Genetically Heterogeneous and Clonally Unrelated Metastases May Arise in Patients With Cutaneous Melanoma

Katona, Terrence M.; Jones, Timothy D.; Wang, Mingsheng; Eble, John N.; Billings, Steven D.; Liu, Cheng

doi:10.1097/pas.0b013e31802b3488

Cited by 56 publications

(31 citation statements)

References 32 publications

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“…[19][20][21][37][38][39] However, the present study is the first to assess clonal genetic relationships between primary melanomas and an uncommon subtype of metastasis, the epidermotropic metastatic melanoma. The importance of studying this relationship is underscored by the fact that histopathology alone may be insufficient to distinguish an epidermotropic metastatic melanoma from a new primary lesion.…”

Section: Discussionmentioning

confidence: 97%

Clonal relationships between epidermotropic metastatic melanomas and their primary lesions: a loss of heterozygosity and X-chromosome inactivation-based analysis

et al. 2007

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Loss of heterozygosity (LOH) has previously been demonstrated at multiple chromosome microsatellites in primary and metastatic melanomas. Epidermotropic metastases of melanoma are unique in their varied histopathologic appearance, which can mimic a primary lesion. Our objective was to compare LOH profiles in primary and epidermotropic metastatic melanoma to delineate their clonal relationship. We examined the pattern of allelic loss in the primary melanomas of nine patients in addition to the 21 corresponding epidermotropic metastatic melanomas (average 2.3 metastases per patient). DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser capture microdissection. Eight DNA microsatellite markers on six different chromosomes were analyzed: D1S214 (1p), D6S305 (6q), D9S171 (9p), D9S157 (9p), IFNA (9p), D10S212 (10q), D11S258 (11q), D18S70 (18q). In addition, X-chromosome inactivation analysis was performed in tumors from four women. LOH was seen in 67% (6/9) of primary melanomas and 81% (17/21) of epidermotropic metastatic melanomas. The most frequent allelic losses in informative cases occurred at 10q (33%), 9p (22%), and 11q (22%) in primary melanomas, and at 10q (50%), 1p (44%), and 6q (39%) in epidermotropic metastatic melanomas. Primary lesions demonstrating LOH had concordant allelic loss in at least one locus in a corresponding epidermotropic metastatic melanoma in 83% (5/6) of cases. X-chromosome analysis showed nonrandom inactivation in 75% (3/4) and 71% (5/7) of primary melanoma and epidermotropic metastatic melanoma cases, respectively. Our LOH and X-chromosome inactivation analysis data suggest that epidermotropically metastatic melanomas are clonally related to their primary lesion in many cases. Our data also indicated that some cases diagnosed as epidermotropic metastatic melanoma might be divergent clones or new primaries rather than metastatic disease.

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Section: Discussionmentioning

confidence: 97%

Clonal relationships between epidermotropic metastatic melanomas and their primary lesions: a loss of heterozygosity and X-chromosome inactivation-based analysis

et al. 2007

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“…As a consequence, the ongoing acquisition of these alterations can result in the emergence of neoplastic subclones with varying genotypes and, consequently, phenotypes,32 leading to discordance between the primary tumor and its metastases. In people, several tumors including melanoma,33 gastrointestinal stromal tumor,34 and lung cancer35 show intratumor and intertumor heterogeneity, indicating the presence of more than one clone of cancer cells within a given neoplastic mass, and the presence of different genetic alterations in different metastatic sites from a single patient, respectively. Therefore, determining if there is homogeneous mutational status between primary tumor and its metastatic sites has important clinical implications, overall to select the appropriate treatment.…”

Section: Discussionmentioning

confidence: 99%

Concordance of c‐kit Mutational Status in Matched Primary and Metastatic Cutaneous Canine Mast Cell Tumors at Baseline

Marconato

Zorzan

Giantin

et al. 2013

Veterinary Internal Medicne

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BackgroundMutation analysis of proto‐oncogene c‐kit (c‐kit) is advisable before starting treatment with tyrosine kinase inhibitors in dogs with mast cell tumor (MCT), including those with metastatic disease. Testing is usually performed on primary tumors, assuming that c‐kit mutation status does not change in metastasis.Hypothesis/ObjectivesTo give an insight into the mutational processes and to make a recommendation on the use of c‐kit mutational analysis in the clinical setting.AnimalsTwenty‐one client‐owned dogs with metastatic MCT.MethodsDogs undergoing resection or biopsy for both primary and matched metastatic MCT were prospectively enrolled. Total RNA or DNA was extracted from primary MCT and corresponding metastases. Exons 8, 9, and 11 were amplified by PCR and sequenced. Genetic features between primary MCT and metastases were compared. Their correlation with clinicopathologic features was investigated.ResultsConcordance (mutated or wild‐type) of mutational status, evaluable in 21 primary and matched metastatic (20 nodal and 1 splenic) MCTs, was 100%. Three new c‐kit mutations were identified. No significant correlation was detected between c‐kit mutation and clinicopathologic features.Conclusions and Clinical ImportanceProto‐oncogene c‐kit mutational status is conserved between any primary and its matched secondary tumor, suggesting that both can be used for c‐kit mutational testing. Targeted therapies might be also used to treat metastatic disease.

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“…An analysis of three breast cancer tumors by single nucleus sequencing has clearly demonstrated the polyclonal nature of cancer (24). Intra-tumor heterogeneity, where more than one cancer cell clone is present within a single tumor, has been identified in a number of cancers (25)(26)(27). The development of therapies targeting specific oncogenes has enabled the use of mutation-detection strategies aimed at these oncogenes for the assessment of intra-tumor heterogeneity (11,18,28).…”

Section: Discussionmentioning

confidence: 99%

Intra-tumor heterogeneity of BRAF V600E mutation in lung adenocarcinomas

Tatematsu

Sasaki

Shimizu

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. BRAF mutations exist in numerous types of cancer, including melanomas, colorectal cancers and lung cancers. The V600E-specific inhibitor vemurafenib has marked clinical activity in patients with BRAF V600E-mutated melanoma. However, there are many cases of resistance to vemurafenib. This may be due to the reported intra-tumor heterogeneity of the BRAF V600E mutation in primary melanomas. BRAF mutations are found in 1-5% of non-small cell carcinomas (NSCLCs), almost exclusively in adenocarcinoma. A few cases have been reported in which vemurafenib was effective against BRAF V600E-mutated lung cancers. In a previous study, five lung adenocarcinomas with BRAF V600E mutation were detected by direct sequencing. The present study analyzed these tumors for the percentage of mutation (%mutation) by competitive allele-specific polymerase chain reaction (CAST-PCR) assay. In addition, sections of all components of the adenocarcinomas were obtained by laser microdissection and analyzed. The %mutations of BRAF V600E within the macrodissected tumors (cases 1-5) were: Case 1, 10.0%; case 2, 8.0%; case 3, 8.9%; case 4, 21.5%; and case 5, 14.9%. In four cases (cases 2-5), the %mutations of each adenocarcinoma component were as follows: Case 2, lepidic growth 6.5-24.5%, papillary 1.3-11.2% and acinar 9.8%; case 3, solid 2.5-69.9%, acinar 12.4-27.1% and papillary 3.7-17.4%; case 4, acinar 10.0-45.0% and papillary 44.0%; and case 5, papillary 3.7-93.4%. Sensitive BRAF mutation detection methods were used and evidence for heterogeneity of the BRAF V600E mutation in these lung adenocarcinoma cases was observed. Targeted therapy with a BRAF V600E inhibitor such as vemurafenib may have potential in the treatment of lung cancer with this mutation; however, it is necessary to consider how the treatment effect of and drug resistance to BRAF V600E inhibitors are affected by the presence of heterogeneity in future studies.

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Genetically Heterogeneous and Clonally Unrelated Metastases May Arise in Patients With Cutaneous Melanoma

Cited by 56 publications

References 32 publications

Clonal relationships between epidermotropic metastatic melanomas and their primary lesions: a loss of heterozygosity and X-chromosome inactivation-based analysis

Clonal relationships between epidermotropic metastatic melanomas and their primary lesions: a loss of heterozygosity and X-chromosome inactivation-based analysis

Concordance of c‐kit Mutational Status in Matched Primary and Metastatic Cutaneous Canine Mast Cell Tumors at Baseline

Intra-tumor heterogeneity of BRAF V600E mutation in lung adenocarcinomas

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