Molecular evidence for a clonal relationship between multiple lesions in patients with unknown primary adenocarcinoma

Unknown primary adenocarcinoma (UPA) comprises a group of heterogeneous cancers of great clinical and biological interest. UPA presents as metastatic disease without a detectable primary site after medical workup. Here we investigated whether or not a clonal relationship exists between multiple tumo...

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Bibliographic Details
Published in:International journal of cancer 2008-09, Vol.123 (6), p.1292-1300
Main Authors: Speel, Ernst‐Jan M., van de Wouw, Agnes J., Claessen, Sandra M.H., Haesevoets, Annick, Hopman, Anton H.N., van der Wurff, Anneke A.M., Osieka, Rainhardt, Buettner, Reinhard, Hillen, Harry F.P., Ramaekers, Frans C.S.
Format: Article
Language:English
Subjects:
adenocarcinoma
Adenocarcinoma - genetics
Aged
Aged, 80 and over
Biological and medical sciences
cancer of unknown primary origin
clonal analysis
Clone Cells
comparative genomic hybridization
Dissemination
Female
Genes, erbB-2
Genes, p16
Genes, p53
Humans
Hyaluronan Receptors - genetics
Immunohistochemistry
In Situ Hybridization
Male
Medical sciences
microsatellite analysis
Microsatellite Repeats
Middle Aged
Neoplasm Metastasis - genetics
Neoplasms, Unknown Primary - genetics
Tumor cell
Tumors
unknown primary tumor
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Summary:Unknown primary adenocarcinoma (UPA) comprises a group of heterogeneous cancers of great clinical and biological interest. UPA presents as metastatic disease without a detectable primary site after medical workup. Here we investigated whether or not a clonal relationship exists between multiple tumors within individual UPA patients. A molecular resemblance would argue for an early clonal outgrowth of tumor cells from the primary lesion, a mutual feature observed within this group of neoplasms. In 14 patients with UPA multiple tumors, obtained at autopsy, were analyzed by molecular allelotyping and immunohistochemistry. In addition, tumors of 4 patients could be analyzed by comparative genomic hybridization (CGH). Similar genetic and phenotypic profiles were used as indicator for a clonal relationship, whereas different profiles implicate independent tumors. The molecular data indicated that the multiple lesions in the 14 UPA patients, including the primary tumors, are clonally related. In agreement with the theory of tumor progression, some metastatic lesions showed additional genetic alterations besides the characteristics that were shared with the primary tumor. Furthermore, 8 UPA patients had tumors with a high frequency of allelic loss and/or imbalance (FALI; 43–71%), while 6 patients demonstrated a lower FALI (14–29%), suggesting the occurrence of chromosomal instability in the former group. Our data provide molecular evidence for a clonal relationship between multiple metastases and the primary tumor within individual UPA patients, independent of the anatomical origin of the cancer. This finding is in agreement with the suggestion that tumor progression is rapid in UPA patients, limiting the chance of clonal divergence. The identification of 2 groups of UPAs with either a high or low FALI indicates that chromosomal instability is not the only driving force behind early tumor cell dissemination. Thus, other molecular mechanisms must underlie the common biology of these tumors. © 2008 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.23616