Epigenomic Alterations in Breast Carcinoma from Primary Tumor to Locoregional Recurrences

Moarii, Matahi; Pinheiro, Alice; Sigal‐Zafrani, Brigitte; Caly, Martial; Servant, Nicolas; Stoven, Véronique; Vert, Jean-Philippe; Reyal, Fabien

doi:10.1371/journal.pone.0103986

Cited by 7 publications

(7 citation statements)

References 40 publications

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“…The level of methylation is targetable by drugs, 34 and discrepancies in methylation between primary and metastatic tumors have been reported. 35 Consistent with this assumption, we found no discrepancies in MSIhigh tumors caused by germline mutations of MMR genes, whereas one patient with a MLH1 promoter 36 and worse prognosis. 36,37 Specifically, 2 patients in this study with MSI-high primary tumors had metastasis to 2 sites, and only the peritoneal metastasis showed MSS, whereas other metastases remained MSI-high.…”

Section: Discussionsupporting

confidence: 84%

Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer

Wang¹,

Wang

et al. 2019

Journal of the National Comprehensive Cancer Network

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Background: Differences between the features of primary cancer and matched metastatic cancer have recently drawn attention in research. This study investigated the concordance in microsatellite instability (MSI) and mismatch repair (MMR) status between primary and corresponding metastatic colorectal cancer (CRC). Methods: Consecutive patients with metastatic CRC who had both primary and metastatic tumors diagnosed at our institution in January 2008 through December 2016 were identified. Immunohistochemistry was used to test the MMR status of both primary and matched metastatic tumors, and PCR analysis was performed to test MSI in patients with deficient MMR (dMMR) status. Results: A total of 369 patients were included. Of the 46 patients with MSI-high primary tumors, 37 (80.4%) also had MSI-high metastatic tumors, whereas 9 (19.6%) had microsatellite stable (MSS) metastatic tumors. A high concordance was found in patients with liver, lung, or distant lymph node metastases. Interestingly, the discrepancy was more likely to be limited to peritoneal (5/20) or ovarian (4/4) metastasis (chi-square test, P<.001). These organ-specific features were also found in the pooled analysis. Along with the change of MSI-high in primary cancer to MSS in metastatic cancer, lymphocyte infiltration decreased significantly (P=.008). However, the change did not influence survival; the median overall survival of MSI-high and MSS metastatic tumors was 21.3 and 21.6 months, respectively (P=.774). The discrepancy rate was 1.6% for patients with proficient MMR primary tumors. Conclusions: For patients with dMMR primary tumors, the concordance of MSI and MMR status in primary CRC and corresponding metastatic cancer is potentially organ-specific. High concordance is found in liver, lung, and distant lymph node metastases, whereas discrepancy is more likely to occur in peritoneal or ovarian metastasis. Rebiopsy to evaluate MSI-high/dMMR status might be needed during the course of anti–PD-1 therapy in cases of peritoneal or ovarian metastasis.

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Section: Discussionsupporting

confidence: 84%

Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer

Wang¹,

Wang

et al. 2019

Journal of the National Comprehensive Cancer Network

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“…CNAs are acquired at early stages of tumourigenesis [ 45 , 46 ] making them the most stable type of biological data in this study. An overlap of tendencies in clonality between the aCGH and DNA methylation data was seen for only 50% of the cohort (BM7, BS7, BS8, and IS4), giving a less optimistic view on using DNA methylation as a clonality tool compared to results from other reported studies [ 47 , 48 ]. In the DNA methylation data, synchronicity accounted for more variation than metachronicity, providing further evidence that synchronous tumours are more different from each other with regard to DNA methylation patterns.…”

Section: Discussionmentioning

confidence: 68%

Clonal relatedness in tumour pairs of breast cancer patients

et al. 2018

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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.

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“…Gene expression regulation by noncoding RNAs and epigenetic mechanisms are likely to play key roles in the metastatic process as the identified metastasis suppressor genes are known to be transcriptionally downregulated, rather than being hit by inactivating mutations . Very few studies have explored differences in the expression of noncoding RNAs and epigenetic mechanisms including methylation patterns or histone acetylation comparing primary tumors and metastases. Differences in the expression levels of miRNAs between matched primary tumors and metastases have been found and also long noncoding RNAs like HOTAIR have been shown to be differentially expressed .…”

Section: Noncoding Rna and Epigeneticsmentioning

confidence: 99%

Molecular Concordance Between Primary Breast Cancer and Matched Metastases

et al. 2016

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n Abstract: Clinical management of breast cancer is increasingly personalized and based on molecular profiling. Often, primary tumors are used as proxies for systemic disease at the time of recurrence. However, recent studies have revealed substantial discordances between primary tumors and metastases, both with respect to traditional clinical treatment targets and on the genomic and transcriptomic level. With the increasing use of molecularly targeted therapy, discordance of actionable molecular targets between primary tumors and recurrences can result in nonoptimal treatment or unnecessary side effects. The purpose of this review is to illuminate the extent of cancer genome evolution through disease progression and the degree of molecular concordance between primary breast cancers and matched metastases. We present an overview of the most prominent studies investigating the expression of endocrine receptors, transcriptomics, and genome aberrations in primary tumors and metastases. In conclusion, biopsy of metastatic lesions at recurrence of breast cancer is encouraged to provide optimal treatment of the disease. Furthermore, molecular profiling of metastatic tissue provides invaluable mechanistic insight into the biology underlying metastatic progression and has the potential to identify novel, potentially druggable, drivers of progression. n

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Epigenomic Alterations in Breast Carcinoma from Primary Tumor to Locoregional Recurrences

Cited by 7 publications

References 40 publications

Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer

Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer

Clonal relatedness in tumour pairs of breast cancer patients

Molecular Concordance Between Primary Breast Cancer and Matched Metastases

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