Phylogenetic analysis of combined lobular and ductal carcinoma of the breast

Kobayashi,Hiroko; Nakai,Tokiko; Nakanishi,Yoko; Esumi,Mariko; Masuda,Shinobu

doi:10.3892/mmr.2021.12357

Phylogenetic analysis of combined lobular and ductal carcinoma of the breast

Authors:
- Hiroko Kobayashi
- Tokiko Nakai
- Yoko Nakanishi
- Mariko Esumi
- Shinobu Masuda
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Affiliations: Division of Oncologic Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173‑8610, Japan, Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba 277‑8577, Japan, Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo 173‑8610, Japan
Published online on: August 10, 2021 https://doi.org/10.3892/mmr.2021.12357
Article Number: 718
Copyright: © Kobayashi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Breast cancer manifests in diverse forms, with particular reference to various cell types harboring different mutations and gene expression profiles. To elucidate the clonal relationship between cancer cells in tumors composed of both ductal and lobular phenotypes, two combined lobular and ductal carcinoma (CLDC) cases were analyzed, including one mixed ductal‑lobular carcinoma (MDL) lesion, by direct sequencing of the mitochondrial DNA D‑loop, digital PCR targeting of chromosomes 1q and 16q, as well as next‑generation sequencing. DNA was extracted from formalin‑fixed paraffin‑embedded tissue sections of different histological types, including invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, flat epithelial atypia, non‑neoplastic mammary gland and extramammary organs, using laser‑assisted microdissection. Mutations detected by the comprehensive cancer panel were validated by SYBR green allele‑specific quantitative PCR (RRM1, AKT1, PIK3CA, RALGDS, EGFR, TP53, IL21R, DPYD, SGK1, CDH1, TIMP3 and KMT2C). CLDC, which shared the basic genetic alterations of 1q gain or 16q loss, progresses to invasive lobular or ductual carcinoma with the accumulation of further mutations. Cancer cells contained in an MDL lesion shared closely related genetic alterations, suggesting that these cells have the same origin, despite different histological features, namely ‘lobular’ or ‘ductal’. By contrast, multiple lesions located away from the main tumor, diagnosed as CLDC (excluding an MDL lesion) were not always identical with different genetic alterations, despite being diagnosed as ductal carcinoma in situ. Thus, MDL should be defined as a distinct category separate from CLDC, whose components of ‘lobular’ and ‘ductal’ may have the same cellular origin.

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