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Microdissection-Based Allelotyping: A Novel Technique to Determine the Temporal Sequence and Biological Aggressiveness of Colorectal Cancer

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Pathologic staging in colorectal adenocarcinoma (CA) is based on the concept that the timing of metastatic tumor spread is directly related to the depth of the primary tumor invasion. To evaluate the temporal sequence of CA metastasis, we performed microdissection mutational profiling at multiple microscopic sites of primary and metastatic CA specimens. Twenty-one cases of CA were selected from fixed-tissue archives. Primary tumors were microdissected at the deepest point of invasion. Comparative mutational profiling for different genomic loci [1p36(CCM = cutaneous malignant melanoma], 3p26(OGGI = 8 oxoguanine DNA glycosylase), 5q23 (APC, MCC = mutated in colorectal cancer), 9p21(p16/CDKN2A = cyclin-dependent kinase 2A), 10q23(PTEN = phosphatase and tensin homolog [mutated in multiple advanced cancers 1]), 12p12(K-ras-2 point mutation), 17p13(TP53), 18q25(DCC= deleted in colorectal cancer) was carried out on each microdissected tissue target using microsatellite loss of heterozygosity determination or DNA sequencing. All primary and metastatic sites of CA manifested acquired mutational change in 18 to 91 per cent of the genomic markers. In 15/21 (71%) cases, metastatic sites lacked a specific allelic loss seen in the corresponding primary tumor, indicating that the metastasis occurred before maximal depth of primary invasion. This was further supported by discordant mutational profiles between primary and secondary tumors, requiring divergent clonal evolution. This is the first report describing the temporal sequence and significance of sequential mutational acquisition in clinical tissue specimens with potential implications for a new molecular pathology approach to classify human cancer.
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Document Type: Research Article

Affiliations: 1: From the Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 2: Redpath Integrated Pathology, Inc., Pittsburgh, Pennsylvania 3: Department of Pediatrics, Children's National Medical Center, Washington, DC 4: Department of Urology, Long Island Jewish Medical Center, New Hyde Park, New York

Publication date: May 1, 2006

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  • The Southeastern Surgical Congress owns and publishes The American Surgeon monthly. It is the official journal of the Congress and the Southern California Chapter of the American College of Surgeons, which all members receive each month. The journal brings up to date clinical advances in surgical knowledge in a popular reference format. In addition to publishing papers presented at the annual meetings of the associated organizations, the journal publishes selected unsolicited manuscripts. If you have a manuscript you'd like to see published in The American Surgeon select "Information for Authors" from the Related Information options below. A Copyright Release Form must accompany all manuscripts submitted.
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