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(12) United States Patent (10) Patent No.: US 9,347,088 B2 Buendia Et Al

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(12) United States Patent (10) Patent No.: US 9,347,088 B2 Buendia Et Al USOO9347088B2 (12) United States Patent (10) Patent No.: US 9,347,088 B2 Buendia et al. (45) Date of Patent: May 24, 2016 (54) MOLECULAR SIGNATURE OF LIVER FOREIGN PATENT DOCUMENTS TUMIOR GRADE AND USE TO EVALUATE PROGNOSIS AND THERAPEUTC REGIMEN EP 1661991 A1 5, 2006 WO WOO3 (010336 A2 2, 2003 (75) Inventors: Marie-Annick Buendia, Le Perreux sur WO WO 2005.0056O1 A2 1, 2005 Marne (FR): Carolina Armengol Niell, OTHER PUBLICATIONS Blanes (ES); Stefano Cairo, Longpont-sur-Orge (FR); Aurélien de International Search Report issued for application No. PCT/IB2009/ Reynies, Paris (FR) 006450 on Dec. 1, 2009. Affymetrix, "Human Genome U95 Set,” announcement, Apr. 1, (73) Assignees: Institut Pasteur, Paris (FR); Institut 2000. National de la Santé et de la Recherche Out et al., “Restoration of Liver Mass after Injury Requires Prolif erative and Not Embryonic Transcriptional Patterns.” The Journal of Médicale, Paris (FR): Centre National Biological Chemistry, vol. 282, No. 15, pp. 11197-11204, Apr. 13, de la Recherche Scientifique, Paris (FR) 2007. Li et al., “Discovery and analysis of hepatocellular carcinoma genes (*) Notice: Subject to any disclaimer, the term of this using cDNA microarrays.” J. Cancer Res. Clin. Oncol., vol. 128, pp. patent is extended or adjusted under 35 369-379, 2002. U.S.C. 154(b) by 374 days. Xu et al., “Expression Profiling Suggested a Regulatory Role of Liver-enriched Transcription Factors in Human Hepatocellular Car (21) Appl. No.: 12/999,907 cinoma.” Cancer Research, vol. 61, pp. 3176-3181, Apr. 1, 2001. Kurokawa et al., “Molecular-based prediction of early recurrence in (22) PCT Filed: Jun. 26, 2009 hepatocellular carcinoma.” Journal of Hepatology, vol. 41, pp. 284 291, 2004. (86). PCT No.: PCT/B2O09/OO64SO Cairo et al., “Hepatic Stem-like Phenotype and Interplay of Wnt/B- Catenin and Myc Signaling in Aggressive Childhood Liver Cancer.” S371 (c)(1), Cancer Cell, vol. 14, No. 6, pp. 471-484, Dec. 9, 2008. (2), (4) Date: Apr. 7, 2011 Affymetrix. "Affymetrix GeneChip Human Genome U133 Array Set HG-U133A.” GEO, Feb. 17, 2002. (87) PCT Pub. No.: WO2009/156858 PCT Pub. Date: Dec. 30, 2009 * cited by examiner Primary Examiner — Anne Gussow (65) Prior Publication Data (74) Attorney, Agent, or Firm — Law Office of Salvatore US 2011 FO183862 A1 Jul. 28, 2011 Arrigo and Scott Lee, LLP US 2012/0040848 A2 Feb. 16, 2012 (57) ABSTRACT (30) Foreign Application Priority Data The present invention concerns a method to determine the gene expression profile on a sample previously obtained from Jun. 27, 2008 (EP) ..................................... O8290628 a patient diagnosed for a liver tumor, comprising assaying the Jan. 30, 2009 (EP) ..................................... O91.51808 expression of a set of genes in this sample and determining the gene expression profile (signature). In a particular embodi (51) Int. Cl. ment, said method enables to determine the grade of the liver CI2O I/68 (2006.01) tumor, such as hepatoblastoma (HB) or a hepatocellular car (52) U.S. Cl. cinoma (HCC). The invention is also directed to kits compris CPC .................................... CI2O I/6809 (2013.01) ing a plurality of pairs of primers or a plurality of probes (58) Field of Classification Search specific for a set of genes, as well as to Solid Support or None composition comprising a set of probes specific for a set of See application file for complete search history. genes. These methods are useful to determine the grade of a liver tumor in a sample obtained from a patient, to determine (56) References Cited the risk of developing metastasis and/or to define the thera U.S. PATENT DOCUMENTS peutic regimen to apply to a patient. 2002/0142981 A1* 10, 2002 Horne et al. .................... 514,44 12 Claims, 35 Drawing Sheets U.S. Patent May 24, 2016 Sheet 1 of 35 US 9,347,088 B2 Affymetrix HG-U33A 25 HBS aid4 NL5 Eitantification of obeist subclusters NT C1 C2 Fig. 1A U.S. Patent May 24, 2016 Sheet 2 of 35 US 9,347,088 B2 E rC1 rC2 L GD . ( wif - O S N On ) win (Olf Orr -3. - - 3. U.S. Patent May 24, 2016 Sheet 3 of 35 US 9,347,088 B2 B Hepatocyte HepatoblastLiver progenitor NLCt C2 Fig. 2 U.S. Patent May 24, 2016 Sheet 5 of 35 US 9,347,088 B2 AFP AQP9 DG7 500 750 400 300 500 200 250 100 O O s: e NL C1 C2 NL C1 C2 NL C1 C2 ALDH2 BUB1 400 GSF1 300 200 1OO 100 O O NL C1 C2 NL C1 C2 NL C1 C2 APCS C1S 750 750 15 E2F5 NLE1 500 500 O 250 250 d 5 s O s O was sea lette NL C1 C2 NL C1 C2 NL C1 C2 APOC4 CYP2E1 GHR 150 4000 75 5OO 3000 400 100 50 2000 300 50 25 200 1000 is 100 O r O NL C1 C2 NL C1 C2 NL C1 C2 NL C1 C2 Fig. 4 U.S. Patent May 24, 2016 Sheet 6 of 35 US 9,347,088 B2 Fig. 5A U.S. Patent May 24, 2016 Sheet 7 of 35 US 9,347,088 B2 APOC4 120 100 80 40 20 U.S. Patent May 24, 2016 Sheet 8 of 35 US 9,347,088 B2 U.S. Patent May 24, 2016 Sheet 9 of 35 US 9,347,088 B2 | 350 3000 2500 1500 000 500 U.S. Patent May 24, 2016 Sheet 10 of 35 US 9,347,088 B2 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 - - - - 4. - - - - - - a. U.S. Patent May 24, 2016 Sheet 11 of 35 US 9,347,088 B2 -s- ...": U.S. Patent May 24, 2016 Sheet 12 of 35 US 9,347,088 B2 180 is... e.. ; 160 140 t20 100 80 60 U.S. Patent May 24, 2016 Sheet 13 of 35 US 9,347,088 B2 s: RPL10A 450 350 300 250 200 150 100 U.S. Patent May 24, 2016 Sheet 14 of 35 US 9,347,088 B2 c1 c2. Citical associations (537 (s24 g-age R Predominant fetal histotype O 92%, 14% * Advanced furror stage. 40% 75%. - Wascular invasion 35% 87% - Distart metastasis at diagnosis 13%, 48% -FRETEXT W 16%. 25% HB subclass C1 n=323 DoD) , 6 He subclass C2 , risis 7 DoD) p = 0.0021 4. so B 100 120 4. Time of survival (months) His subclass C1 ina7 (ODOD) HBsubclass C2 sist8 (5000) me of survival (Tonths) Multivariate analysis HR (95% CI) p-value • 16-gene signature 80 (22-29.9) 0.02 s Tumor stage 46 (1.1-21.1) 0.050 Predominant histotype 2.5 (0.3-19,1) Q,385 Fig. 6 U.S. Patent May 24, 2016 Sheet 15 Of 35 US 9,347,088 B2 Microarray set qPCR set Complete na-24 n-37 set n=61 - Male gender (%) 17 (71%) 20 (54%) 37 (61%) - Median age, years (range) 2 (0-17) 2 (0-10) 2 (0-17) - AFP at diagnosis (ng/mL): median 131000 75873 84000 range 180-1990.800 44-2265OOO 44-2265.000 - Preoperative chemotherapy 19 (79%) 29 (78%) 48 (79%) Treatment protocol (SR/HR/NA) 9/9/1 16/9/4 25/18/5 - Tumor characteristics Tumor stage (SIOPEL): Distant metastasis at diagnosis 6 (25%) 10 (27%) 16 (26%) Vascular invasion' 14 (58%) 15 (40%) 29 (47%) PRETEXT stage (I/II/III/IV) 3/10/7/4 5/1/13/8 8/21/20/12 Multifocality 9 (37%) 9 (24%) 18 (29%) Histology: Epithelial/Mixed 1915 23/14 43/19 Predominant Epith. histotype (Fetal/others"/NA) 16/8/O 21/13/3 37/21/3 CTNNB1 mutation 19 (79%) 28 (76%) 47 (77%) AXN mutation 1 (4%) 0 (0%) 1 (2%) - Median follow-up, months (range) 40 (4-120) 22(1-135) 32 (1-135) Alive/DOD/complication-related death 16/7/1 28/8/1 44/15/2 ig. 7 U.S. Patent May 24, 2016 Sheet 18 Of 35 US 9,347,088 B2 C1 C2 PVal Clinical associations (n=53) (n=33) Wale o Predominant fetal histotype 92% 21% <0.001 Advanced tumor stage: 38% 70% O.OO5 - Vascular invasion 29% 61% O.OO5 - Distant metastasis at diagnosis 19% 48% 0.004 - PRETEXT IV 18% 23% O.393 HB Subclass C1 n=47 (3 DOD) HB subclass C2 n=26 (9 DOD) P = O.OOO2 40 SO 80 100 120 140 Time of survival (months) Fig. 9A U.S. Patent May 24, 2016 Sheet 19 of 35 US 9,347,088 B2 HB subclass C1 n=12 (ODOD) 0. 6 O .4 0. 2 HB Subclass C2 P = 0.0164 n=17 (6 DOD) 40 60 Time of survival (months) Multivariate analysis HR (95% CI) P-value • 16-gene signature 0.11 (0.03-0.41) <0.001 Tumor stage 4.52 (0.99-20.4) 0.021 • Predominant histotype 0.29 (0.04-1.96) 0.176 Fig. 9B U.S. Patent May 24, 2016 Sheet 20 of 35 US 9,347,088 B2 1. 8 C1 Subclass n = 36 (9 deaths) U 6 C2 Subclass n = 28 (13 deaths) 2 0. Log rank: p=0.020 0. 50.00 OOOO 1500 20.O Time follow-up (months) C1 Subclass n = 37 (9 deaths) C2 Subclass n = 27 (13 deaths) Log rank, p=0.024 O. 500 1OOOO 150.00 2OOOO Time follow-up (months) Fig. 10 U.S. Patent May 24, 2016 Sheet 21 of 35 US 9,347,088 B2 apaog - atrata score2 opec - strata : score 2 apeds - atrata : a core 2 Log-rank p.
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