Clonal relatedness in tumour pairs of breast cancer patients

Abstract

BackgroundMolecular classification of tumour clonality is currently not evaluated in multiple invasive breast carcinomas, despite evidence suggesting common clonal origins. There is no consensus about which type of data (e.g. copy number, mutation, histology) and especially which statistical method is most suitable to distinguish clonal recurrences from independent primary tumours.MethodsThirty-seven invasive breast tumour pairs were stratified according to laterality and time interval between the diagnoses of the two tumours. In a multi-omics approach, tumour clonality was analysed by integrating clinical characteristics (n = 37), DNA copy number (n = 37), DNA methylation (n = 8), gene expression microarray (n = 7), RNA sequencing (n = 3), and SNP genotyping data (n = 3). Different statistical methods, e.g. the diagnostic similarity index (SI), were used to classify the tumours as clonally related recurrences or independent primary tumours.ResultsThe SI and hierarchical clustering showed similar tendencies and the highest concordance with the other methods. Concordant evidence for tumour clonality was found in 46% (17/37) of patients. Notably, no association was found between the current clinical guidelines and molecular tumour features.ConclusionsA more accurate classification of clonal relatedness between multiple breast tumours may help to mitigate treatment failure and relapse by integrating tumour-associated molecular features, clinical parameters, and statistical methods. Guidelines need to be defined with exact thresholds to standardise clonality testing in a routine diagnostic setting.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1022-y) contains supplementary material, which is available to authorized users.

Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival

“…According to the last recommendations of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) for the validation of cases scored as HER2-2+ by IHC in HBC 31 , and in agreement with the high concordance reported between HER2-amplifications detected using FISH/ISH and CNGs detected by different high-resolution sequencing methods to validate HER2 status in human breast cancer (HBC) [136][137][138] , we correlated fHER2 IHC-based expression with CNGs affecting HER2 gene coding region (FCA E1 40,780,250-40,804,241 Mb). As reported elsewhere [136][137][138][139] , log2-ratio threshold for HER2 amplification was set at a higher amplitude (>0.5) for fHER2+ tumours detection to better show gene-level CNV events 140 . Accordingly, cases scored as 2+ with CNGs (log2-copy-number-ratio >0.5 141 ) in FCA E1 harbouring HER2 were considered as fHER2-positive.…”

Genomic profiling defines variable clonal relatedness between invasive breast cancer and primary ductal carcinoma in situ

“…There is no consensus about which type of data and statistical method is most suitable to distinguish clonal recurrences from independent primary tumours. Bierman and colleagues have shown that the type of molecular data analyzed had a stronger impact on clonality determination than the analytical methods used 20 . Our data show, as does the data of Bierman et al , that assessment of clonal relatedness by different types of molecular data is not always concordant.…”

Mitochondrial DNA analysis efficiently contributes to the identification of metastatic contralateral breast cancers

“…In recent years, WES and WGS have been applied to demonstrate the metastatic nature of recurrent tumors in a wide range of solid cancers, including breast cancer, through the detection of nuclear tumor-specific mutations (Ding et al 2012 , 2013 ; Haffner et al 2013 ; Van Allen et al 2014 ). These expensive techniques, particularly cumbersome in their data analysis, yielded indications for clonality in 10–22% of cases, according to whether cohorts of only metachronous, or both synchronous and metachronous tumors were investigated (Klevebring et al 2015 ; Alkner et al 2015 ; Biermann et al 2018 ). Albeit ours was a pilot study, and the cohort relatively limited in size, mtDNA displayed a higher informative potential, reaching 26% within the metachronous-only cohort.…”

“…Different techniques have been used to demonstrate this assertion, starting with genetic approaches such as X-chromosome inactivation (Noguchi et al 1994 ; Shibata et al 1996 ; Banelli et al 2010 ), TP53 mutations (Janschek et al 2001 ), allele imbalance (AI) (Imyanitov et al 2002 ; Schlechter et al 2004 ), microsatellite size alterations (Saad et al 2008 ), loss of heterozygosity (LOH) (Schlechter et al 2004 ; Saad et al 2008 ), comparative genomic hybridization (CGH) (Teixeira et al 2004 ; Brommesson et al 2008 ), and DNA methylation profile (Huang et al 2015 ). Recently, a clonal relationship between paired CBC and primary breast cancer was determined in a subset of cases using massively parallel sequencing assay (Begg et al 2018 ), whole exome and genome sequencing (WES and WGS) (Bao et al 2015 ; Klevebring et al 2015 ; Alkner et al 2015 ) and multi-omics approaches (Biermann et al 2018 ). Despite the existence of such an abundant literature, today’s practice is to consider bilateral tumors as two independent entities.…”