European Journal of Human Genetics - Abstract of article: A clinical and genetic analysis of multiple primary cancer referrals to genetics services

European Journal of Human Genetics - Abstract of article: A clinical and genetic analysis of multiple primary cancer referrals to genetics services

European Journal of Human Genetics advance online publication 24 September 2014; doi: 10.1038/ejhg.2014.157

A clinical and genetic analysis of multiple primary cancer referrals to genetics services

James Whitworth^1,2, Jon Hoffman², Cyril Chapman², Kai Ren Ong², Fiona Lalloo³, D Gareth Evans³ and Eamonn R Maher^1,4

1. ¹Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
2. ²West Midlands Regional Genetics Service, Birmingham Women’s Hospital NHS Trust, Birmingham, UK
3. ³Manchester centre for genomic medicine, Central Manchester University Hospitals NHS Trust, Manchester, UK
4. ⁴Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge, UK

Correspondence: Dr ER Maher, Department of Medical Genetics, Level 6, Addenbrooke’s Treatment Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. Tel: +44 (0)1223 746 715; Fax: +44 (0)1223 746 777; E-mail: erm1000@medschl.cam.ac.uk

Received 3 February 2014; Revised 23 June 2014; Accepted 9 July 2014
Advance online publication 24 September 2014

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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.