Clinical Implications of Real-time Integrative Sequencing in Management of Patients With Suspected Germline BAP1 Mutations

Our plain-English summary of Clinical Implications of Real-time Integrative Sequencing in Management of Patients With Suspected Germline BAP1 Mutations, by S. Sengupta, A.C. Weyand, S.A. Upadhyaya, et al (Journal of Pediatric Hematology/oncology, 2019).

The study

• Authors: S. Sengupta, A.C. Weyand, S.A. Upadhyaya, Y.M. Wu, D.R. Robinson, R.J. Mody
• Journal: Journal of Pediatric Hematology/oncology
• Published: 2019;41(4):e263-e265
• Type of article: Case report
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Germline mutation of BRCA-associated protein-1 has been implicated in the development of tumor predisposition syndrome and high risk for malignant mesothelioma, lung adenocarcinoma, uveal melanoma, and cutaneous melanoma. Here, we present the case of a patient with recurrent metastatic melanoma who was found to have germline BAP1 and somatic BRAF mutation by clinical genomic sequencing. Detection of a germline mutation prompted screening for other cancers and surveillance in family members. Prospective integrative sequencing for pediatric cancer patients may identify pathogenic germline mutations and may improve outcomes and treatment-related morbidity by early diagnosis of malignancy.

In plain English

This is a case report about one patient, a 16-year-old girl with melanoma of the skin behind the right ear. At further surgery, 2 of 3 sentinel lymph nodes contained melanoma. All 53 nodes later removed from the neck were negative. About 1 year after diagnosis the melanoma returned in a lymph node. That node was removed and three cycles of chemotherapy followed, and the patient remained in remission more than 2 years after treatment. In a research sequencing trial comparing tumor with normal tissue, the tumor showed a BRAF (V600E) mutation, and she was found to have a germline BAP1 mutation, one present in her normal cells, not only the tumor. This led to a recommended eye examination and genetic screening for the parents and two siblings. The patient's mother had earlier had ovarian cancer and negative BRCA1 and BRCA2 testing. She was diagnosed with peritoneal mesothelioma four months after the patient's melanoma diagnosis. The article does not mention asbestos. The authors concluded that sequencing children with cancer, regardless of family history, may identify harmful germline mutations and may improve outcomes through early diagnosis.

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: Case report (one patient)
• Who was studied: One 16-year-old girl with melanoma, enrolled in a prospective clinical sequencing trial (PEDS-MIONCOSEQ). The authors are at the University of Michigan.
• Exposure: No asbestos or other environmental exposure is described. The article concerns a germline BAP1 gene mutation (one present in normal cells, not only the tumor) found by paired tumor and normal genetic sequencing.
• Main results:
  • Patient: 2 of 3 sentinel lymph nodes were positive for melanoma.
  • Patient: in the later neck dissection, all 53 lymph nodes were negative for melanoma.
  • Patient: about 1 year after diagnosis, melanoma recurred in a lymph node.
  • Patient: after treatment, the patient remained in remission more than 2 years after completing treatment.
  • Patient: paired tumor and normal sequencing found a somatic (tumor-only) BRAF V600E mutation and a germline BAP1 p.D567X pathogenic variant. The article does not report parental test results showing whether the BAP1 variant was inherited.
  • Family: genetic screening was recommended for the patient's 2 siblings and parents.
  • Mother: had ovarian cancer diagnosed at age 44, and earlier BRCA1 and BRCA2 testing had found no mutation.
  • Mother: diagnosed with peritoneal mesothelioma four months after the patient's melanoma diagnosis. The article does not report the result of any BAP1 test in the mother.
• The authors' conclusion: The authors concluded that prospective integrative sequencing of pediatric cancer patients, regardless of family history, may identify pathogenic germline mutations and may improve outcomes and treatment-related morbidity through early diagnosis of cancer.

Topics

Medical terms in this study, explained in our Lexicon: BAP1 Tumor Predisposition Syndrome, Germline Mutation, Malignant Mesothelioma, Lung Adenocarcinoma, BAP1.

Related studies

• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Histomorphologic spectrum of BAP1 negative melanocytic neoplasms in a family with BAP1-associated cancer susceptibility syndrome — Z. Marušić, M. Buljan, et al. (2015)
• Histologically Diverse BAP1-Deficient Melanocytic Tumors in a Patient With BAP1 Tumor Predisposition Syndrome — A. Louw, J. Creaney, et al. (2020)
• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases — R. Pilarski, C.M. Cebulla, et al. (2014)
• Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy — P. Star, A. Goodwin, et al. (2018)

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