Unsupervised analysis uncovers changes in histopathologic diagnosis in supervised genomic studies.
Human gastrointestinal stromal tumors (GIST) have recently emerged as a distinct mesenchymal tumor type that has a unique phenotype characterized by a gain of function mutations in c-kit. In contrast, leiomyosarcomas (LMS) of the gastrointestinal tract or retroperitoneum, which were previously classified together with GISTs as gastrointestinal sarcomas, have much less frequent mutations of c-kit. We performed microarray analyses to gain a comprehensive understanding of the difference between the two types of soft-tissue sarcomas at the level of gene expression. Microarray experiments were performed on 30 GISTs and 30 LMSs that were collected at the time of surgical resection. These tumors were categorized based on the histopathologic diagnosis recorded in our institutional database. Prior to our search for genes that are differentially expressed between these two types of cancers, we first carried out an unsupervised analysis using multidimensional scaling (MDS) to determine whether the two groups have marked overall differences in gene expression. Initially, the MDS did not reveal a good separation between the two groups. We then re-reviewed the histopathology of these tumors and realized that some of the cases included in our study were acquired 10 years ago when the diagnosis of gastrointestinal sarcoma was made according to histopathologic criteria alone without immunohistochemistry for c-kit. An experienced pathologist reviewed all of the specimens and this revealed that a number of the GIST cases were classified as LMS in the clinical database. Correction of the histopathologic diagnosis and relabeling of the samples resulted in a much more pronounced separation of GIST and LMS in the MDS analysis. This study underscores the need to re-review histopathology as reclassification occurs. While updating the clinical database may be desired, this is usually impractical. For molecular studies that use archival samples, it is critical to have the archival samples re-reviewed by a pathologist. Further, unsupervised analysis often proves to be a critical quality control step in identifying structural problems that may exist. Finally, MDS analysis further supports that GIST is a distinct type of sarcoma.
Nykter
Matti
M
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Hunt
Kelly K
KK
Pollock
Raphael E
RE
El-Naggar
Adel K
AK
Taylor
Ellen
E
Shmulevich
Ilya
I
Yli-Harja
Olli
O
Zhang
Wei
W
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D003937:Diagnosis, Differential; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007890:Leiomyosarcoma / Q000175:diagnosis* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*
D014408:Biomarkers, Tumor; D019009:Proto-Oncogene Proteins c-kit