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

Kader, Tanjina; Elder, Kenneth; Zethoven, Magnus; Semple, Timothy; Hill, Prue; Goode, David; Thio, Niko; Cheasley, Dane; Rowley, Simone M.; Byrne, David; Pang, Jia-Min; Miligy, Islam M.; Green, Andrew; Rakha, Emad A.; Fox, Stephen B.; Mann, G Bruce; Gorringe, Kylie L.

doi:10.1038/s41523-020-0150-6

Cited by 20 publications

(29 citation statements)

References 56 publications

(97 reference statements)

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“…SF3B1 c.2098A>G) or ADH ( GATA3 c.925-3_925-2del). This is consistent with previous reports and reports of field effect mutations in normal ducts or benign lesions [32,33], though the contribution of these mutations to the lesion progression remains to be determined.…”

Section: Resultssupporting

confidence: 93%

The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ

Nachmanson

Mori

et al. 2021

Preprint

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The increased detection and treatment of early stage breast cancer as well as ductal carcinoma in situ (DCIS) has not led to significant survival benefits. Therefore, the current standard treatment of DCIS is questionable. An informed evidence-based treatment strategy, and likely de-escalation from the current standards requires new prognostic models built from more comprehensive characterization with objective criteria. Parallel profiling of the molecular landscape and micro-environment in pure DCIS remains challenging due to histological heterogeneity and the inevitable reliance on small archived specimens. Leveraging recent methodological advances, we characterized the mutational, transcriptional, histological and microenvironmental landscape across multiple micro-dissected regions from 39 cases to generate a multi-modal breast precancer atlas. The histological architecture was associated with grade, adiposity, and intrinsic expression subtypes. Similar to previous findings, high-grade lesions had higher mutational burden, including TP53 mutations, while low-grade lesions had more frequent 16q losses and GATA3 mutations. Multi-region analysis revealed most somatic alterations, including whole genome duplication events, were clonal, but genetic divergence increased with distance between regions. In 7/12 evaluable cases, somatic mutations in putative driver genes affected a subset of regions only. This genetic heterogeneity often accompanied phenotypic heterogeneity and regions with low risk features (Normal-like, Luminal A) occurred earlier than those with high-risk features (Her2-like, Basal or necrosis) according to the phylogenetic analysis. The immune-environment was evaluated using multiplex immuno-histochemistry to measure relative stromal and epithelial densities of B lymphocyte (B-cell), T lymphocyte (T-cell) and regulatory T cells (T-reg) and identify 3 immune-states: Active, Suppressed and Excluded (lower epithelial density). All states included both DCIS and adjacent benign regions, and none associated with intrinsic subtypes. The Excluded state was enriched in high-grade DCIS and, compared to benign areas, more likely acquired in DCIS, showing transcriptional evidence of stronger immune-suppression and possible evasion. The breast pre-cancer atlas therefore reveals correlated levels of phenotypic and genotypic heterogeneity, including at sub-histological resolution. These uniquely integrated observations will help scope future studies, prioritize candidate markers for progression risk modelling and identify functional similarities in precursor lesions from other types of adenocarcinomas.

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Section: Resultssupporting

confidence: 93%

The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ

Nachmanson

Mori

et al. 2021

Preprint

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“…Kader et al recently published data suggesting that IDP with no copies number alterations (CNA), independently of the histological subtype, clinical data or age of the patient, lack malignant progression potential. This evidence arises the possibility to avoid surgical excision in these patients [78]. It has also been demonstrated IDP may progress directly into DCIS and IDC of any grade, showing that these different entities can share molecular genetic features and have a common etiology [79].…”

Section: Future Perspectivementioning

confidence: 94%

“…This information suggests that the absence of CNA (16q loss, 1q gain, 11q loss) and the presence of PIK3CA mutation in IDPs may be a biomarker of low risk for malignant transformation, regardless of pathologic features (benign or atypical IDP) and clinical findings. Further studies are needed to confirm these data [78]. With molecular biomarkers advances, a genome-wide CNA and/or targeted mutation analysis should be considered as the presence/absence of CNA (16q loss, 1q gain, 11q loss) and PIK3CA mutation may serve as potential biomarkers for predicting malignant progression/transformation.…”

Section: Future Perspectivementioning

confidence: 99%

Papillary Lesions of the Breast: A Review

González

Ibargüengoitia

Corona

et al. 2020

Breast Cancer Manag.

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Papillary breast lesions are rare breast tumors that comprise a broad spectrum of diseases. Pathologically they present as mass-like projections attached to the wall of the ducts, supported by fibrovascular stalks lined by epithelial cells. On mammogram they appear as masses that can be associated with microcalcifications. Ultrasound is the most used imaging modality. On ultrasound papillary lesions appear as homogeneous solid lesions or complex intracystic lesions. A nonparallel orientation, an echogenic halo or posterior acoustic enhancement associated with microcalcifications are highly suggestive of malignancy. MRI has proven to be useful to establish the extent of the lesion. Core needle biopsy is the gold standard for diagnosis. Surgical excision is usually recommended, although treatment for papillomas without atypia is still controversial.

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“…Earlier molecular studies suggested that alterations of c-Met, RET/PTC, α3β1 integrin, Sonic hedgehog (Shh), and Bone Morphogenetic Protein (BMP) play a role in the development of papillary breast lesions [71]. Recently, progression to DCIS and invasive carcinoma was hypothesized for a subset of intraductal papilloma [40]. Intraductal papillomas were clonally related to synchronous DCIS and invasive carcinoma in more than 50%, even without papillary histology of the latter.…”

Section: Intraductal Papilloma With Adh Dcis or Lobular Neoplasiamentioning

confidence: 99%

Papillary lesions of the breast

et al. 2021

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Papillary lesions of the breast represent a heterogeneous group of lesions including benign papillomas, papillomas with focal epithelial atypia, fully fledged ductal carcinoma in situ (DCIS) or lobular neoplasia, papillary DCIS, encapsulated papillary carcinomas without or with invasion, solid papillary carcinomas, and invasive papillary carcinomas. A micropapillary pattern characterized by lack of fibrous stalks within the papillae is observed in micropapillary DCIS and invasive micropapillary carcinoma. In addition, a variety of other rare breast lesions reveals a papillary architecture such as tall cell carcinoma with reversed polarity (TCCRP) and mucinous cystadenocarcinoma, adenomyoepithelioma, and secretory carcinoma. In addition, benign lesions such as usual ductal hyperplasia, apocrine metaplasia, gynecomastia, and juvenile papillomatosis may show a papillary or micropapillary architecture. Fragments of a benign papilloma in a breast biopsy are considered a lesion of uncertain malignant potential (B3 in the European classification) and excision is mostly recommended. Although the knowledge about molecular pathology of papillary breast lesions has increased, there is not sufficient evidence for diagnostically useful molecular features, yet. The aim of this review is to provide an update on papillary and micropapillary lesions with emphasis on problematic areas for daily diagnostic work including biopsies.

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

Cited by 20 publications

References 56 publications

The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ

The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ

Papillary Lesions of the Breast: A Review

Papillary lesions of the breast

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