05). Controlling for differences in age, sex, WBC, LDH, and stage resulted in an adjusted p-value of p=0.03. Only four patients had p53 mutations, preventing analysis of this biologic feature independently. Using the Dohner hierarchical classification, the frequency CR rate and PFS for each group are summarized below. Cytogenetic Abnormality: del(17p) del(11q) del(6q) tris 12 del(13q) Normal No. (%) pts 3 (3%) 15 (17%) 1 (1%) 23 (26%) 24 (27%) 22 (25%) CR (%) 0 53 100 25 38 64 PFS (months) 18 25 42 42 45 49 Using the hierarchical classification of Dohner, there was not a difference in CR rate (p=0.25) and PFS (p=0.10). Controlling for differences in age, sex, WBC, LDH, and stage resulted in an adjusted p-value of p=0.04. The PFS for the del(17p13.1) and del(11q22.3) patients was significantly shorter than that observed for the remaining cytogenetic groups (p=0.03). We next sought to define a high-risk group of CLL patients, as having any of the following: VH un-mutated (≥97%), del(17p), del (11q), or non-silent p53 mutation. Using this classification, 35 patients were assigned to the low-risk and 53 to the high-risk groups. The CR rate in each group was 43%. However, the median PFS among the low risk patients was 45 months with 95% CI (45, NA) whereas the median PFS among the high-risk patients was 32 months with 95% CI (22, 42) (p=0.004). These data demonstrate that high risk CLL patients characterized by VH un-mutated (≥97%), del(17p), del (11q), or non-silent p53 mutation appear to have a shorter PFS with chemoimmunotherapy and define a subset of patients for whom additional novel treatment approaches should be targeted.

Prognostic Value of Molecular Markers for Guiding Post-Remission Therapy in Patients with De Novo Acute Myeloid Leukemia (AML) and Intermediate-Risk Cytogenetics

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2522-2522
Author(s):  
Marta Pratcorona ◽  
Mireia Camós ◽  
Montserrat Torrebadell ◽  
Maria Rozman ◽  
Ana Carrió ◽  
...  
Keyword(s):  
High Risk ◽  
Prognostic Value ◽  
De Novo ◽  
Low Risk ◽  
High Dose ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Molecular Features ◽  
Mutational Status

Abstract The heterogeneous prognosis of patients with intermediate-risk cytogenetics AML (AML-IR) can be partially clarified by screening of NPM1 mutations (NPMmut) and internal tandem duplication of FLT3 (FLT3-ITD). Nonetheless, additional factors might influence the prognostic effect of these molecular lesions, such as the FLT3-ITD mutant level. Moreover, the optimal post-remission strategy might differ depending on the underlying molecular lesion. In this regard, we analyzed the outcome, according to NPM1 and FLT3 mutations and post-remission therapy given, of a series of patients diagnosed with de novo AML-IR in a single institution who received intensive chemotherapy. Patients were treated following 4 sequential protocols of CETLAM group during the period 1994–2006, consisting of 1 or 2 cycles of standard induction chemotherapy and 1 course of high-dose cytarabine-based consolidation therapy. Thereafter, patients underwent hematopoietic stem cell transplantation (HSCT) according to donor availability and presumed risk (protocols LAM 99 & 2003). NPM1 mutations and FLT3-ITD were screened in diagnostic DNA by PCR amplification followed by Genescan analysis. The ratio between FLT3-ITD and wildtype FLT3 alleles (ITD/wt ratio) was calculated using the area under the peak of corresponding alleles. Overall, 134 patients (51% male; median age, 53; range: 17–70) with AML-IR (normal karyotype, 66%) were studied. NPM1mut and FLT3-ITD were found in 45% and 37% of patients, respectively, with a median ITD/wt ratio of 0.59 (0.045–5.5). After induction regimen, 109 patients (81%) achieved complete response (CR). The only variables predictive of a favorable response were NPMmut (90% vs. 75%; p=0.01) and age <60 (85% vs. 72.5%; p=0.05). After a median follow-up of 69 months, relapse risk (RR) at 5 years was 54% (±5%). RR was higher in patients presenting with hyperleukocytosis (>50 × 109/L), NPMwt, and FLT3-ITD. Interestingly, the prognostic value of FLT3-ITD depended on the relative mutant level, and detection of FLT3-ITD with a low ITD/wt ratio (i.e.,<0.3) did not increase the risk conferred by underlying NPM1 mutational status. In accordance, a composite variable based on NPMmut and quantitative FLT3-ITD was created defining 2 prognostic categories: a low-risk group (LOWmol), constituted by patients with NPMmut and either absence of FLT3-ITD or low ITD/wt ratio, and a high-risk subset (HIGHmol), defined by the absence of NPMmut and/or high ITD/wt ratio. This molecular stratification showed independent prognostic value for RR (5-year RR: 24%±10% vs. 81%±7 in LOWmol vs. HIGHmol patients, respectively; p<0.001), and survival (OS; relative risk: 2.8, 95% CI:1.6-5, p<0.001; figure Moreover, the effect of post-remission therapy varied in both molecular-defined subgroups. Thus, among patients with an age ≤60, 5-year survival in LOWmol patients with a planned autologous HSCT (autoHSCT) was 83%±9%, not differing significantly from that of patients undergoing allogeneic HSCT (intention-to-treat analysis; figure On the other hand, 5-year OS of HIGHmol patients who underwent allogeneic HSCT in first CR was 73%±13, which compared favorably with other post-remission strategies (5-yr OS: 27%±7%; p=0.019). In conclusion, in patients with intermediate-risk AML, the combined assessment of NPM1 mutations and quantitative estimation of FLT3-ITD allows the distinction of 2 categories of patients with different prognosis. Thus, whereas autoHSCT arises as an effective postremission therapy in patients harboring low-risk molecular features, allogeneic HSCT in first CR seems to overcome adverse prognosis of patients with high-risk disease. Nonetheless, the validity of this molecularly-based therapeutic algorithm warrants confirmation in other studies. Figure Figure

Should Hematopoietic Stem Cell Transplantation in First Complete Remission Be Restricted to High-Risk Patients in Childhood Acute Myeloid Leukemia?.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1094-1094
Author(s):  
Hideki Muramatsu ◽  
Nobuhiro Nishio ◽  
Asahito Hama ◽  
Hiroshi Yagasaki ◽  
Yoshiyuki Takahashi ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Low Risk ◽  
Hematopoietic Stem ◽  
High Risk Patients ◽  
Risk Patients ◽  
Group A ◽  
Group B ◽  
First Complete Remission

Abstract Hematopoietic stem cell transplantation (HSCT) has been used as an effective consolidation therapy for children with acute myeloid leukemia (AML) in first complete remission (CR). Although it is effective in relapse prevention, often it causes severe late sequelae, such as short stature and infertility. There is a recent trend to restrict the use of HSCT in first CR for high-risk patients. However, there is no study comparing which strategy is better, risk-adapted or general recommendation for HSCT in AML children in first CR. In our institutes, all such children in first CR were recommended either allogeneic or autologous HSCT until 1997. After 1998, patients were classified into three risk-groups. Low-risk patients (t(8;21) and inv(16)) were not recommended to undergo HSCT. High-risk patients (−7, 5q-, Ph1, t(16;21) and remission failure) were recommended to undergo HSCT. Intermediate-risk (other karyotypes) patients received HSCT in first CR if a suitable donor was available. In this study, we retrospectively compared the prognosis of 66 patients who were diagnosed with de novo AML between 1991 and 1997 (group A; n=37) and between 1998 and 2003 (group B; n=29). AML with Down syndrome and AML-M3 were excluded. The median (range) age was five (0–15) years. FAB classifications were M0 (n = 1), M1 (n = 10), M2 (n = 22), M4 (n = 6), M4E (n = 5), M5 (n = 14), M6 (n = 0), and M7 (n = 8). Chromosome analysis data were t(8;21) (n = 18), inv(16) (n = 4), 11q23 (n = 10), other abnormalities (n = 14), normal karyotype (n = 14), and unknown (n = 6). Induction chemotherapy comprised VP-16, cytarabine, and mitoxantrone. Sixty-three of 66 patients (95.5%) achieved CR. HSCT in first CR was done in 24 patients (64.9%) in group A and seven patients (24.1%) in group B (p = 0.0044). Age, sex, WBC count at diagnosis, FAB classification and chromosomal abnormalities did not differ between the two groups. Fourteen (five in group A and nine in group B) patients relapsed. Six (three in group A and three in group B) of them were salvaged by HSCT. Both 5-year event-free survival (EFS) and overall survival (OS) were statistically higher in group A than in group B (5-year EFS: 83.8 ± 6.1% versus 62.1 ± 9.0%, p = 0.0404; 5-year OS: 91.6 ± 4.7% versus 71.6 ± 8.5%, p = 0.0364). Although intensified chemotherapy without HSCT for low-risk AML patients is desirable to avoid the late complications of HSCT, our analysis showed that the introduction of risk-stratified treatment strategy significantly worsened the chances of EFS and OS. Our risk stratification based on chromosomal abnormalities only may be insufficient to identify low-risk AML children. Development of more sophisticated risk classification, including molecular markers, may be required to identify true low-risk patients who should avoid HSCT in first CR.

Risk-Stratification Treatment Directed by Minimal Residual Disease Improves the Outcome of Acute Myeloid Leukemia with t(8;21) in First Complete Remission: Results of the AML05 Multicentre Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 139-139
Author(s):  
Honghu Zhu ◽  
Xiao-hui Zhang ◽  
Yazhen Qin ◽  
Hao Jiang ◽  
Dai-Hong Liu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Hazard Ratio ◽  
Low Risk ◽  
Hematopoietic Stem ◽  
Risk Patients ◽  
First Complete Remission ◽  
Acute Myeloid

Abstract Abstract 139 Background Although patients with acute myeloid leukemia (AML) and the t(8;21) translocation generally have a favorable prognosis, relapse occurs in about 40% of cases and long-term (>5years) survival less than 50%. Patients with a KIT-mutation had an even higher relapse rate up to 70% and dismal survial. Once relapse, the outcome is extremely poor, even receiving allogeneic hematopoietic stem-cell transplantation (allo-HSCT).Therefore, rapidly identifying high-risk relapse patients and preemptively treating them with more aggressive therapy, such as HSCT, may decrease the chance of relapse and improve patient survival. We sought to improve outcome in patients with t(8;21) acute myeloid leukemia(AML) in first complete remission (CR) by applying risk-directed therapy that was based on measurements of minimal residual disease (MRD) by quantitative PCR during treatment. Methods From June 1,2005, to Dec 31, 2011, 137 patients with t(8;21) AML were enrolled at three centres. MRD was detected using quantitative PCR to detect the RUNX1/RUNX1T1 transcript. High-risk was defined by not achieving major molecular remission (MMR,> 3 log reduction of RUNX1/RUNX1T1 transcript from baseline) after second consolidation therapy or loss of MMR within 6 months since achieving MMR. Low-risk was defined by achieving MMR after second consolidation therapy and maintenance of MMR within 6 months thereafter. High-risk patients were recommended to receive allogeneic hematopoietic stem-cell transplantation (allo-HSCT) and low-risk patients to high-dose cytarabine-based consolidation chemotherapy. 116 patients who achieved CR and completed second consolidation were assigned to risk-directed therapy. Finally, sixty-nine patients actually received risk-directed therapy and 47 patients received a non risk-directed treatment for patients¡ bias. Findings With a median follow-time of 36 months in patients alive, risk-directed therapy and non risk-directed therapy achieved 5 year cumulative incidence of relapse(CIR) of 15.0%±4.7% and 57.5%±8.0%(p<0.0001), disease-free survival(DFS) of 74.7%±5.8% and 37.1%±7.4%(p<0.0001) and overall survival (OS) of 82.7%±5.1% and 49.8%±8.5% (p=0.002) (Figure 1). Allo-HSCT benefited high-risk as well as KIT-mutated but impaired low-risk patients' DFS and OS (all p<0.05) (Figure 2). Multivariate analysis revealed that MRD status (high-risk vs. low-risk) and treatment (risk-directed vs. no risk-directed) were independent prognostic factor for relapse(hazard ratio 8.85, 95% CI 2.05–38.13, p=0.003; 0.26, 95% CI 0.12–0.61, p=0.002), DFS(hazard ratio 9.32, 95% CI 2.21–39.3; p=0.002; 0.36, 95% CI 0.17–0.75, p=0.007) and OS (hazard ratio10.53, 95% CI 1.41–78.83; p=0.022; 0.37, 95% CI 0.15–0.93, p=0.035).KIT-mutation was an independent prognostic factor for relapse(hazard ratio 2.12, 95% CI 1.01–4.48, p=0.049) but not for DFS and OS. Interpretation Risk-stratification treatment directed by MRD could improve the outcome of AML with t(8;21) in first complete remission. Allo-HSCT benefits high-risk as well as KIT-mutated but impairs low-risk patients¡ survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Allogeneic hematopoietic stem cell transplantation can improve the prognosis of high-risk pediatric t (8;21) acute myeloid leukemia in first remission based on MRD-guided treatment

2020 ◽  
Author(s):  
Guan-hua Hu ◽  
Yi-fei Cheng ◽  
Ai-dong Lu ◽  
Yu Wang ◽  
Ying-xi Zuo ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Low Risk ◽  
Hematopoietic Stem ◽  
High Risk Patients ◽  
Risk Patients ◽  
The Difference ◽  
Acute Myeloid ◽  
Better Than

Abstract Background Pediatric acute myeloid leukemia (AML) with t (8;21) (q22;q22) or RUNX1-RUNX1T1 rearrangement is classified as a low-risk group. However, relapse is still the main factor affecting survival. The purpose of this study was to investigate the effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on reducing recurrence and improving the survival of high-risk pediatric t (8;21) AML based on MRD-guided treatment, and to further explore the prognostic factors to guide risk stratification treatment and define who will benefit from allo-HSCT. Methods Overall, 129 newly diagnosed pediatric patients with AML with t (8;21) were included in this study. The patients were divided into a high-risk and low-risk group according to RUNX1-RUNX1T1 transcript levels after two cycles of consolidation chemotherapy. We recommended allo-HSCT for the high-risk group and chemotherapy for the low-risk group. The characteristics and outcomes of 125 patients were analyzed.Results For the high-risk patients, allo-HSCT improved event-free survival (EFS) compared to chemotherapy (87.4% [95% CI, 86%–108.7%]) vs. 61.9% [95% CI, 51.96%–80.41%]; P = 0.026). Overall survival (OS) of the high-risk HSCT group was better than that of the high-risk-chemo group but the difference was not statistically significant (82.8% [95% CI, 78.6%–101.7%]) vs. 71.4% [95% CI, 62.09%–87.6%]; P = 0.26). The EFS of the C-KIT+ high-risk-HSCT group was better than that of the C-KIT+ high-risk-chemo group but the difference was not statistically significant (82.9% [95% CI, 59.3%–84.8%]) vs. 75% [95% CI, 49.3%–85.6%]; P = 0.4). Extramedullary infiltration (EI) at diagnosis was associated with high cumulative incidence of relapse for high-risk patients (50% [95% CI, 17.2%–66.5%]) vs. 18.4% [95% CI, 3.0%–18.9%]; P = 0.004); allo-HSCT can improve survival (P = 0.009). Conclusions allo-HSCT can improve the prognosis of high-risk pediatric t (8;21) AML based on MRD-guided treatment. Patients with KIT mutation may benefit from allo-HSCT, but this result was not statistically significant. EI is an independent prognostic factor for high-risk patients and allo-HSCT can improve the prognosis.

scholarly journals Echocardiography and EuroSCORE II for the stratification of low-gradient severe aortic stenosis and preserved left ventricular ejection fraction

2021 ◽  
Author(s):  
Yan Fan ◽  
Hong Shen ◽  
Brandon Stacey ◽  
David Zhao ◽  
Robert J. Applegate ◽  
...  
Keyword(s):  
High Risk ◽  
Left Ventricular Ejection Fraction ◽  
Risk Group ◽  
Severe Aortic Stenosis ◽  
Left Ventricular ◽  
High Risk Group ◽  
Low Risk ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Risk Patients

AbstractThe purpose of this study was to explore the utility of echocardiography and the EuroSCORE II in stratifying patients with low-gradient severe aortic stenosis (LG SAS) and preserved left ventricular ejection fraction (LVEF ≥ 50%) with or without aortic valve intervention (AVI). The study included 323 patients with LG SAS (aortic valve area ≤ 1.0 cm2 and mean pressure gradient < 40 mmHg). Patients were divided into two groups: a high-risk group (EuroSCORE II ≥ 4%, n = 115) and a low-risk group (EuroSCORE II < 4%, n = 208). Echocardiographic and clinical characteristics were analyzed. All-cause mortality was used as a clinical outcome during mean follow-up of 2 ± 1.3 years. Two-year cumulative survival was significantly lower in the high-risk group than the low-risk patients (62.3% vs. 81.7%, p = 0.001). AVI tended to reduce mortality in the high-risk patients (70% vs. 59%; p = 0.065). It did not significantly reduce mortality in the low-risk patients (82.8% with AVI vs. 81.2%, p = 0.68). Multivariable analysis identified heart failure, renal dysfunction and stroke volume index (SVi) as independent predictors for mortality. The study suggested that individualization of AVI based on risk stratification could be considered in a patient with LG SAS and preserved LVEF.

scholarly journals Accuracy of upper endoscopies with random biopsies to identify patients with gastric premalignant lesions who can safely be exempt from surveillance

2021 ◽  
Vol 24 (3) ◽  
pp. 680-690
Author(s):  
Michiel C. Mommersteeg ◽  
Stella A. V. Nieuwenburg ◽  
Wouter J. den Hollander ◽  
Lisanne Holster ◽  
Caroline M. den Hoed ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
High Risk ◽  
Low Risk ◽  
Premalignant Lesions ◽  
High Risk Patients ◽  
European Guidelines ◽  
Progression Of Disease ◽  
Risk Patients ◽  
Progression Risk

Abstract Introduction Guidelines recommend endoscopy with biopsies to stratify patients with gastric premalignant lesions (GPL) to high and low progression risk. High-risk patients are recommended to undergo surveillance. We aimed to assess the accuracy of guideline recommendations to identify low-risk patients, who can safely be discharged from surveillance. Methods This study includes patients with GPL. Patients underwent at least two endoscopies with an interval of 1–6 years. Patients were defined ‘low risk’ if they fulfilled requirements for discharge, and ‘high risk’ if they fulfilled requirements for surveillance, according to European guidelines (MAPS-2012, updated MAPS-2019, BSG). Patients defined ‘low risk’ with progression of disease during follow-up (FU) were considered ‘misclassified’ as low risk. Results 334 patients (median age 60 years IQR11; 48.7% male) were included and followed for a median of 48 months. At baseline, 181/334 (54%) patients were defined low risk. Of these, 32.6% were ‘misclassified’, showing progression of disease during FU. If MAPS-2019 were followed, 169/334 (51%) patients were defined low risk, of which 32.5% were ‘misclassified’. If BSG were followed, 174/334 (51%) patients were defined low risk, of which 32.2% were ‘misclassified’. Seven patients developed gastric cancer (GC) or dysplasia, four patients were ‘misclassified’ based on MAPS-2012 and three on MAPS-2019 and BSG. By performing one additional endoscopy 72.9% (95% CI 62.4–83.3) of high-risk patients and all patients who developed GC or dysplasia were identified. Conclusion One-third of patients that would have been discharged from GC surveillance, appeared to be ‘misclassified’ as low risk. One additional endoscopy will reduce this risk by 70%.

scholarly journals A Novel Epigenetic Machine Learning Model to Define Risk of Progression for Hepatocellular Carcinoma Patients

2021 ◽  
Vol 22 (3) ◽  
pp. 1075
Author(s):  
Luca Bedon ◽  
Michele Dal Bo ◽  
Monica Mossenta ◽  
Davide Busato ◽  
Giuseppe Toffoli ◽  
...  
Keyword(s):  
Machine Learning ◽  
Hepatocellular Carcinoma ◽  
High Risk ◽  
Progression Free Survival ◽  
Low Risk ◽  
Functional Enrichment ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Of Progression ◽  
Risk Patients

Although extensive advancements have been made in treatment against hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfied. It is now clearly established that extensive epigenetic changes act as a driver in human tumors. This study exploits HCC epigenetic deregulation to define a novel prognostic model for monitoring the progression of HCC. We analyzed the genome-wide DNA methylation profile of 374 primary tumor specimens using the Illumina 450 K array data from The Cancer Genome Atlas. We initially used a novel combination of Machine Learning algorithms (Recursive Features Selection, Boruta) to capture early tumor progression features. The subsets of probes obtained were used to train and validate Random Forest models to predict a Progression Free Survival greater or less than 6 months. The model based on 34 epigenetic probes showed the best performance, scoring 0.80 accuracy and 0.51 Matthews Correlation Coefficient on testset. Then, we generated and validated a progression signature based on 4 methylation probes capable of stratifying HCC patients at high and low risk of progression. Survival analysis showed that high risk patients are characterized by a poorer progression free survival compared to low risk patients. Moreover, decision curve analysis confirmed the strength of this predictive tool over conventional clinical parameters. Functional enrichment analysis highlighted that high risk patients differentiated themselves by the upregulation of proliferative pathways. Ultimately, we propose the oncogenic MCM2 gene as a methylation-driven gene of which the representative epigenetic markers could serve both as predictive and prognostic markers. Briefly, our work provides several potential HCC progression epigenetic biomarkers as well as a new signature that may enhance patients surveillance and advances in personalized treatment.

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