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Refined diagnosis and prognosis in soft tissue sarcoma - genetic profiles, biomarkers and prognostic models

Carneiro, Ana LU (2011) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2011:56.
Abstract
This work aimed at evaluate diagnosis and prognosis in soft tissue sarcoma (STS):

In study I, 32K bacterial artificial chromosome (BAC) arrays and gene expression

profiling were applied to 18 leiomyosarcomas and 31 undifferentiated pleomorphic

sarcomas (UPS), with the aim of identifying molecular subtype signatures. Both the

gains/losses profiles and the gene expression signatures revealed striking similarities

between the two tumour types. Leiomyosaromas and UPS were indistinguishable

using unsupervised hierarchical cluster analysis and significance analysis for

microarrays, which suggests a shared lineage.

In study II, whole-tumour sections from 239 STS were reviewed... (More)
This work aimed at evaluate diagnosis and prognosis in soft tissue sarcoma (STS):

In study I, 32K bacterial artificial chromosome (BAC) arrays and gene expression

profiling were applied to 18 leiomyosarcomas and 31 undifferentiated pleomorphic

sarcomas (UPS), with the aim of identifying molecular subtype signatures. Both the

gains/losses profiles and the gene expression signatures revealed striking similarities

between the two tumour types. Leiomyosaromas and UPS were indistinguishable

using unsupervised hierarchical cluster analysis and significance analysis for

microarrays, which suggests a shared lineage.

In study II, whole-tumour sections from 239 STS were reviewed for size, vascular

invasion, necrosis, and peripheral growth pattern. All factors provided independent

prognostic information with hazard ratios (HRs) of 2.2-2.6 for development of

metastases in multivariate analysis. When combined into a prognostic model, referred

to as SING (Size, Invasion, Necrosis, Growth), high-risk tumours were identified

with a sensitivity of 74% and a specificity of 85%. SING compared favourably with

other currently used prognostic systems.

In study III, the prognostic value and clinical applicability of five proliferation

markers were assessed: Ki-67, Top2a, p21, p27Kip1 and S-phase fraction in a mixed

series of 196 STS of the extremities and the trunk wall, encompassing MFH/UPS,

leiomyosarcomas and liposarcomas. High S-phase fraction and high expression of Ki-

67 and Top2a significantly correlated to risk for metastasis with HRs of 1.9-4.4.

Classification and regression tree analysis showed that Ki-67, Top2a and S-phase

identified different prognostic subgroups. This explorative analysis suggests that

proliferation markers could have a role in STS prognostication, in particular when

few other factors can be evaluated, as in the preoperative setting.

In study IV, ezrin expression was evaluated by immunohistochemistry on tissue

microarrays from a mixed series of 256 STS. Positive ezrin expression predicted

development of metastasis (HR=1.8) and local recurrence (HR=1.8) and was strongly

correlated to necrosis and growth pattern. Ezrin represents therefore a potential

marker for identification of high-risk sarcoma patients. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • MD, PhD Nielsen, Ole Steen, Department of Oncology, Aarhus University Hospital
organization
publishing date
type
Thesis
publication status
published
subject
keywords
MFH, microarrays, prognostic factors, metastasis, local recurrence, proliferation, Ki67, Top2a, p21, p27, S-phase fraction, erzin.
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2011:56
pages
154 pages
publisher
Institute of Clinical Sciences, Department of Oncology, Skane University Hospital, Lund
defense location
Alwall Lecture Hall
defense date
2011-06-01 10:00
ISSN
1652-8220
ISBN
978-91-86871-05-5
language
English
LU publication?
yes
id
82cd3520-15c1-479c-bac2-c0c84e5eac74 (old id 1951742)
date added to LUP
2011-05-16 09:47:10
date last changed
2016-09-19 08:44:46
@phdthesis{82cd3520-15c1-479c-bac2-c0c84e5eac74,
  abstract     = {This work aimed at evaluate diagnosis and prognosis in soft tissue sarcoma (STS):<br/><br>
In study I, 32K bacterial artificial chromosome (BAC) arrays and gene expression<br/><br>
profiling were applied to 18 leiomyosarcomas and 31 undifferentiated pleomorphic<br/><br>
sarcomas (UPS), with the aim of identifying molecular subtype signatures. Both the<br/><br>
gains/losses profiles and the gene expression signatures revealed striking similarities<br/><br>
between the two tumour types. Leiomyosaromas and UPS were indistinguishable<br/><br>
using unsupervised hierarchical cluster analysis and significance analysis for<br/><br>
microarrays, which suggests a shared lineage.<br/><br>
In study II, whole-tumour sections from 239 STS were reviewed for size, vascular<br/><br>
invasion, necrosis, and peripheral growth pattern. All factors provided independent<br/><br>
prognostic information with hazard ratios (HRs) of 2.2-2.6 for development of<br/><br>
metastases in multivariate analysis. When combined into a prognostic model, referred<br/><br>
to as SING (Size, Invasion, Necrosis, Growth), high-risk tumours were identified<br/><br>
with a sensitivity of 74% and a specificity of 85%. SING compared favourably with<br/><br>
other currently used prognostic systems.<br/><br>
In study III, the prognostic value and clinical applicability of five proliferation<br/><br>
markers were assessed: Ki-67, Top2a, p21, p27Kip1 and S-phase fraction in a mixed<br/><br>
series of 196 STS of the extremities and the trunk wall, encompassing MFH/UPS,<br/><br>
leiomyosarcomas and liposarcomas. High S-phase fraction and high expression of Ki-<br/><br>
67 and Top2a significantly correlated to risk for metastasis with HRs of 1.9-4.4.<br/><br>
Classification and regression tree analysis showed that Ki-67, Top2a and S-phase<br/><br>
identified different prognostic subgroups. This explorative analysis suggests that<br/><br>
proliferation markers could have a role in STS prognostication, in particular when<br/><br>
few other factors can be evaluated, as in the preoperative setting.<br/><br>
In study IV, ezrin expression was evaluated by immunohistochemistry on tissue<br/><br>
microarrays from a mixed series of 256 STS. Positive ezrin expression predicted<br/><br>
development of metastasis (HR=1.8) and local recurrence (HR=1.8) and was strongly<br/><br>
correlated to necrosis and growth pattern. Ezrin represents therefore a potential<br/><br>
marker for identification of high-risk sarcoma patients.},
  author       = {Carneiro, Ana},
  isbn         = {978-91-86871-05-5},
  issn         = {1652-8220},
  keyword      = {MFH,microarrays,prognostic factors,metastasis,local recurrence,proliferation,Ki67,Top2a,p21,p27,S-phase fraction,erzin.},
  language     = {eng},
  pages        = {154},
  publisher    = {Institute of Clinical Sciences, Department of Oncology, Skane University Hospital, Lund},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Refined diagnosis and prognosis in soft tissue sarcoma - genetic profiles, biomarkers and prognostic models},
  volume       = {2011:56},
  year         = {2011},
}