title: PTEN germline mutations in patients initially tested for other hereditary cancer syndromes: would use of risk assessment tools reduce genetic testing?
abstract: OBJECTIVE
  PTEN Hamartoma Tumor syndrome (PHTS) includes patients with Cowden syndrome or other syndromes with germline mutation of the PTEN tumor suppressor gene. The risk for breast, colorectal, and endometrial cancer and polyposis is increased, creating clinical overlap with hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS), and adenomatous polyposis syndromes (APS). We reviewed our series of patients with PHTS to determine how often testing criteria for these syndromes were met and how often other-gene testing was ordered before testing PTEN.
  
  
  METHODS
  Patients were prospectively recruited by relaxed International Cowden Consortium criteria or presence of known germline PTEN mutation. Mutations were identified by mutation scanning/multiplex ligation-dependent probe amplification analysis and confirmed by sequencing/quantitative polymerase chain reaction. Patients were excluded if they were adopted, were <18 years of age, or if they were diagnosed with Cowden syndrome before 1998. Standard risk-assessment models were applied to determine whether patients met HBOC testing criteria, LS-relevant Amsterdam II/Bethesda 2004 criteria, or had adenomatous polyps. Prior probability of PTEN mutation was estimated with the Cleveland Clinic PTEN risk calculator.
  
  
  RESULTS
  Of 137 PTEN mutation-positive adult probands, 59 (43.1%) met testing criteria for HBOC or LS. Of these, 45 (32.8%) were first offered HBOC, LS, or APS testing. Of those who underwent APS testing, none of the six patients met criteria. Initial risk assessment by a genetics specialist was significantly associated with immediate PTEN testing in patients also meeting HBOC testing criteria. Using this PTEN risk assessment tool could have spared gene testing for 22 unlikely syndromes, at a total cost of $66,080.
  
  
  CONCLUSIONS
  PHTS is an important differential diagnosis for patients referred for HBOC, LS, or APS. Risk assessment tools may help focus genetic analysis and aid in the interpretation of multiplex testing.
authors.affiliation: Genomic Medicine Institute.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Mester
authors.forename: Rebekah A
authors.initials: RA
authors.lastname: Moore
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D003362:Cost-Benefit Analysis; D003937:Diagnosis, Differential; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D018570:Risk Assessment
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Cowden syndrome; Genetic testing; Hereditary cancer syndromes; PTEN hamartoma tumor syndrome; Risk assessment
references.citation: Am J Hum Genet. 1995 Jan;56(1):265-71
references.pmid: 7825587
references.citation: Am J Hum Genet. 2011 Jan 7;88(1):42-56
references.pmid: 21194675
references.citation: Genet Med. 2006 Jun;8(6):361-70
references.pmid: 16778598
references.citation: Dis Colon Rectum. 1991 May;34(5):424-5
references.pmid: 2022152
references.citation: Hum Mol Genet. 1999 Aug;8(8):1461-72
references.pmid: 10400993
references.citation: BMJ. 2012 May 03;344:e3174
references.pmid: 22556053
references.citation: J Clin Oncol. 2001 Oct 15;19(20):4074-80
references.pmid: 11600610
references.citation: J Med Genet. 2004 May;41(5):323-6
references.pmid: 15121767
references.citation: J Clin Oncol. 2002 Mar 15;20(6):1480-90
references.pmid: 11896095
references.citation: Clin Cancer Res. 2012 Jan 15;18(2):400-7
references.pmid: 22252256
references.citation: Breast Cancer Res Treat. 2010 Nov;124(2):459-65
references.pmid: 20349131
references.citation: Nat Rev Cancer. 2007 Jan;7(1):35-45
references.pmid: 17167516
references.citation: Gastroenterology. 2010 Dec;139(6):1927-33
references.pmid: 20600018
references.citation: J Natl Cancer Inst. 2004 Feb 18;96(4):261-8
references.pmid: 14970275
references.citation: Cancer J. 2012 Jul-Aug;18(4):287-92
references.pmid: 22846728
references.citation: Am J Hum Genet. 1998 Jan;62(1):145-58
references.pmid: 9443863
references.citation: J Clin Gastroenterol. 2005 Apr;39(4):298-302
references.pmid: 15758623
references.citation: Int J Cancer. 1999 Apr 12;81(2):214-8
references.pmid: 10188721
references.citation: JAMA. 2006 Sep 27;296(12):1479-87
references.pmid: 17003396
references.citation: Gastroenterology. 2005 May;128(6):1696-716
references.pmid: 15887160
references.citation: J Natl Compr Canc Netw. 2010 Jan;8(1):8-61
references.pmid: 20064289
references.citation: Thyroid. 2011 May;21(5):505-10
references.pmid: 21417916
references.citation: Gastroenterology. 2011 Jan;140(1):73-81
references.pmid: 20727894