Clinical application of array-based comparative genomic hybridization to define the relationship between multiple synchronous tumors

Abstract

Array-based comparative genomic hybridization (CGH) is a technique that allows genome wide screening of gains and losses in DNA copy number. In cases where multiple tumors are encountered, this genetic technique may prove useful in differentiating new primary tumors from recurrences. In this case report, we used arraybased CGH to examine the genomic relationships among two leiomyosarcomas and two breast cancers in the same patient, three of which were diagnosed synchronously. Array-based CGH was performed on the four tumor samples using random prime amplified microdissected DNA. Samples were hybridized onto bacterial artificial chromosome arrays composed of approximately 2400 clones. Patterns of alterations within the tumors were compared and genetic alterations among the leiomyosarcomas and breast lesions were found. Overall, three distinct genetic profiles were observed. While the two leiomyosarcomas shared a similar pattern of genetic alterations, the two invasive breast lesions did not. The nearly identical pattern of genetic alterations belonging to the two metachronous leiomyosarcomas confirmed metastatic recurrence while the two different genetic profiles of the invasive ductal carcinomas suggest that the two lesions represented two distinct foci of multifocal disease rather than clonal extension of the primary tumor. We conclude that genetic analysis by array-based CGH can clearly elucidate the relationships between multiple tumors and may potentially serve as an important clinical tool. Modern Pathology (2005) 18, 591-597, advance online publication, 14 January 2005; doi:10.1038/modpathol.3800332 Keywords: breast cancer; comparative genomic hybridization; leiomyosarcoma Comparative genomic hybridization (CGH) is a technique that has greatly facilitated detection of gains and losses in DNA copy number, and has been of particular utility in elucidating the pattern of genomic alterations in tumors. Although this technique remains primarily a research tool, it has potential clinical use in cases with complex presentation. Array CGH may be of clinical value in differentiating new primary tumors from recurrent lesions, particularly in patients with unusual recurrence patterns. Genomic analysis can also help elucidate the relationship between multiple tumor foci. These determinations may in some cases significantly alter the course of further treatment. Array CGH can thus serve as an important adjunct to immunohistochemistry and histopathology. In this study, we examined the genomic relationships between four separate cancers in the same patient, using array CGH. This case illustrates the potential clinical application of genomic technology in defining the relationship between multiple tumors. Case reportA 43-year old woman 5 years status post resection of a high-grade left retroperitoneal leiomyosarcoma presented with masses in the left breast and right thigh. Mammography showed a highly suspicious spiculated lesion in the lower inner left breast, corresponding to the palpable mass. Fineneedle aspiration of t...

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation

“…Quantitative measurement of DNA copy numbers across the genome has revealed various oncogenes (Tanami et al, 2005) or tumour suppressor genes (Takada et al, 2005(Takada et al, , 2006) that had not been detected by earlier techniques. In addition, the higher resolution of array-CGH has allowed precise mapping of the boundaries of the gained and lost regions, thereby helping to elucidate the clonal relationship between multifocal tumours (Shelley Hwang et al, 2004;Wa et al, 2005). In conclusion, we investigated the genetic alterations that occur during the development of multifocal low-grade superficial urothelial tumours by using array-CGH, and assessed the mechanism underlying the heterotopic recurrence of urothelial cancer.…”

Unlocking pathology archives for molecular genetic studies: a reliable method to generate probes for chromogenic and fluorescent in situ hybridization

“…Array-based comparative genomic hybridization (aCGH) is a powerful screening tool to detect DNA copy changes and hence to identify cancer-associated chromosomal aberrations. 2,[4][5][6][7][8][9] The high resolution of aCGH has been demonstrated in several contexts, particularly in the case of small amplicons, previously undetected by chromosomal CGH (cCGH), which have been identified in a number of cell lines and human tumours. 2,[4][5][6][7][8][9] Although the principles of aCGH are rather simple, it is an expensive and labour-intensive method.…”

“…2,[4][5][6][7][8][9] The high resolution of aCGH has been demonstrated in several contexts, particularly in the case of small amplicons, previously undetected by chromosomal CGH (cCGH), which have been identified in a number of cell lines and human tumours. 2,[4][5][6][7][8][9] Although the principles of aCGH are rather simple, it is an expensive and labour-intensive method. Furthermore, while our group and others have successfully performed aCGH with DNA extracted from formalin-fixed archival material, 2,[4][5][6]8,9 this is associated with considerable difficulties.…”

“…2,[4][5][6][7][8][9] Although the principles of aCGH are rather simple, it is an expensive and labour-intensive method. Furthermore, while our group and others have successfully performed aCGH with DNA extracted from formalin-fixed archival material, 2,[4][5][6]8,9 this is associated with considerable difficulties. Therefore, it is unlikely that this technique will be easily applied to large cohorts of archival samples.…”

Leiomyosarcoma of the breast - a case report

“…De la Pena and Wapnir (13) reported a case of leiomyosarcoma of the breast with a 10-year-history of cyclophosphamide exposure. A case demonstrated two separate breast cancers and metastatic leiomyosarcoma of the thigh from retroperitoneum was reported as multiple synchronous tumors (14). The present case was diagnosed as leiomyosarcoma after excluding the possibility of metaplastic carcinoma by demonstrating pancytokeratin negativity in several tumor sections.…”