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PMC 2361658 Table 1.htm
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<body lang=EN-US link=blue vlink=purple style='tab-interval:.5in'>
<div class=WordSection1>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span style='mso-no-proof:yes'><img width=313 height=71
id="_x0000_i1029" src="PMC%202361658%20Table%201_files/image001.png"></span><span
style='font-size:12.0pt;font-family:"Times New Roman","serif";mso-no-proof:
yes'><img width=500 height=75 id="_x0000_i1028"
src="PMC%202361658%20Table%201_files/image002.gif" alt="Logo of brjcancer"></span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
mso-ansi-language:EN'>Br J Cancer. 2005 Oct 17; 93(8): 949952. </span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
mso-ansi-language:EN'>Published online 2005 Sep 20. doi: <a
href="http://dx.doi.org/10.1038%2Fsj.bjc.6602790" target="pmc_ext">10.1038/sj.bjc.6602790</a></span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
mso-ansi-language:EN'>PMCID: PMC2361658</span></p>
<p class=MsoNormal style='line-height:normal'><b><span lang=EN
style='font-size:24.0pt;font-family:"Times New Roman","serif";mso-ansi-language:
EN'>Interaction between the bone morphogenetic proteins and Ras/MAP-kinase
signalling pathways in lung cancer</span></b></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
mso-ansi-language:EN'><a
href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Kraunz%20KS%5Bauth%5D">K S
Kraunz</a>,<sup>1</sup> <a
href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Nelson%20HH%5Bauth%5D">H H
Nelson</a>,<sup>2</sup> <a
href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Liu%20M%5Bauth%5D">M Liu</a>,<sup>1</sup>
<a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Wiencke%20JK%5Bauth%5D">J K
Wiencke</a>,<sup>3</sup> and <a
href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Kelsey%20KT%5Bauth%5D">K T
Kelsey</a><sup>1,*</sup></span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><sup><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
display:none;mso-hide:all;mso-ansi-language:EN'>1</span></sup><span lang=EN
style='font-size:12.0pt;font-family:"Times New Roman","serif";display:none;
mso-hide:all;mso-ansi-language:EN'>Department of Genetics and Complex Diseases,
Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA</span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><sup><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
display:none;mso-hide:all;mso-ansi-language:EN'>2</span></sup><span lang=EN
style='font-size:12.0pt;font-family:"Times New Roman","serif";display:none;
mso-hide:all;mso-ansi-language:EN'>Department of Environmental Health, Harvard
School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA</span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><sup><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
display:none;mso-hide:all;mso-ansi-language:EN'>3</span></sup><span lang=EN
style='font-size:12.0pt;font-family:"Times New Roman","serif";display:none;
mso-hide:all;mso-ansi-language:EN'>Department of Neurological Surgery,
Laboratory for Molecular Epidemiology, University of California at San
Francisco, San Francisco, CA 94143-0441, USA</span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><sup><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
display:none;mso-hide:all;mso-ansi-language:EN'>*</span></sup><span lang=EN
style='font-size:12.0pt;font-family:"Times New Roman","serif";display:none;
mso-hide:all;mso-ansi-language:EN'>Author for correspondence: Email: <a
href="mailto:dev@null">ude.dravrah.hpsh@yeslek</a></span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
mso-ansi-language:EN'><a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/">Author information ►</a>
<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/">Article notes ►</a>
<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/">Copyright and
License information ►</a></span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
display:none;mso-hide:all;mso-ansi-language:EN'>Received 2005 May 27; Revised
2005 Jul 25; Accepted 2005 Aug 17.</span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
display:none;mso-hide:all;mso-ansi-language:EN'><a
href="http://www.ncbi.nlm.nih.gov/pmc/about/copyright.html">Copyright</a> 2005,
Cancer Research UK</span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
mso-ansi-language:EN'>This article has been <a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/citedby/">cited by</a>
other articles in PMC.</span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
mso-ansi-language:EN'><a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/"
title="Go to other sections in this page">Go to:</a></span></p>
<div style='border:none;border-bottom:solid #97B0C8 1.0pt;padding:0in 0in 0in 0in'>
<p class=MsoNormal style='line-height:normal'><b><span lang=EN
style='font-size:18.0pt;font-family:"Times New Roman","serif";text-transform:
uppercase;mso-ansi-language:EN'>Abstract</span></b></p>
</div>
<p class=MsoNormal style='line-height:normal'><span lang=EN style='font-size:
12.0pt;font-family:"Times New Roman","serif";background:yellow;mso-highlight:
yellow;mso-ansi-language:EN'>Bone morphogenetic proteins (BMPs) are an integral
component of the TGF<i>β</i> superfamily, responsible for regulation of
cell proliferation, differentiation, migration and programmed cell death in a
variety of cell types.</span><span lang=EN style='font-size:12.0pt;font-family:
"Times New Roman","serif";mso-ansi-language:EN'> The BMPs transduce their
signals directly through the SMAD family of proteins but they also have been
reported to interact with the MAPK and Erk pathways. Inactivation of the BMP
pathway genes has been implicated as important in several cancers. Recent work
has shown that <i>BMP3b</i> is epigenetically inactivated in cancer and
suggests that <i>BMP6</i> can be epigenetically inactivated. <span
style='background:yellow;mso-highlight:yellow'>We investigated whether <i>BMP6</i>
is epigenetically inactivated in cell lines and whether <i>BMP3b</i> and <i>BMP6</i>
are epigenetically inactivated in non-small-cell lung cancer (NSCLC).</span> <span
style='background:yellow'>We also studied the relationship between BMP
methylation and <i>k-ras</i> mutation.</span> <span style='background:yellow;
mso-highlight:yellow'>Here, we demonstrate that the <i>BMP3b</i> and <i>BMP6</i>
genes are common targets of epigenetic inactivation in NSCLC, and that they are
significantly more likely to be concurrently inactivated (<i>P</i>=0.009).</span>
<span style='background:yellow;mso-highlight:yellow'>Furthermore, this
coinactivation of <i>BMP3b</i> and <i>BMP6</i> is significantly associated with
mutation of <i>k-ras</i> codon 12 in lung cancer (<i>P</i>=0.003)</span>; those
with a <i>k-ras</i> mutation were six times more likely to have concurrent
methylation of these BMP loci. Hence, these data suggest that concurrent
inactivation of the BMP and activation of the Ras signalling pathways are
important in lung carcinogenesis.</span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><b><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
background:yellow;mso-highlight:yellow;mso-ansi-language:EN'>Keywords: </span></b><span
lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
background:yellow;mso-highlight:yellow;mso-ansi-language:EN'>bone morphogenetic
proteins, methylation, epigenetic inactivation, <i>k-ras</i> mutation,
non-small-cell lung cancer</span><span style='background:yellow;mso-highlight:
yellow'><o:p></o:p></span></p>
<p class=MsoNormal style='line-height:normal'><i><span lang=EN
style='font-size:12.0pt;font-family:"Times New Roman","serif";background:yellow;
mso-highlight:yellow;mso-ansi-language:EN'>k-ras</span></i><span lang=EN
style='font-size:12.0pt;font-family:"Times New Roman","serif";background:yellow;
mso-highlight:yellow;mso-ansi-language:EN'> mutation</span><span lang=EN
style='font-size:12.0pt;font-family:"Times New Roman","serif";mso-ansi-language:
EN'>, which leads to aberrant Ras/MAP-K pro-growth signalling, has been well
studied in cancer (<a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib4">Cunningham and
Weinberg, 1985</a>; <a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib17">Nelson <i>et
al</i>, 1999</a>; <a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib8">Huber and
Stratakis, 2004</a>). However, additional signalling pathways are acknowledged
to play important roles in malignant disease, with the bone morphogenetic
protein (BMP) signalling pathway emerging as important in multiple cancers (<a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib14">Nagatake <i>et
al</i>, 1996</a>; <a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib20">Tamada <i>et
al</i>, 2001</a>; <a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib2">Baldus <i>et
al</i>, 2004</a>; <a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib5">Dai <i>et al</i>,
2004</a>; <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib9">Kim
<i>et al</i>, 2004</a>). It is well recognised that the BMP signalling pathways
are crucial for all stages of embryonic development, including regulation of
lung development and airway branching (<a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib22">Weaver <i>et
al</i>, 1999</a>; <a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib12">Lu <i>et al</i>,
2001</a>; <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib18">Rosendahl
<i>et al</i>, 2002</a>). The BMPs have been shown to be growth inhibitory by
suppressing proliferation (<a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib5">Dai <i>et al</i>,
2004</a>; <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib7">Haudenschild
<i>et al</i>, 2004</a>). They act through upregulation of the cell cycle
proteins p21 and p27 (<a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib15">Nakamura <i>et
al</i>, 2003</a>; <a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib3">Brubaker <i>et
al</i>, 2004</a>; <a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib7">Haudenschild <i>et
al</i>, 2004</a>). The relationship between the TGF<i>β</i>/BMP antigrowth
and Ras/MAP-K progrowth signalling pathways remains unclear, but there is
recent evidence of crosstalk between them (<a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib10">Kretzschmar <i>et
al</i>, 1997</a>; <a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib24">Yue <i>et al</i>,
1999</a>; <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib21">Wach
<i>et al</i>, 2001</a>). While BMP-2 stimulation of osteoblasts leads to
activation of Ras (<a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib16">Nakayama <i>et
al</i>, 2003</a>), in <i>Xenopus</i>, BMP-4-stimulated erythroid
differentiation is inhibited by dominant-negative activation of the Ras pathway
(<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib23">Xu <i>et
al</i>, 1996</a>). SMAD7, one of the inhibitory SMADs of the BMP/TGF<i>β</i>
signalling pathway, has been shown to cooperate with oncogenic Ras to escape
growth arrest (<a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib11">Liu <i>et al</i>,
2003</a>). While there is experimental evidence of an association between the
BMP signalling proteins and oncogenic Ras, the nature of any interaction of BMP
cytokine inactivation and <i>k-ras</i> mutation has been relatively unexplored
in human tumours. As a result of the known importance of BMP signalling in the
respiratory tract and the <i>in vitro</i> evidence of crosstalk between
signalling pathways, we hypothesised that concurrent BMP inactivation and
oncogenic <i>k-ras</i> mutation would be important in <span style='background:
yellow;mso-highlight:yellow'>non-small-cell lung cancer (NSCLC).</span></span></p>
<p class=MsoNormal style='margin-bottom:0in;margin-bottom:.0001pt;line-height:
normal'><span lang=EN style='font-size:12.0pt;font-family:"Times New Roman","serif";
mso-ansi-language:EN'><a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/"
title="Go to other sections in this page">Go to:</a></span></p>
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<p class=MsoNormal style='line-height:normal'><b><span lang=EN
style='font-size:18.0pt;font-family:"Times New Roman","serif";text-transform:
uppercase;mso-ansi-language:EN'>MATERIALS AND METHODS</span></b></p>
</div>
<p class=MsoNormal style='line-height:normal'><b><span lang=EN
style='font-size:13.5pt;font-family:"Times New Roman","serif";mso-ansi-language:
EN'>Study population </span></b></p>
<p class=MsoNormal style='line-height:normal'><span lang=EN style='font-size:
12.0pt;font-family:"Times New Roman","serif";mso-ansi-language:EN'>Eligible
cases consisted of all the newly diagnosed patients with resectable lung cancer
who received treatment at the Massachusetts General Hospital Thoracic Surgery
Service from November 1992 to December 1996 (<a
href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361658/#bib17">Nelson <i>et
al</i>, 1999</a>). All patients involved provided written informed consent in
accordance with the appropriate institutional review boards. Patients with
recurrent disease or nonoperable tumours were excluded. Tumours were
snap-frozen in liquid nitrogen and stored at −80°C until genomic
preparation. <span style='background:yellow;mso-highlight:yellow'>There were
155 cases with fresh tumour DNA available to be tested for BMP3b and BMP6
methylation.</span> Demographic and epidemiologic data, including all of the
data on tobacco use and occupational asbestos exposure, were obtained from a
self-administered questionnaire completed by patients and subsequently reviewed