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An interstitial deletion within 9p21.3 and extending beyond CDKN2A predisposes to melanoma, neural system tumours and possible haematological malignancies
  1. Maria J Baker1,
  2. Alisa M Goldstein2,
  3. Patricia L Gordon3,
  4. Kimberly S Harbaugh4,
  5. Heath B Mackley5,
  6. Michael J Glantz4,
  7. Joseph J Drabick1
  1. 1Department of Medicine, Penn State Milton S. Hershey Medical Center, Penn State Hershey Cancer Institute, Hershey, Pennsylvania, USA
  2. 2Division of Cancer Epidemiology and Genetics, Genetic Epidemiology Branch, National Cancer Institute, Bethesda, Maryland, USA
  3. 3Department of Pediatrics, Penn State Milton S. Hershey Medical Center, Penn State Hershey Cancer Institute, Hershey, Pennsylvania, USA
  4. 4Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Penn State Hershey Cancer Institute, Hershey, Pennsylvania, USA
  5. 5Department of Radiation Oncology, Penn State Milton S. Hershey Medical Center, Penn State Hershey Cancer Institute, Hershey, Pennsylvania, USA
  1. Correspondence to Dr Maria J Baker, Department of Medicine, Penn State Milton S. Hershey Medical Center, Penn State Hershey Cancer Institute, 500 University Drive CH46, Hershey, PA 17033-0850, USA; mbaker{at}hmc.psu.edu

Abstract

Familial atypical multiple mole melanoma syndrome (FAMMM) is characterised by dysplastic naevi, malignant melanoma and pancreatic cancer. Given that large deletions involving CDKN2A (cyclin-dependent kinase inhibitor 2A) account for only 2% of cases, we describe a family that highlights the co-occurrence of both melanoma and neural system tumours to aid clinical recognition and propose a management strategy. A patient with multiple neurofibromas was referred with a provisional diagnosis of neurofibromatosis type 1 (NF1). Prior molecular testing, though, had failed to identify an NF1 mutation by sequencing and multiplex ligation-dependent probe amplification. His family history was significant for multiple in situ/malignant melanomas at young ages and several different cancers reminiscent of an underlying syndrome. A search of the Familial Cancer Database, FaCD Online, highlighted several families with cutaneous melanoma and nervous system tumours who were subsequently identified to have large deletions spanning CDKN2A. Although sequencing of CDKN2A and TP53 failed to identify a mutation, a heterozygous CDKN2A deletion was identified by targeted array comparative genomic hybridisation (CGH). Whole-genome oligonucleotide array CGH and SNP analysis identified an interstitial deletion of at least 1.5 Mb within 9p21.3 and spanning approximately 25 genes. Identification of the underlying molecular abnormality permits predictive testing for at-risk relatives. Given the young cancer diagnoses, a surveillance regimen was developed and a clinical team organised for ongoing management so that genetic testing could be offered to both adults and minor children. Surveillance recommendations addressed cancer risks associated with FAMMM, and other cancers exhibited by this family with a large contiguous gene deletion.

  • Cancer: CNS
  • Cancer: dermatological
  • Clinical genetics
  • Genetic screening/counselling
  • Molecular genetics

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