Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma

Our plain-English summary of Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma, by K.G. Ewens, E. Lalonde, J. Richards-Yutz, et al (BMC Cancer, 2018).

The study

• Authors: K.G. Ewens, E. Lalonde, J. Richards-Yutz, C.L. Shields, A. Ganguly
• Journal: BMC Cancer
• Published: 2018;18(1):1172
• Cited by: 46 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This study looked at 142 people with uveal melanoma, an eye cancer, treated in Philadelphia between 1998 and 2016. It did not study asbestos. Its background describes mesothelioma, on exposure to asbestos, as one cancer of BAP1 tumor predisposition syndrome (BAP1-TPDS), an inherited tendency to several cancers. The authors sequenced BAP1 in tumor and matched blood samples. Eleven tumors had an inherited (germline) mutation, 43 had a tumor-only (somatic) mutation, and 88 had none. The cancer spread (metastasized) in 32 of 43 somatic, 4 of 11 germline and 23 of 88 mutation-negative tumors. After adjusting for other factors, somatic mutations were associated with metastasis compared with mutation-negative tumors (hazard ratio 2.20, 95% confidence interval 1.13 to 4.30). Germline mutations were not significantly associated (hazard ratio 0.87, interval 0.28 to 2.72); this does not rule out a risk. All eight germline carriers with history information reported personal or family BAP1-TPDS cancers. The authors concluded that metastasis risk differed between somatic and germline mutations, noting few germline cases as a limitation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genetic study of tumor and matched blood samples from uveal melanoma patients, with clinical data from retrospective chart review
• Who was studied: 142 uveal melanoma cases managed at the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, USA, between 1998 and 2016 (23 enucleated tumors, 119 fine needle aspirate biopsies)
• Exposure: BAP1 gene mutation status (germline, somatic, or none). No asbestos or fiber exposure was studied.
• Main results:
  • Overall, 59 of the 142 tumors (42%) metastasized, within a median of 19 months
  • Metastasis occurred in 32 of 43 tumors with somatic mutations (74%), compared with 4 of 11 with germline mutations (36%, P=0.03) and 23 of 88 mutation-negative tumors (26%, P less than 0.001)
  • The frequency of metastasis did not differ significantly between tumors with germline mutations and mutation-negative tumors (P=0.72)
  • In multivariate Cox regression compared with mutation-negative tumors, a somatic BAP1 mutation was significantly associated with metastasis (hazard ratio 2.20, 95% confidence interval 1.13 to 4.30, P=0.02)
  • In the same multivariate analysis compared with mutation-negative tumors, a germline BAP1 mutation was not significantly associated with metastasis (hazard ratio 0.87, 95% confidence interval 0.28 to 2.72, P=0.81)
  • Median time to metastasis was 16.0 months (range 2 to 107) for tumors with somatic mutations, compared with 26 months (range 0 to 84) for mutation-negative tumors (P=0.04)
  • People with somatic mutations were older at diagnosis (median 61.8 years) than those with mutation-negative tumors (median 52.2 years, P=0.002)
  • Chromosome 3 monosomy was present in 10 tumors with germline mutations (91%) and 40 tumors with somatic mutations (93%); both proportions were significantly higher than in mutation-negative tumors
  • Personal or family history information was available for 79 cases. All 8 germline carriers with this information had a history of BAP1-TPDS cancers, compared with 10 somatic cases (44%) and 11 mutation-negative cases (23%)
• The authors' conclusion: The authors concluded that the risk of metastasis differed significantly between tumors with somatic and those with germline BAP1 mutations. They recommended testing a matched blood sample when a tumor carries a BAP1 mutation, to tell germline from somatic mutations.
• Limitations the authors state:
  • Only a small number of tumors had germline mutations; the authors said the findings need confirming in a larger group
  • BAP1-TPDS history was self-reported and may be imprecise

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Metastasis, Germline Mutation, BAP1 Tumor Predisposition Syndrome, Mesothelioma, Carcinoma, Somatic Mutation, Multivariate Analysis.

Related studies

• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy — P. Star, A. Goodwin, et al. (2018)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation — C. Ribeiro, S. Campelos, et al. (2013)
• A population-based analysis of germline BAP1 mutations in melanoma — S.J. O'Shea, C.D. Robles-Espinoza, et al. (2017)

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