Morphogenomics and Morphoproteomics: A Role for Anatomic Pathology in Personalized Medicine by ProQuest


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									                    Morphogenomics and Morphoproteomics
                      A Role for Anatomic Pathology in Personalized Medicine
                                                              Robert E. Brown, MD

I   would like to discuss a practice we have implemented
    in our department (Department of Pathology, Univer-
sity of Texas Health Science Center, Houston) and some-
                                                                           plication? Even if we apply trastuzumab, as a single agent, to
                                                                           those cases, what is the response rate? It is approximately 15%.
                                                                           So, there is something else missing here, basically, in terms of its
thing that was born at the Geisinger Medical Health Sys-                   utility in predicting response to trastuzumab, used alone, in a
                                                                           given patient. The story is even a little more disturbing with re-
tem (Danville, Pennsylvania) in 2003. Here, I discuss the                  gard to EGFR. As we heard yesterday, just a little more than 1%
application of morphogenomics and morphoproteomics1                        of the tumor cells have to show any plasmalemmal expression of
as a role for anatomic pathology in personalized medicine.                 EGFR to be considered a positive result.
                                                                              The sorry truth is that if we have 1 expression, 6% of the
                 MATERIALS AND METHODS                                     patients will respond to cetuximab. If we have 2 expression,
  The list of immunohistochemical probes and their sources for             13% of patients respond, and if we have 3 expression, no pa-
morphoproteomics and the fluorescence in situ hybridization                 tients respond. So, there is something wrong with this picture.
probe for morphogenomics are contained in Table 1.                         Even patients with ‘‘no expression’’ can respond. We need to do
                                                                           a little better.
● Morphogenomics, as it relates to medicine, incorporates mor-                                    Morphogenomics
  phology plus genomics.                                                      Many are familiar with the fluorescence in situ hybridization
● Morphoproteomics comprises morphology plus proteomics.                   probe, which directs a probe for DNA hybridization to the HER2/
● Personalized medicine is therapy customized for the individ-             neu gene on chromosome 17. This results in a red fluorescent
  ual patient.                                                             signal for the HER2/neu gene. There is also an internal control,
                                                                           where the probe to the centromere on chromosome 17 is used,
       Morphoproteomics: Evolution of Concept and                          which results in a green fluorescent signal. We score each cell
                 Historical Perspective                                    and determine the ratio of red to green. Nonamplified expression
   Most anatomic pathologists are familiar with applying a probe           is defined as a ratio of less than 1.8:1, whereas a ratio of HER2/
to detect the presence or absence of estrogen receptor (ER) . We           neu (red) to centromere on chromosome 17 (green) signals of
have been practicing this process routinely for some time in our           more than 2.2:1 is amplified. The level of amplification, as deter-
laboratories, looking for the presence of ER-positive breast cancer        mined by such numerical ratios, and its predictive value in terms
tumors versus ER-negative tumors, so that we can provide some              of responsiveness for an individual patient’s tumor to trastuzum-
guidance to the clinician with respect to the role of antiestrogenic       ab therapy are currently under study.
therapy, such as tamoxifen. Then along came immunohistochem-
ical testing for human epidermal growth factor receptor 2                      MORPHOPROTEOMICS IN GUIDING TARGETED
(HER2/neu), c-erb-B2, and many of us have been applying this                     CANCER THERAPIES: PROOFS OF CONCEPT
to assess the level of plasmalemmal (cell membrane) expression               When focusing on morphoproteomics in guiding tar-
of HER2 total protein as one guide for the application of trastu-
                                                                           geted cancer therapies, we can talk about concepts and
zumab therapy. More recently, our clinical colleagues requested
that we assess the plasmalemmal expression level of epidermal              proofs of concept and then application. But first, how do
growth factor receptor (EGFR) in carcinoma of the colon as a               we define the clinical application of morphoproteomics?
guide to therapy in terms of cetuximab (an antibody that is di-
rected against the ectodomain of EGFR).                                                        Concept and Definition
   However, we have to put the predictive value of these latter               The application of morphoproteomics, in its most com-
assessments into perspective. If we identify 3 (strong) plas-              plete sense, involves the immunohistochemical assessment
malemmal expression of HER2/neu, what is the therapeutic im-               of the activation of metabolic pathways in cancer cells, and
                                                                           actually, in any diseased cells, to predict susceptibility to
   Accepted for publication November 7, 2008.                              small-molecule inhibitors, specific chemotherapeutic
   From the Department of Pathology, University of Texas Health Sci-       agents, and possibly, differentiating agents. What is the
ence Center, Houston Medical School, Houston, Texas.                       morphologic component of that? Well, the morphologic
   The author has no relevant financial interest in the products or com-    component is essential; it is a sine qua non. By using mor-
panies described in this article.                                          phologic analysis, we can assess translocation of a protein
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