Giovanni Blandino MD Translational Oncogenomic Unit Rome, University La Sapienza, October 16, 2013 From Lombroso to the Weizmann Institute of Science across Italian National Cancer Institute “Regina Elena”
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Giovanni Blandino MD Translational Oncogenomic Unit
Rome, University La Sapienza, October 16, 2013
From Lombroso to the Weizmann Institute of Science across Italian National Cancer Institute “Regina Elena”
Full Time Personnel
• Clinicians & Researchers 843
• Other Professionals 4
• Technicians 149
• Administrative Pers. 193
TOTAL 1189
Admitted Patients (2007)
• Abd. Surgery 516 (235) • Surgery A 646 (94) • Plast. Surgery 412 (76) • Thorac. Surgery 751 (333) • Hematology 204 (76) • Gynec. 519 (116) • Medic Oncol A 1,049 (33) • Medic Oncol B 1,503 (43) • Medic Oncol C 496 (30) • Radioth. 477 (07) • Neurochir. 370 (76) • Head & Neck 424 (95) • Orthop. 139 (61) • Urology 851 (255) • Pain Therapy 41 (17)
• TOTAL 10,128
Admitted Patients Day Hospital (2007) • Abd. Surgery 554 (8) • Plast. Surgery 412 (76) • Hematology 388 (58) • Gynecol. 310 (34) • Medic Oncol A 602 (0) • Medic Oncol B 695 (0) • Medic Oncol C 334 (0) • Radioth. 100 (1) • Urology 128 (7) Total 5,894
• TOTAL 10,128
Italian National Cancer Institute “Regina Elena” Research Areas
Basi molecolari e cellulari per la ricerca traslazionale in oncologia
Approcci innovativi nelle classificazioni diagnostiche e prognostiche del paziente oncologico
Ricerca traslazionale e clinica sulle terapie innovative in ambito oncologico
Prevenzione primaria e secondaria e qualità della vita
Molecular Medicine Area
mutant p53 and chemoresistance first evidence in 1999
“...These findings define a new type of mutant p53 selective gain of function, which may compromise the efficacy of cancer chemotherapy. “
expression of mutant p53 proteins in stable H1299 transfectants
Generation of H1299 cell populations expressing p53 mutants
Mutant p53 confers resistance to low but not high concentrations of cisplatin
clonogenic survival assay of H-175 versus H-273 without or with cisplatin treatment
“...the presence of particular p53 mutations may render a tumor less responsive to particular therapy regimens.”
Mutant p53 reaches target promoters through sequence-specific transcription factors
Stambolsky et al.,
Cancer Cell 2010
Vitamin D3
p300 mp53
VDR
VDRE
RXR
HIRA
CYP24A1
ETC…
p300 mp53
E2F1
CDE
ID4
ID2
Fontemaggi et al.,
Nat Struct Mol Biol 2009
Fontemaggi et al.,
Cell Cycle 2010
Dell’Orso et al.,
Oncotarget 2010
Di Agostino et al., Cancer Cell
2006; Strano et
al.,Oncogene,2008; Valenti et al.,
Cell Cycle, 2011.
p300 mp53
NF-Y
CCAAT
DNA damage
CyclinA
CyclinB
Cdk1
Cdc25c
PLK2
mp53
p65
NF-kB
Bcl-xL ID4
Weisz et al., Cancer Res 2007 Fontemaggi et al., Nat Struct Mol Biol 2009
Memorandum of Understanding between Italian National Cancer Institute in Rome “Regina Elena” (IFO), and the Bioinformatic Unit (BU) at the Weizmann Institute The overarching aim of the collaboration between BU ad IFO is to facilitate excellence in science by promoting collaborative scientific cancer research projects and research mentoring…….. Signed on October 17, 2007
Translational Oncogenomics Unit Dott. Francesca Biagioni
Dott. Valeria Canu Dott. Giulia Fontemaggi
Molecular Chemoprevention Unit Dott. Federica Mori
Dott. Raffaela Santoro Dott. Sabrina Strano
Pathology Department Dott. Anna Di Benedetto Dott. Barbara Antoniani
Dott. Marcella Mottolese
Department of Physics of Complex Systems Dott. Noa Bossel
Prof. Eytan Domany
Department of Biological Regulation Prof. Yosef Yarden
CELL LINES
TUMOR SAMPLES
RNA HYBRIDIZATION
RNA EXTRACTION
and QUALITY CONTROL TOTAL RNA LABELLING
Expression matrix
TN
3T
TN
8T
TN
5T
TN
6T
TN
7T
TN
1T
TN
2T
TN
4T
TN
3P
T
TN
7P
T
TN
8P
T
TN
1P
T
TN
6P
T
TN
5P
T
TN
2P
T
hsa-miR-195hsa-miR-139-3p
hsa-miR-145hsa-miR-139-5p
hsa-miR-204hsa-miR-513c
hsa-miR-513a-5phsa-miR-513b
hsa-miR-887hsa-miR-1225-5p
hsa-miR-10b*hsa-miR-486-5p
hsa-miR-630hsa-miR-133b
hsa-miR-125b-2*hsa-miR-101*
hsa-miR-135a*hsa-miR-100hsa-miR-378
hsa-miR-1229hsa-miR-106a
hsa-miR-17*hsa-miR-17
hsa-miR-106bhsa-miR-18b
hsa-miR-146ahsa-miR-93
hsa-miR-18ahsa-miR-301a
hsa-miR-155hsa-miR-454hsa-miR-107
hsa-miR-374ahsa-miR-660hsa-miR-340
hsa-miR-532-5phsa-miR-425hsa-miR-103
microRNA PROFILE
tumor vs normal
BIOINFORMATIC
ANALYSIS
total RNA
small RNAs
Translational Approach: Agilent microRNA microarrays
Deregulation of miRs expression between tumoral and peritumoral breast cancer tissues
A
C D
B
Search for miR-10b* putative targets
Target gene Correlation
P-value
CCNA2 -0,37 0,0001
PLK1 -0,36 0,0002
BUB1 -0,35 0,0003
CHEK1 -0,34 0,0005
CHEK2 -0,31 0,0015
CCNB3 -0,28 0,0045
CUL1 -0,26 0,0083
D C
A B
Clinical association of miR-10b* target genes’ expression with survival of breast cancer patients
miR-10b* represses cell cycle regulatory genes with prognostic power in breast cancer
METABRIC DATABASE
a
Association between disease-specific survival and the expression levels of miR-10b* and three of its target genes (BUB1, PLK1 and CCNA2). (a) Kaplan-Meier analysis based on the METABRIC miR expression data (REF). Survival of the 370 patients with the highest (top third) expression levels of miR-10b* (red line) was compared to the 370 patients with the lowest expression levels (blue line). The plot was truncated at 15 years, p-value is indicated in the title. (b-d) Kaplan-Meier analysis based on the METABRIC mRNA expression data (REF). The two compared groups are 565 patients with the highest (top third) expression levels of each target gene (red line) versus 565 patients with the lowest (bottom third) expression levels (blue line). The plot was truncated at 15 years, p-values are indicated in the titles. (Biagioni et al., Cell Cycle, 2013)
b c d
Translational Oncogenomics Unit Dott. Federica Ganci Dott. Andrea Sacconi
Dott. Giulia Fontemaggi
Molecular Chemoprevention Unit Dott. Federica Mori Dott. Sabrina Strano
Head and Neck Surgical Pathology Department
Prof. Giuseppe Spriano Prof. Edoardo Pescarmona Dott. Valentina Manciocco
Dott. Renato Covello Dr. Maria Benevolo
Department of Physics of Complex Systems Dott. Noa Bossel
Prof. Eytan Domany
Department of Molecular Cell Biology Prof. Moshe Oren
miR-10b* controls the expression of BUB1, PLK1 and CCNA2 proteins in breast cancer patients
Clinical association of miR-10b* target genes’ expression with survival of breast cancer patients
miR-10b* represses cell cycle regulatory genes with prognostic power in breast cancer
Intratumoral delivery of miR-10b* reduces tumor size in a breast cancer xenograft model
miR-10b*
+
_
MDA_MB_468 were cultured
Inject 10x106 into SCID mice
Waiting for tumor formation
0 22 30
Subcutaneously Injection into the
lower back Euthanize
MIMIC treatment: 6,25 ug twice
weeklly for 2 weeks
Days
Trang et al, Oncogene, 2010
Intratumoral delivery of miR-10b* impairs its targets expression
Intratumoral delivery of miR-10b* associates with lower expression of proliferative markers
miR-10b* has a key role in controlling breast cancer cell proliferation in vivo
• miRNA expression profile on 61 breast samples: tumor and peritumor from the same patient
Confirmed deregulation of many microRNAs already reported in the
literature
New microRNAs discovered which expression is modulated in the transformed status
• 5 microRNAs (miR-425, miR-454, miR-301a, miR-10b* and miR-139-5p) are
commonly deregulated among different subtypes
• microRNA-10b* Is downregulated in tumor versus peritumor tissue by hypermethylation
of its regulatory regions Controls cell cyle and proliferation targeting three key components: BUB1,
PLK1 and CCNA2
When injected in xenografted human breast tumors, it impairs tumor growth
microRNA-10b precursor
miR-10b*
PLK1 BUB1 CCNA2
PROLIFERATION
Biagioni et al., EMBO Mol Med. 2012 Nov;4(11) 1214-29
Summary
METABRIC DATABASE
a
Association between disease-specific survival and the expression levels of miR-10b* and three of its target genes (BUB1, PLK1 and CCNA2). (a) Kaplan-Meier analysis based on the METABRIC miR expression data (REF). Survival of the 370 patients with the highest (top third) expression levels of miR-10b* (red line) was compared to the 370 patients with the lowest expression levels (blue line). The plot was truncated at 15 years, p-value is indicated in the title. (b-d) Kaplan-Meier analysis based on the METABRIC mRNA expression data (REF). The two compared groups are 565 patients with the highest (top third) expression levels of each target gene (red line) versus 565 patients with the lowest (bottom third) expression levels (blue line). The plot was truncated at 15 years, p-values are indicated in the titles. (Biagioni et al., Cell Cycle, 2013)
b c d
Translational Oncogenomics Unit Dott. Federica Ganci Dott. Andrea Sacconi
Dott. Giulia Fontemaggi
Molecular Chemoprevention Unit Dott. Federica Mori Dott. Sabrina Strano
Head and Neck Surgical Pathology Department
Prof. Giuseppe Spriano Prof. Edoardo Pescarmona Dott. Valentina Manciocco
Dott. Renato Covello Dr. Maria Benevolo
Department of Physics of Complex Systems Dott. Noa Bossel
Prof. Eytan Domany
Department of Molecular Cell Biology Prof. Moshe Oren
TP53 status correlates with the deregulation of miRNA expression
49 TP53 related miRs are deregulated in T vs N samples only in mutant TP53 subset
miRNAs are differentially expressed between TP53 wild type and mutated HNSCC samples
Table 3. Deregulation of TP53 related miRs in Tumor vs Normal tissues
TP53-related miRs upregulated in T versus N mutant TP53 subset wild type TP53 subset
miR folds T/N P value folds T/N P value
'hsa-miR-21-5p' 4.44 4.76E-15 2.60 0.0003
'hsa-miR-196b-5p' 4.13 3.94E-10 1.87 0.01
'hsa-miR-7-5p' 3.98 1.55E-10 / NS
'hsa-miR-21-3p' 3.96 7.04E-12 2.44 0.002
'hsa-miR-182-5p' 3.77 2.81E-08 / NS
'hsa-miR-18a-5p' 3.50 1.55E-09 / NS
'hsa-miR-455-3p' 3.48 3.10E-09 / NS
'hsa-miR-455-5p' 3.39 7.76E-07 / NS
'hsa-miR-135b-5p' 3.22 8.39E-06 / NS
'hsa-miR-183-5p' 3.21 1.70E-09 / NS
'hsa-miR-96-5p' 3.18 1.17E-10 / NS
'hsa-miR-424-5p' 3.17 3.69E-12 1.98 0.008
'hsa-miR-301a-3p' 2.96 3.23E-06 / NS
'hsa-miR-450a-5p' 2.89 1.26E-08 1.84 0.01
'hsa-miR-130b-3p' 2.74 2.99E-12 1.60 0.030
'hsa-miR-18b-5p' 2.70 1.72E-08 / NS
'hsa-miR-224-5p' 2.51 1.76E-05 / NS
'hsa-miR-19a-3p' 2.40 1.72E-05 / NS
'hsa-miR-429' 2.21 0.0002 / NS
'hsa-miR-205-5p' 2.21 1.74E-05 / NS
'hsa-miR-20a-5p' 1.88 2.27E-05 / NS
'hsa-miR-200c-3p' 2.19 9.78E-06 / NS
'hsa-miR-200a-3p' 2.17 0.0002 / NS
'hsa-miR-93-5p' 2.13 1.39E-07 1.51 0.02
'hsa-miR-106b-5p' 2.05 5.63E-07 1.41 0.05
'hsa-miR-17-5p' 1.96 2.56E-07 / NS
'hsa-miR-374b-5p' 1.91 0.001 / NS
'hsa-miR-193b-3p' 1.89 0.0002 / NS
'hsa-miR-454-3p' 1.86 3.58E-05 / NS
'hsa-miR-331-3p' 1.83 3.39E-05 / NS
'hsa-miR-452-5p' 1.83 0.002 / NS
'hsa-miR-17-3p' 1.81 2.27E-05 / NS
'hsa-miR-324-5p' 1.80 2.34E-06 / NS
'hsa-miR-20b-5p' 1.77 0.0002 / NS
'hsa-miR-25-3p' 1.71 5.31E-05 1.33 0.05
'hsa-miR-98-5p' 1.67 0.0009 / NS
'hsa-miR-151a-3p' 1.59 5.73E-05 / NS
'hsa-miR-103a-3p' 1.58 0.0001 / NS
'hsa-miR-185-5p' 1.55 0.0004 / NS
'hsa-miR-365a-3p' 1.51 0.007 / NS
'hsa-miR-652-3p' 1.48 0.001 / NS
'hsa-miR-16-2-3p' 1.48 0.004 / NS
'hsa-miR-151a-5p' 1.29 0.04 / NS
mutated TP53 wild type TP53
mp53
a) Do gain of function mutant p53 proteins behave as oncogenic transcription factors?
mp53
TFs ?
?
mp53
NF-Y
mp53
mp53
E2F1
Id4
p63
p73 mp53
DNA binding protein-protein interaction
Proliferation
Invasion
Metastatization
Genomic Instability
Chemoresistance
p73
mp53
cyclin A cyclin B1
cdk1 cdc25C
DNA damage
Id2
VDR
NFkB
PLK2
mp53
PLK2 P
Baseline characteristics of HNSCC patients Table 1. Baseline characteristics of the patients
Demographic Characteristics All pts Pts with WT TP53 Pts with Mut TP53 P value
N. N. (%) Age (median 62 years) Age < 62 years 60 22 (36.7) 38 (63.3) 0.20 Age >62 years 60 29 (48.4) 31 (51.6) Unkwnon 1 1 (100.0) 0 (0.0) Sex Male 89 35 (39.3) 54 (60.7) 0.29 Female 32 16 (50.0) 16 (50.0) Smoking history Never smoked 27 14 (51.9) 13 (48.1) 0.29 Smoker or ex (cigarettes) 94 37 (39.4) 57 (60.6) Alcohol use Not drinking 50 28 (56.0) 22 (44.0) 0.01* Drinking or ex 70 23 (32.9) 47 (67.1) Unknown 1 0 (0.0) 1 (100.0) HPV status (28 Genotypes screened) Negative 114 48 (42.1) 68 (59.6) / Positive 5 3 (60.0) 2 (40.0) Unknown 2 2 (100.0) 0 (0.0)
Clinical Characteristics All pts Pts with WT TP53 Pts with Mut TP53 P value
N. N. (%) Primary tumor site Oral cavity 73 29 (39.7) 44 (60.3) 0.30 Larynx 29 16 (55.2) 13 (44.8) Hypopharynx 9 2 (22.2) 7 (77.8) Oropharynx 10 4 (40.0) 6 (60.0) Cell differentiation (G) Well differentiated (G1) 8 5 (62.5) 3 (37.5) 0.55 Moderately differentiated (G2) 68 29 (42.6) 39 (57.4) Poorly differentiated (G3-G4) 44 17 (38.6) 27 (61.4) Unknown 1 0 (0.0) 1(100.0) Pathological tumor stage (T) T1-T2 56 25 (44.0) 31 (56.0) 0.58 T3-T4 65 26 (40.0) 39 (60.0) Pathological nodal stage (N) N0 or Nx 63 30 (47.6) 33 (52.4) 0.24 N1-N3 58 21 (36.2) 37 (63.8) Metastasis development No 108 47 (43.5) 61 (56.5) / Yes 13 4 (30.7) 9 (69.3) Overall FU time (median=31 months) <=31 months 55 21 (38.2) 34 (61.8) 0.21 >31 months 54 27 (50.0) 27 (50.0) Not available 12 4 (33.3) 8 (66.7) Overall survival Alive 72 32 (44.4) 40 (55.6) 0.16 Died by cancer 35 14 (40.0) 21 (60.0) Died not by cancer 2 2 (100.0) 0 (0.0) Not available 11 2 (18.2) 9 (81.8) Overall death time (median=16.8 months) <=16.8 months 19 7 (36.8) 12 (63.2) / >16.8 months 16 7 (43.8) 9 (56.2) Local recurrence development No 72 36 (50.0) 36 (50.0) 0.08
•pts with HNSCC admitted to Department of Otolaryngology Head Neck Surgery; •Histologically proven SCC; •Primary tumor site eligible:oral cavity,pharynx, larynx; •Signed informed consent prior to beginning protocol specific procedures;
Study design
•Any previous treatment with radiotherapy or chemotherapy • Any concomitant treatment with other anticancer therapy
Exclusion criteria
Inclusion criteria
Months
60483624120
Recurr
ence-F
ree-S
urv
ival
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
42%
27%
9%
18%
4%
TP53 status
wild type
missense
nonsense
frame-shift
splice site
(N=109,p=0.059)
65.6%
48.1%
TP53 w.t. TP53 mut.
Table 2. Results of Multivariate Analysis of prognostic factors
Recurrence-Free-Survival Cancer-Specific-Survival
Factors HR (CI95%) P Value HR (CI95%) P Value
Primary tumor site pharynx vs
larynx and oral cavity 3.58 (1.69-7.57) 0.001 4.49 (2.17-9.29) <0.0001
Adjuvant therapy yes vs no 2.09 (0.97-4.50) 0.06 4.03 (1.63-10.0) 0.003
TP53 status mut vs w.t 1.92 (0.94-3.94) 0.07 NS NS
.
TP53 status is an independent prognostic factor for Local Recurrence development in HNSCC
TP53 status correlates with the deregulation of miRNA expression
49 TP53 related miRs are deregulated in T vs N samples only in mutant TP53 subset
miRNAs are differentially expressed between TP53 wild type and mutated HNSCC samples
Table 3. Deregulation of TP53 related miRs in Tumor vs Normal tissues
TP53-related miRs upregulated in T versus N mutant TP53 subset wild type TP53 subset
miR folds T/N P value folds T/N P value
'hsa-miR-21-5p' 4.44 4.76E-15 2.60 0.0003
'hsa-miR-196b-5p' 4.13 3.94E-10 1.87 0.01
'hsa-miR-7-5p' 3.98 1.55E-10 / NS
'hsa-miR-21-3p' 3.96 7.04E-12 2.44 0.002
'hsa-miR-182-5p' 3.77 2.81E-08 / NS
'hsa-miR-18a-5p' 3.50 1.55E-09 / NS
'hsa-miR-455-3p' 3.48 3.10E-09 / NS
'hsa-miR-455-5p' 3.39 7.76E-07 / NS
'hsa-miR-135b-5p' 3.22 8.39E-06 / NS
'hsa-miR-183-5p' 3.21 1.70E-09 / NS
'hsa-miR-96-5p' 3.18 1.17E-10 / NS
'hsa-miR-424-5p' 3.17 3.69E-12 1.98 0.008
'hsa-miR-301a-3p' 2.96 3.23E-06 / NS
'hsa-miR-450a-5p' 2.89 1.26E-08 1.84 0.01
'hsa-miR-130b-3p' 2.74 2.99E-12 1.60 0.030
'hsa-miR-18b-5p' 2.70 1.72E-08 / NS
'hsa-miR-224-5p' 2.51 1.76E-05 / NS
'hsa-miR-19a-3p' 2.40 1.72E-05 / NS
'hsa-miR-429' 2.21 0.0002 / NS
'hsa-miR-205-5p' 2.21 1.74E-05 / NS
'hsa-miR-20a-5p' 1.88 2.27E-05 / NS
'hsa-miR-200c-3p' 2.19 9.78E-06 / NS
'hsa-miR-200a-3p' 2.17 0.0002 / NS
'hsa-miR-93-5p' 2.13 1.39E-07 1.51 0.02
'hsa-miR-106b-5p' 2.05 5.63E-07 1.41 0.05
'hsa-miR-17-5p' 1.96 2.56E-07 / NS
'hsa-miR-374b-5p' 1.91 0.001 / NS
'hsa-miR-193b-3p' 1.89 0.0002 / NS
'hsa-miR-454-3p' 1.86 3.58E-05 / NS
'hsa-miR-331-3p' 1.83 3.39E-05 / NS
'hsa-miR-452-5p' 1.83 0.002 / NS
'hsa-miR-17-3p' 1.81 2.27E-05 / NS
'hsa-miR-324-5p' 1.80 2.34E-06 / NS
'hsa-miR-20b-5p' 1.77 0.0002 / NS
'hsa-miR-25-3p' 1.71 5.31E-05 1.33 0.05
'hsa-miR-98-5p' 1.67 0.0009 / NS
'hsa-miR-151a-3p' 1.59 5.73E-05 / NS
'hsa-miR-103a-3p' 1.58 0.0001 / NS
'hsa-miR-185-5p' 1.55 0.0004 / NS
'hsa-miR-365a-3p' 1.51 0.007 / NS
'hsa-miR-652-3p' 1.48 0.001 / NS
'hsa-miR-16-2-3p' 1.48 0.004 / NS
'hsa-miR-151a-5p' 1.29 0.04 / NS
mutated TP53 wild type TP53
mut w.t.
7
6
4
5
3
1
2
0
Log
exp
ress
ion
P=2.59a-0.5
6.5
6
5
5.5
4.5
3.5
4
3
2.5
2
Log
exp
ress
ion
mut w.t.
P=0.04
miR-370 and miR-7 are respectively down- and up-regulated in TP53-mutated versus wild type tumors
miRNAs are differentially expressed between TP53 wild type and mutated HNSCC samples: validation by qRT-PCR
miR-370 and miR-7 are respectively down- and up-regulated in tumors versus normal samples only TP53-mutated subset
miR-370
miR-370
miR-7-5p
miR-7-5p
TP53 mutated tumor subset TP53 wild type tumor subset TP53 mutated tumor subset TP53 wild type tumor subset
Table 4. Results of Kaplan-Meier, T-test and Multivariable Analyses of prognostic microRNAs
Recurrence-Free-Survival KM Analysis* T-Test* Multivariable Analyis*
microRNA Logrank P P Value HR (CI95%) P Value 'hsa-miR-205-5p' 0.003 1,05E-14 4.98(1.67-14.9) 0.004 'hsa-miR-429' 0.007 1,69E-21 4.45(1.59-12.45) 0.004 'hsa-miR-21-3p' 0.007 3,50E-17 3.12(1.28-7.6) 0.01 'hsa-miR-331-3p' 0.008 2,49E-22 3.45(1.24-9.64) 0.01 'hsa-miR-200a-3p' 0.039 1,45E-18 3.1(1.18-7.9) 0.02 'hsa-miR-19a-3p' 0.055 2,89E-22 2.86(1.1-7.7) 0.03 'hsa-miR-21-5p' 0.055 1,86E-18 2.77(1.04-7.38) 0.04 'hsa-miR-151a-3p' 0.03 2,01E-30 3(1-8.97) 0.04 'hsa-miR-17-3p' 0.01 9,99E-22 2.82(0.98-8.14) 0.05 'hsa-miR-18b-5p' 0.009 1,49E-27 2.54(0.97-6.69) 0.06 'hsa-miR-324-5p' 0.03 1,09E-21 2.62(0.85-8) 0.09 'hsa-miR-96-5p' 0.018 1,40E-22 2.19(0.87-5.53) 0.1 Cancer-Specific-Survival
KM Analysis* T-Test* Multivariable Analyis* microRNA Logrank P P Value HR (CI95%) P Value 'hsa-miR-139-3p' 0.004 1,08E-25 0.33(0.12-0.87) 0.02 'hsa-miR-21-5p' 0.04 4,29E-05 2.41(1.1-5.53) 0.04 'hsa-miR-21-3p' 0.03 5,20E-08 2.17(0.98-4.83) 0.06 'hsa-miR-17-3p' 0.02 3,33E-07 2.1(0.91-4.71 0.08
miRNAs expression predicts clinical outcome of HNSCC patients
*The analyses were performed considering high versus low expression groups excluding the patients with an intermediate signal.
A signature of TP53-related microRNAs functions as independent prognostic factor for clinical outcome in HNSCC patients
Recurrence-Free-Survival (signature of 12 miRs)
p=0.006
Cancer-Specific-Survival (signature of 4 miRs)
p=0.006
Cancer-Specific-Survival:
Mutivariable analysis of microRNAs and clinical variables
miR site adj therapy
HR (CI95%), P value HR (CI95%), P value HR (CI95%), P value
2.34(1.18-4.65),
p=0,01
4.46(2.19-9.1),
p=3,98E-05
3.65(1.18-4.65),
p=0.005
Recurrence-Free-Survival:
Mutivariable analysis of microRNAs and clinical variables
miR site adj therapy TP53 status
HR (CI95%),
P value
HR (CI95%),
P value
HR (CI95%),
P value
HR (CI95%),
P value
2.45(1.1-5.4), p=0.01 4.7(2.1-10.4), p=0.0001 NS NS
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