Identification of the genetic basis of multicentric tumourigenesis

Multiple primary malignant tumours (MPMT) are an indicator of potential inherited cancer susceptibility and occur at appreciable frequency among unselected cancer patients and, particularly, among referrals to cancer genetics services. However, there is little information on the clinical genetic evaluation of cohorts of MPMT patients representing a variety of tumour types. A referral based case series was ascertained and is described. Service-based molecular genetic testing had demonstrated a pathogenic germline variant in a cancer predisposition gene in less than a quarter of referrals. To assess for evidence of unidentified variants in those who tested negative, comparisons were made with those who tested positive, revealing considerable overlap between the two groups with respect to clinical characteristics indicative of an inherited cancer syndrome. A subset of unexplained MPMT cases was subsequently analysed for mutations in \(TP53\), \(PTEN\) and \(CDKN2B\) but none were detected. MPMT individuals may receive negative genetic test results for a number of reasons, which are discussed. They include referral bias and MPMT cases from a population based registry were also analysed and compared with the referral based series. The increasing application of next generation sequencing techniques in clinical services is likely to address many of these issues.