Clonal heterogeneity in sporadic melanomas as revealed by loss‐of‐heterozygosity analysis

Abstract

The major obstacle preventing effective treatment of melanoma is the biological heterogeneity of tumor cells. This study was performed to determine clonal genetic heterogeneity within primary melanoma and the evolution of these heterogeneous sub‐clones during disease progression. DNA samples were obtained from 44 morphologically distinct areas identified within 10 primary tumors and from 15 metastases in the same patients. Loss of heterozygosity (LOH) analyses were performed using 17 microsatellite markers that mapped to chromosomes 6q, 9p, 10q and 18q, the most frequently deleted in melanoma. Of 10 primary tumors, 8 were revealed to have intratumoral genetic heterogeneity in terms of LOH of the 4 chromosome arms examined, 7 containing at least 2 different sub‐clones harboring LOH of different chromosome areas, while the remaining one tumor showed prominent intratumoral genetic heterogeneity consisting of at least 6 genetically distinct sub‐clones. LOH of 6q was detected only in a sub‐set of multiple microdissected samples in most of the primary tumors, but was most frequently detected in metastases, suggesting that loss of this chromosome arm occurred late and played an important part in metastatic progression. Comparison of LOH between sub‐clones within primary tumors and within metastases showed the divergence of metastatic clones from dominant populations within the primary tumor in 5 patients, whereas in the remaining three patients parent sub‐clones were not identified, or constituted only a minor sub‐population within the primary tumors. These results, showing considerable genetic heterogeneity in sporadic melanoma, have profound implications for the choice of future therapeutic strategies. Int. J. Cancer 85:492–497, 2000. © 2000 Wiley‐Liss, Inc.

Primary iris melanoma: diagnostic features and outcome of conservative surgical treatment

“…We looked at the variability of pigmentation within a lesion and found that heterogeneity of pigmentation more often was associated with a malignant histology compared with a uniform pigmentation. This perhaps reflects increasing cellular heterogeneity associated with malignant progression resulting in clones of tumour cells with divergent phenotypic features associated with the variable accumulation of genetic errors 23. New angiographic techniques with improved transmission through melanin such as indocyanine green combined with confocal image analysis may have potential implications for more precise evaluation of these features in clinical practice 26…”

Co-existence of BRAF and NRAS driver mutations in the same melanoma cells results in heterogeneity of targeted therapy resistance

“…Due to these different tumor subclones within a patient (intra-patient heterogeneity), it is believed that diverse resistance mechanisms can co-exist within one patient [17, 5]. However, where these resistance mechanisms originate from and how they evolve under treatment remains poorly understood [6, 11].…”

Limited genomic heterogeneity of circulating melanoma cells in advanced stage patients

“…The genetic heterogeneity of cancer cells within a patient can potentially contribute to treatment resistance and the high rate of recurrence, and represents a major challenge for personalized cancer therapy. In melanoma, genomic heterogeneity has been observed among tumors in a single patient (6–8), but also at separated locations within individual tumors (9). This inter- and intra-tumoral heterogeneity, which has been demonstrated also in other solid tumors (10,11), reflects the evolutionary complexity that tumor cells display under specific microenviromental and therapeutic pressures during the course of the disease (5,7,11).…”