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Somatic and germline analyses of a long term melanoma survivor with a recurrent brain metastasis.

ABSTRACT: Median overall survival (OS) of patients with melanoma brain metastases (MBM) is usually 6 months or less. There are rare reports of patients with treated MBM who survived for years. These outlier cases represent valuable opportunities to study the somatic and germline factors that may have influenced patient outcome and led to extended survival.Here we report the clinical scenario of a 67 year old man with a recurrent brain metastasis from melanoma who has survived over 12 years post-resection. We review the literature relating to clinical and molecular variables associated with long term survival post-brain metastasis. We present the somatic characteristics of this individual patient's tumor as well as an analysis of inherited genetic variants related to immune function. The patient's resected brain tumor is BRAF V600E mutated, NRAS wild type (WT), and TERT C250T mutated. The patient is a carrier of germline variants in immunomodulatory loci associated with prolonged survival.Our data suggest that genetic variants in immunomodulatory loci may partially contribute to this patient's unusually favorable outcome and should not be overlooked. With further and future investigation, knowledge of inherited single nucleotide polymorphisms (SNPs) may provide clinicians with more individualized prognostic information for melanoma patients, with potential implications for surveillance strategies and therapeutic interventions.

SUBMITTER: Weiss S

PROVIDER: S-EPMC4657192 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Somatic and germline analyses of a long term melanoma survivor with a recurrent brain metastasis.

Weiss Sarah S Darvishian Farbod F Tadepalli Jyothi J Shapiro Richard R Golfinos John J Pavlick Anna A Polsky David D Kirchhoff Tomas T Osman Iman I

BMC cancer 20151123

<h4>Background</h4>Median overall survival (OS) of patients with melanoma brain metastases (MBM) is usually 6 months or less. There are rare reports of patients with treated MBM who survived for years. These outlier cases represent valuable opportunities to study the somatic and germline factors that may have influenced patient outcome and led to extended survival.<h4>Case presentation</h4>Here we report the clinical scenario of a 67 year old man with a recurrent brain metastasis from melanoma w ...[more]

PMID: 26597176

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Project description:While a number of genes have been implicated in melanoma susceptibility, the role of protein-coding variation in melanoma development and progression remains underexplored. To better characterize the role of germline coding variation in melanoma, we conducted a whole-exome case-control and somatic-germline interaction study involving 322 skin cutaneous melanoma cases from The Cancer Genome Atlas and 3607 controls of European ancestry. We controlled for cross-platform technological stratification using XPAT and conducted gene-based association tests using VAAST 2. Four established melanoma susceptibility genes achieved nominal statistical significance, MC1R (p = .0014), MITF (p = .0165) BRCA2 (p = .0206), and MTAP (p = .0393). We also observed a suggestive association for FANCA (p = .002), a gene previously implicated in melanoma survival. The association signal for BRCA2 was driven primarily by likely gene disrupting (LGD) variants, with an Odds Ratio (OR) of 5.62 (95% Confidence Interval (CI) 1.03-30.1). In contrast, the association signals for MC1R and MITF were driven primarily by predicted pathogenic missense variants, with estimated ORs of 1.4 to 3.0 for MC1R and 4.1 for MITF. MTAP exhibited an excess of both LGD and predicted damaging missense variants among cases, with ORs of 5.62 and 3.72, respectively, although neither category was significant. For individuals with known or predicted damaging variants, age of disease onset was significantly lower for two of the four genes, MC1R (p = .005) and MTAP (p = .035). In an analysis of germline carrier status and overlapping copy number alterations, we observed no evidence to support a two-hit model of carcinogenesis in any of the four genes. Although MC1R carriers were represented proportionally among the four molecular tumor subtypes, these individuals accounted for 69% of ultraviolet (UV) radiation mutational signatures among triple-wild type tumors (p = .040), highlighting the increased sensitivity to UV exposure among individuals with loss-of-function variants in MC1R.

Project description:BACKGROUND:Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis. In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors. METHODS:DNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations. RESULTS:Eleven of 142 UM (8%) carried germline BAP1 mutations, 43 (30%) had somatic mutations, and 88 (62%) were mutation-negative. All BAP1 mutations identified in blood samples were also present in the matched UM. There were 52 unique mutations in 54 tumors. All were pathogenic or likely pathogenic. A comparison of tumors carrying somatic vs. germline mutations, or no mutations, showed a higher frequency of metastasis in tumors carrying somatic mutations: 74% vs. 36%, P=0.03 and 74% vs. 26% P<0.001, respectively. Tumors with a somatic mutation compared to mutation-negative had an older age of diagnosis of (61.8 vs. 52.2 years, P=0.002), and shorter time to metastasis (16 vs. 26 months, P=0.04). Kaplan-Meier analysis further showed that tumors with somatic (vs. germline) mutations demonstrated a greater metastatic risk (P=0.03). Cox multivariate analysis showed in addition to chromosome-3 monosomy and larger tumor diameter, the presence of BAP1 somatic, but not germline mutations, was significantly associated with risk of metastasis(P=0.02). Personal or family history of BAP1-TPDS was available for 79 of the cases. All eight cases with germline mutations reported a history of BAP1-TPDS, which was significantly greater than what was observed in cases with somatic mutations (10 of 23, P=0.009) or mutation-negative cases (11 of 48, P<0.001). CONCLUSIONS:Defining germline vs. somatic nature of BAP1 mutations in UM can inform the individual about both the risk of metastasis, and the time to metastasis, which are critically important outcomes for the individual. This information can also change the cascade screening and surveillance of family members.

Dataset Information

Somatic and germline analyses of a long term melanoma survivor with a recurrent brain metastasis.

Publications

Somatic and germline analyses of a long term melanoma survivor with a recurrent brain metastasis.

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