Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma

Kader, Tanjina; Hill, Prue; Zethoven, Magnus; Goode, David; Elder, Kenneth; Thio, Niko; Doyle, Maria A.; Semple, Timothy; Sufyan, Wajiha; Byrne, David; Pang, Jia-Min; Murugasu, Anand; Miligy, Islam M.; Green, Andrew; Rakha, Emad A.; Fox, Stephen B.; Mann, G Bruce; Gorringe, Kylie L.

doi:10.1002/path.5262

Cited by 24 publications

(34 citation statements)

References 56 publications

(96 reference statements)

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“…CN profiles (pure, clonal and non-clonal IDPs) were compared to cases of DCIS (previously published) 26,27,39 , and IDC cases from METABRIC 28 . CNA segments were exported from Nexus and the percentage of genome altered by copy number in base pairs resolution or the weighted fraction of the genome altered (FGA) was calculated.…”

Section: Resultsmentioning

confidence: 99%

“…Genomic data for LG DCIS cases (n = 21) and HG DCIS cases (n = 38) was derived from our previously published work 26,27,39 where cases were obtained from the RMH, the Peter MacCallum Cancer Centre and the Nottingham University Hospitals NHS Trust, City Hospital, Nottingham, UK. Histological review of all these cases was performed by the same pathologist (P. Hill).…”

Section: Tumour Samplesmentioning

confidence: 99%

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The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma

et al. 2020

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Intraductal papillomas (IDP) are challenging breast findings because of their variable risk of progression to malignancy. The molecular events driving IDP development and genomic features of malignant progression are poorly understood. In this study, genome-wide CNA and/or targeted mutation analysis was performed on 44 cases of IDP, of which 20 cases had coexisting ductal carcinoma in situ (DCIS), papillary DCIS or invasive ductal carcinoma (IDC). CNA were rare in pure IDP, but 69% carried an activating PIK3CA mutation. Among the synchronous IDP cases, 55% (11/20) were clonally related to the synchronous DCIS and/or IDC, only one of which had papillary histology. In contrast to pure IDP, PIK3CA mutations were absent from clonal cases. CNAs in any of chromosomes 1, 16 or 11 were significantly enriched in clonal IDP lesions compared to pure and non-clonal IDP. The observation that 55% of IDP are clonal to DCIS/IDC indicates that IDP can be a direct precursor for breast carcinoma, not limited to the papillary type. The absence of PIK3CA mutations and presence of CNAs in IDP could be used clinically to identify patients at high risk of progression to carcinoma.

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Section: Resultsmentioning

confidence: 99%

Section: Tumour Samplesmentioning

confidence: 99%

The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma

et al. 2020

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“…The FGA was calculated as described previously. 48,49 In brief, the weighted FGA was calculated by the summation of the CNA in base pairs for each chromosome and then dividing by the length of that chromosome. The final FGA for a sample was calculated by taking the average of the percentage of CNAs across all chromosomes.…”

Section: Data Analyses For Lc-wgsmentioning

confidence: 99%

Loss of SMAD4 Is Sufficient to Promote Tumorigenesis in a Model of Dysplastic Barrett’s Esophagus

Gotovac

Kader

Milne

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Loss of the tumor-suppressor gene SMAD4 promotes progression of high-grade Barrett's esophagus toward esophageal adenocarcinoma. This study provides an Q7 in vivo model of dysplastic Barrett's esophagus progression toward invasive esophageal adenocarcinoma upon SMAD4 inactivation.BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) develops from its precursor Barrett's esophagus through intermediate stages of low-and high-grade dysplasia. However, knowledge of genetic drivers and molecular mechanisms implicated in disease progression is limited. Herein, we investigated the effect of SMAD4 loss on transforming growth factor b (TGF-b) signaling functionality and in vivo tumorigenicity in high-grade dysplastic Barrett's cells. METHODS:An in vivo xenograft model was used to test tumorigenicity of SMAD4 knockdown or knockout in CP-B highgrade dysplastic Barrett's cells. RT 2 Q8polymerase chain reaction arrays were used to analyze TGF-b signaling functionality, and low-coverage whole-genome sequencing was performed to detect copy number alterations upon SMAD4 loss. RESULTS:We found that SMAD4 knockout significantly alters the TGF-b pathway target gene expression profile. SMAD4 knockout positively regulates potential oncogenes such as CRYAB, ACTA2, and CDC6, whereas the CDKN2A/B tumorsuppressor locus was regulated negatively. We verified that SMAD4 in combination with CDC6-CDKN2A/B or CRYAB genetic alterations in patient tumors have significant predictive value for poor prognosis. Importantly, we investigated the effect of SMAD4 inactivation in Barrett's tumorigenesis. We found that genetic knockdown or knockout of SMAD4 was sufficient to promote tumorigenesis in dysplastic Barrett's esophagus cells in vivo. Progression to invasive EAC was accompanied by distinctive and consistent copy number alterations in SMAD4 knockdown or knockout xenografts.CONCLUSIONS: Altogether, up-regulation of oncogenes, downregulation of tumor-suppressor genes, and chromosomal instability within the tumors after SMAD4 loss implicates SMAD4 as a protector of genome integrity in EAC development and progression. Foremost, SMAD4 loss promotes tumorigenesis from dysplastic Barrett's toward EAC.

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“…Each of these lesions harbour genetic alterations and are considered clonal neoplastic proliferations; CCL harbour both DNA copy number alterations and gene mutations, including an usually high rate of PIK3CA mutations (54%) [44][45][46]. Likewise, ADH may be considered a genetically advanced precursor lesion [47].…”

Section: The Early Clonal Nature Of Breast Cancer-going Back To the Bmentioning

confidence: 99%

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

Kutasovic

Reed

Sokolova

et al. 2020

Cancers

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Breast cancer is a remarkably complex and diverse disease. Subtyping based on morphology, genomics, biomarkers and/or clinical parameters seeks to stratify optimal approaches for management, but it is clear that every breast cancer is fundamentally unique. Intra-tumour heterogeneity adds further complexity and impacts a patient’s response to neoadjuvant or adjuvant therapy. Here, we review some established and more recent evidence related to the complex nature of breast cancer evolution. We describe morphologic and genomic diversity as it arises spontaneously during the early stages of tumour evolution, and also in the context of treatment where the changing subclonal architecture of a tumour is driven by the inherent adaptability of tumour cells to evolve and resist the selective pressures of therapy.

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Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma

Cited by 24 publications

References 56 publications

The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma

The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma

Loss of SMAD4 Is Sufficient to Promote Tumorigenesis in a Model of Dysplastic Barrett’s Esophagus

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

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