Evaluation of the Clonal Origin of Multiple Primary Melanomas Using Molecular Profiling

Orlow, Irene; Tommasi, Diana V.; Bloom, Bradley S.; Ostrovnaya, Irina; Cotignola, Javier; Mujumdar, Urvi; Busam, Klaus J.; Jungbluth, Achim A.; Scolyer, Richard A.; Thompson, John F.; Armstrong, Bruce K.; Berwick, Marianne; Thomas, Nancy E.; Begg, Colin B.

doi:10.1038/jid.2009.4

Cited by 27 publications

(27 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…37 More reliable classification is based on correlation of several clinical and pathologic features, such as location, the presence of an associated precursor/in-situ lesion, lymphatic invasion and dense lymphocytic inflammation, although both primary and metastatic melanomas may share some of these characteristics. In a recent study, Orlow and colleagues 38 compared the somatic mutational profiles of pairs of melanomas designated as independent primary tumors on the basis of their clinical and pathologic characteristics. They found no significant evidence of clonal origin of the two primaries in 17 of the 19 patients examined by molecular profiling using a set of highly polymorphic genetic markers.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic Features of Incident and Subsequent Tumors in Patients with Multiple Primary Cutaneous Melanomas

et al. 2011

Self Cite

View full text Add to dashboard Cite

Background 0.6–12.7% of patients with primary cutaneous melanoma will develop additional melanomas. Pathologic features of tumors in patients with multiple primary cutaneous melanomas have not been well described. In this large international multi-center case-control study, we compared the clinicopathologic features of a subsequent melanoma with the preceding (usually the first) melanoma in patients with multiple primary cutaneous melanomas, and with those of melanomas in patients with single primary cutaneous melanomas. Methods Multiple primary melanoma (cases) and single primary invasive melanoma (controls) patients from the Genes, Environment and Melanoma (GEM) study were included if their tumors were available for pathologic review and confirmed as melanoma. Clinicopathologic characteristics of invasive subsequent and first melanomas in cases and invasive single melanomas in controls were compared. Results 473 pairs comprising a subsequent and a first melanoma and 1989 single melanomas were reviewed. Forward stepwise regression modeling in 395 pairs with complete data showed that, compared to first melanomas, subsequent melanomas were: more commonly contiguous with a dysplastic nevus; more prevalent on the head/neck and legs than other sites; and thinner. Compared with single primary melanomas, subsequent melanomas were also more likely to be: associated with a contiguous dysplastic nevus; more prevalent on the head/neck and legs; and thinner. The same differences were observed when subsequent melanomas were compared with single melanomas. First melanomas were more likely than single melanomas to have associated solar elastosis and no observed mitoses. Conclusions Thinner subsequent than first melanomas suggest earlier diagnosis, perhaps due to closer clinical scrutiny. The association of subsequent melanomas with dysplastic nevi is consistent with the latter being risk factors or risk markers for melanoma.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinicopathologic Features of Incident and Subsequent Tumors in Patients with Multiple Primary Cutaneous Melanomas

et al. 2011

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several studies apparently support the evidence that most synchronous or metachronous primary melanomas occur independently [1,17]. As 45% of cutaneous malignant melanomas are found to be BRAF mutated [6], at least half the melanomas of our patient were expected to be of wild type.…”

Section: Discussionmentioning

confidence: 77%

Association of CDK4 germline and BRAF somatic mutations in a patient with multiple primary melanomas and BRAF inhibitor resistance

et al. 2015

View full text Add to dashboard Cite

Many genetic alterations, including predisposing or somatic mutations, may contribute toward the development of melanoma. Although CDKN2A and CDK4 are high-penetrance genes for melanoma, MC1R is a low-penetrance gene that has been associated most consistently with the disease. Moreover, BRAF is the most frequently somatically altered oncogene and is a validated therapeutic target in melanoma. This paper reports a case of multiple primary melanoma with germline CDK4 mutation, MC1R variant, and somatic BRAF mutation in nine out of 10 melanomas, indicating that a common pathogenesis, because of a predisposing genetic background, may be shared among distinct subsequent melanomas of probable clonal origin. After 3 months of targeted therapy with BRAF inhibitor, our patient developed resistance with rapid progression of the disease leading to death. This is the first case in which early resistance to BRAF inhibitor has been reported in a patient with CDK4 germline mutation.

show abstract

“…We will illustrate the problem of testing multiple tumors with an example from a prior study of melanoma (Orlow et al, 2009). The data from two patients, one with 3 tumors and another one with 4 tumors, are shown in Table 2.…”

Section: Examplementioning

confidence: 99%

“… Notations: “-” – uninformative marker; “0” – informative marker, no LOH; S and L – LOH at opposite alleles; x – marker is excluded from consideration to maintain the assumption of independence between markers; % LOH – frequency of LOH at these markers in the remaining 22 melanoma patients in Orlow et al, (2009). …”

Section: Figurementioning

confidence: 99%

“…Previously we have successfully developed statistical methods for testing whether two tumors from the same patient are clonal or independent based on these LOH profiles (Begg et al, 2007; Ostrovnaya et al, 2008). In many studies, however, patients may present with 3 or more tumors; see, for example, Orlow et al, 2009; Lindgren et al, 2008; Hampl et al, 1999. Some studies specifically focus on triplicates of tumors where clonality of all of them is in question, e.g.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Testing clonality of three and more tumors using their loss of heterozygosity profiles

Ostrovnaya

2012

Statistical Applications in Genetics and Molecular Biology

Self Cite

View full text Add to dashboard Cite

Cancer patients often develop multiple malignancies that may be either metastatic spread of a previous cancer (clonal tumors) or new primary cancers (independent tumors). If diagnosis cannot be easily made on the basis of the pathology review, the patterns of somatic mutations in the tumors can be compared. Previously we have developed statistical methods for testing clonality of two tumors using their loss of heterozygosity (LOH) profiles at several candidate markers. These methods can be applied to all possible pairs of tumors when multiple tumors are analyzed, but this strategy can lead to inconsistent results and loss of statistical power. In this work we will extend clonality tests to three and more malignancies from the same patient. A non-parametric test can be performed using any possible subset of tumors, with the subsequent adjustment for multiple testing. A parametric likelihood model is developed for 3 or 4 tumors, and it can be used to estimate the phylogenetic tree of tumors. The proposed tests are more powerful than combination of all possible pairwise tests.

show abstract

Evaluation of the Clonal Origin of Multiple Primary Melanomas Using Molecular Profiling

Cited by 27 publications

References 51 publications

Clinicopathologic Features of Incident and Subsequent Tumors in Patients with Multiple Primary Cutaneous Melanomas

Clinicopathologic Features of Incident and Subsequent Tumors in Patients with Multiple Primary Cutaneous Melanomas

Association of CDK4 germline and BRAF somatic mutations in a patient with multiple primary melanomas and BRAF inhibitor resistance

Testing clonality of three and more tumors using their loss of heterozygosity profiles

Contact Info

Product

Resources

About