title: A clinical and genetic analysis of multiple primary cancer referrals to genetics services.
abstract: Multiple primary malignant tumours (MPMT) are frequently taken as an indicator of potential inherited cancer susceptibility and occur at appreciable frequency both among unselected cancer patients and, particularly, among referrals to cancer genetics services. However, there is a paucity of information on the clinical genetic evaluation of cohorts of MPMT patients representing a variety of tumour types. We ascertained a referral-based series of MPMT cases and describe the patterns of tumours observed. Service-based molecular genetic testing had demonstrated a pathogenic germline variant in an inherited cancer gene in fewer than one in four unselected referrals. To assess for evidence of thus far unidentified variants in those who tested negative, comparisons were made with those who tested positive. This revealed considerable overlap between the two groups with respect to clinical characteristics indicative of an inherited cancer syndrome. We therefore proceeded to test a subset of unexplained MPMT cases (n=62) for pathogenic germline variants in TP53 and PTEN but none were detected. Individuals with MPMT may receive negative genetic test results for a number of reasons, which are discussed. Many of these may be addressed by the increasing application of next generation sequencing techniques such as inherited cancer gene panels.
authors.affiliation: 1] Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK [2] West Midlands Regional Genetics Service, Birmingham Women's Hospital NHS Trust, Birmingham, UK.
authors.forename: James
authors.initials: J
authors.lastname: Whitworth
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's Hospital NHS Trust, Birmingham, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Hoffman
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's Hospital NHS Trust, Birmingham, UK.
authors.forename: Cyril
authors.initials: C
authors.lastname: Chapman
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's Hospital NHS Trust, Birmingham, UK.
authors.forename: Kai Ren
authors.initials: KR
authors.lastname: Ong
authors.affiliation: Manchester centre for genomic medicine, Central Manchester University Hospitals NHS Trust, Manchester, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Lalloo
authors.affiliation: Manchester centre for genomic medicine, Central Manchester University Hospitals NHS Trust, Manchester, UK.
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.affiliation: 1] Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK [2] Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D053843:DNA Mismatch Repair / Q000235:genetics; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D009378:Neoplasms, Multiple Primary / Q000175:diagnosis* / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D012017:Referral and Consultation; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human