Abstract 1477: Tumor cell-leukocyte fusion in human cancer: A melanoma brain metastasis with a donor-patient hybrid genome following allogeneic BMT

Abstract

Abstract Tumor cell fusion with motile bone marrow-derived cells (BMDCs) has long been proposed as a mechanism for metastasis, but while such fusion has been demonstrated in animal models little is known of this in human cancer. Here we report the first genetic evidence for BMDC-tumor fusion and genomic hybridization in a human melanoma brain metastasis from a patient with a prior allogeneic bone marrow transplant (male-male, sibling). STR analyses of DNA from melanoma cells throughout the tumor revealed the presence of both donor and patient alleles, with common aberrant allelic patterns at multiple chromosomal loci indicating a clonal origin of the tumor. Methods. All procedures were in accordance with HIPAA regulations and approved by the Yale HIC. Donor and patient DNAs were obtained from frozen lymphocytes and from a patient buccal swab. Formalin-fixed, paraffin-embedded tumor specimens were stained by immuniohistochemistry with common leucocyte antigen (CLA) in order to avoid leucocytes during microdissection of tumor cells. LCA-negative tumor cells were isolated with an Arturus XT laser dissection microscope system. DNA was extracted and analyzed for donor and patient alleles using forensic STR analyses at 13 chromosomal loci and amelogenin for the X and Y. Tissue sections were analyzed from 14 areas throughout the tumor. Results. DNA from donor and patient lymphocytes showed balanced diploidy at all loci and the allelic patterns were consistent with the sibling relationship. On the other hand, DNA from tumor cells contained a mixture of donor and host alleles at some loci, only donor or patient alleles at others, and numerous allelic imbalances throughout–particularly for the X and Y (X:Y = 2.8:1) that pointed to a probable tumor genotype of XXXY. With few exceptions, aberrant genetic profiles seen in one tumor section were seen in all, demonstrating a clonal origin of the tumor. Conclusions. The results provide the first genetic proof of leucocyte-tumor fusion and genomic hybridization in human cancer and indicate that the tumor was generated from a single fusion event. While this report concerns only one case, we demonstrate that forensic genetic analyses of tumors arising as secondary malignancies represents a fruitful area for research in tumor cell fusion in human cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1477. doi:10.1158/1538-7445.AM2011-1477