Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

Pang, Jia-Min; Savas, Peter; Fellowes, Andrew; Arnau, Gisela Mir; Kader, Tanjina; Vedururu, Ravikiran; Hewitt, Chelsee; Takano, Elena A.; Byrne, David; Choong, David Y.H.; Millar, Ewan K.A.; Lee, C. Soon; O’Toole, Sandra A.; Lakhani, Sunil R.; Cummings, Margaret C.; Mann, G. Bruce; Campbell, Ian; Dobrovic, Alexander; Loi, Sherene; Gorringe, Kylie L.; Fox, Stephen B.

doi:10.1038/modpathol.2017.21

Cited by 52 publications

(52 citation statements)

References 45 publications

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“…There are currently no known functional determinants of DCIS progression to an invasive lesion; in fact, DCIS and IDC lesions are very similar transcriptionally and epigenetically . This study profiles global lncRNA expression in a unique patient‐based model of breast cancer progression wherein early DCIS lesions are directly contiguous with an IDC lesion.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA BHLHE40‐AS1 promotes early breast cancer progression through modulating IL‐6/STAT3 signaling

DeVaux

Ropri

Grimm

et al. 2020

J of Cellular Biochemistry

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Ductal carcinoma in situ (DCIS) is a nonobligate precursor to invasive breast cancer. Only a small percentage of DCIS cases are predicted to progress; however, there is no method to determine which DCIS lesions will remain innocuous from those that will become invasive disease. Therefore, DCIS is treated aggressively creating a current state of overdiagnosis and overtreatment. There is a critical need to identify functional determinants of progression of DCIS to invasive ductal carcinoma (IDC). Interrogating biopsies from five patients with contiguous DCIS and IDC lesions, we have shown that expression of the long noncoding RNA BHLHE40-AS1 increases with disease progression.BHLHE40-AS1 expression supports DCIS cell proliferation, motility, and invasive potential. Mechanistically, BHLHE40-AS1 modulates interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) activity and a proinflammatory cytokine signature, in part through interaction with interleukin enhancer-binding factor 3. These data suggest that BHLHE40-AS1 supports early breast cancer progression by engaging STAT3 signaling, creating an immune-permissive microenvironment.

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Section: Discussionmentioning

confidence: 99%

Long noncoding RNA BHLHE40‐AS1 promotes early breast cancer progression through modulating IL‐6/STAT3 signaling

DeVaux

Ropri

Grimm

et al. 2020

J of Cellular Biochemistry

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“…During progression from in‐situ to invasive disease interactions between intraductal malignant cells and peripheral MECs, which are thought to act as a ‘gatekeeper’ exerting tumour‐suppressive effects, take place leading to loss of MECs unleashing the progression to invasive disease . Molecular studies of DCIS and invasive breast cancer (IBC) suggest that this progression is driven not only by genomic aberrations in the malignant cells but also a result of complex processes involving interactions and cross‐talks of tumour cells with the surrounding stromal environment including BM, stromal cells, vascular spaces and immune cells (Figure ). In fact, the process of progression to invasive disease is multifactorial and complex.…”

Section: Features Of Dcis Progression To Invasive Carcinomamentioning

confidence: 99%

Invasion in breast lesions: the role of the epithelial–stroma barrier

et al. 2018

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Despite the significant biological, behavioural and management differences between ductal carcinoma in situ (DCIS) and invasive carcinoma of the breast, they share many morphological and molecular similarities. Differentiation of these two different lesions in breast pathological diagnosis is based typically on the presence of an intact barrier between the malignant epithelial cells and stroma; namely, the myoepithelial cell (MEC) layer and surrounding basement membrane (BM). Despite being robust diagnostic criteria, the identification of MECs and BM to differentiate in-situ from invasive carcinoma is not always straightforward. The MEC layer around DCIS may be interrupted and/or show an altered immunoprofile. MECs may be absent in some benign locally infiltrative lesions such as microglandular adenosis and infiltrating epitheliosis, and occasionally in non-infiltrative conditions such as apocrine lesions, and in these contexts this does not denote malignancy or invasive disease with metastatic potential. MECs may also be absent around some malignant lesions such as some forms of papillary carcinoma, yet these behave in an indolent fashion akin to some DCIS. In Paget's disease, malignant mammary epithelial cells extend anteriorly from the ducts to infiltrate the epidermis of the nipple but do not typically infiltrate through the BM into the dermis. Conversely, BM-like material can be seen around invasive carcinoma cells and around metastatic tumour cell deposits. Here, we review the role of MECs and BM in breast pathology and highlight potential clinical implications. We advise caution in interpretation of MEC features in breast pathology and mindfulness of the substantive evidence base in the literature associated with behaviour and clinical outcome of lesions classified as benign on conventional morphological examination before changing classification to an invasive lesion on the sole basis of MEC characteristics.

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“…Mutations in patient 1 were evaluated at 155 mutated positions, of which 141 were confidently identified in all 3 regions, and 14 were either missing or absent from one or more region (Additional file 1: Table S8). While a portion of these may be shared mutations may be germline variants, we identified a GATA3 splice-site deletion in regions 1A and 1B previously observed in DCIS studies, disrupting a canonical splice site and for which the resulting transcript has been shown to lead to an abnormally high number of neoantigens [51,52]. Similarly, mutations in patient 3 were evaluated at 183 positions, 160 of which were shared by all 4 regions, including normal, and likely residual germline variants.…”

Section: Mutational Profiling Of Breast Pmlmentioning

confidence: 66%

Mutational profiling of micro-dissected pre-malignant lesions from archived specimens

Nachmanson

Steward²,

Yao

et al. 2020

Preprint

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Background: Systematic cancer screening has led to the increased detection of pre-malignant lesions (PMLs). The absence of reliable prognostic markers can lead to inadequate treatment resulting in unnecessary stress or avoidable progression. Importantly, most mutational profiling studies have relied on PML synchronous to invasive cancer, or performed in patients without outcome information, hence limiting their utility for biomarker discovery. The limitations in comprehensive mutational profiling of PMLs are in large part due to the significant technical and methodological challenges: most PML specimens are small, fixed in formalin and paraffin embedded (FFPE) and lack matching normal DNA. Methods:Using test DNA from a highly degraded FFPE specimen, multiple targeted sequencing approaches were evaluated, varying DNA input amount (3-200 ng), library preparation strategy (BE: Blunt-End, SS: Single-Strand, AT: A-Tailing) and target size (whole exome vs cancer gene panel). Variants in high-input DNA from FFPE and mirrored frozen specimens were used for PML-specific variant calling training and testing, respectively. The resulting approach was applied to profile and compare multiple regions micro-dissected (mean area 5 mm 2 ) from 3 breast ductal carcinoma in situ (DCIS). Results:Using low-input FFPE DNA, BE and SS libraries resulted in 4.9 and 3.7 increase over AT libraries in the fraction of whole exome covered at 20x (BE:87%, SS:63%, AT:17%).Compared to high-confidence somatic mutations from frozen specimens, PML-specific variant filtering increased recall (BE:79%, SS:74%, AT:62%) and precision (BE:87%, SS:88%, AT:80%) to levels expected from sampling variation. Copy number alterations were consistent across all tested approaches and only impacted by the design of the capture probe-set. Applied to DNA extracted from 9 micro-dissected regions (8 PML, 1 normal epithelium), the approach achieved comparable performance, identified candidate driver events (gains of ERBB2 or FGFR1, loss of TP53) and illustrated the adequacy of the data to identify candidate driver mutations and measure intra-lesion genetic heterogeneity. Conclusion:The approach presented enables mutational profiling from archived microdissected PML regions, supporting the identification of pre-malignant drivers, and the characterization of PML molecular heterogeneity and evolution, all critical milestones the development of biology-informed prognostic markers and precision chemo-prevention strategies.

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Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

Cited by 52 publications

References 45 publications

Long noncoding RNA BHLHE40‐AS1 promotes early breast cancer progression through modulating IL‐6/STAT3 signaling

Long noncoding RNA BHLHE40‐AS1 promotes early breast cancer progression through modulating IL‐6/STAT3 signaling

Invasion in breast lesions: the role of the epithelial–stroma barrier

Mutational profiling of micro-dissected pre-malignant lesions from archived specimens

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