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
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Document Type: Research Article
From the Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Redpath Integrated Pathology, Inc., Pittsburgh, Pennsylvania
Department of Pediatrics, Children's National Medical Center, Washington, DC
Department of Urology, Long Island Jewish Medical Center, New Hyde Park, New York
Publication date: May 1, 2006
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