Abstract
BackgroundPatients with breast cancer have an increased risk of developing subsequent breast cancers. It is important to distinguish whether these tumours are de novo or recurrences of the primary tumour in order to guide the appropriate therapy. Our aim was to investigate the use of DNA methylation profiling and array comparative genomic hybridization (aCGH) to determine whether the second tumour is clonally related to the first tumour.MethodsMethylation-sensitive high-resolution melting was used to screen promoter methylation in a panel of 13 genes reported as methylated in breast cancer (RASSF1A, TWIST1, APC, WIF1, MGMT, MAL, CDH13, RARβ, BRCA1, CDH1, CDKN2A, TP73, and GSTP1) in 29 tumour pairs (16 ipsilateral and 13 contralateral). Using the methylation profile of these genes, we employed a Bayesian and an empirical statistical approach to estimate clonal relationship. Copy number alterations were analysed using aCGH on the same set of tumour pairs.ResultsThere is a higher probability of the second tumour being recurrent in ipsilateral tumours compared with contralateral tumours (38 % versus 8 %; p <0.05) based on the methylation profile. Using previously reported recurrence rates as Bayesian prior probabilities, we classified 69 % of ipsilateral and 15 % of contralateral tumours as recurrent. The inferred clonal relationship results of the tumour pairs were generally concordant between methylation profiling and aCGH.ConclusionOur results show that DNA methylation profiling as well as aCGH have potential as diagnostic tools in improving the clinical decisions to differentiate recurrences from a second de novo tumour.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1676-0) contains supplementary material, which is available to authorized users.
Highlights
Patients with breast cancer have an increased risk of developing subsequent breast cancers
The median time interval for the second tumours to develop was similar between ipsilateral patients (4 years; range, 0–14 years) and contralateral patients (5 years; range, 1–9 years) (P = 0.60) after the initial breast tumour diagnosed
Ipsilateral tumours have a higher probability of being recurrent compared with contralateral tumours, which had a higher chance of being de novo tumours
Summary
Patients with breast cancer have an increased risk of developing subsequent breast cancers. When the second tumour is detected, it is important to determine whether the tumour is a de novo (new primary) tumour or a recurrence of the first tumour [3, 4] as the tumour staging and management for the patient will be different [5]. Histopathological features and clinical characteristics are most commonly used to determine the clonal origin of the tumours. These include histological type, degree of differentiation, presence of an in situ component, evidence for metastatic spread and the interval between tumour onsets [3]. Tumours of distinct clonal origins may still have very similar histological features
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