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. 2024 Aug;485(2):291-297.
doi: 10.1007/s00428-024-03814-8. Epub 2024 May 7.

CDH1 methylation analysis in invasive lobular breast carcinomas with and without gene mutation

Silvia González-Martínez  1   2   3 , Viera Horvathova Kajabova  4 , Belén Pérez-Mies  2   3   5   6 , Irene Carretero-Barrio  2   3   5   6 , Tamara Caniego-Casas  2   3 , David Sarrió  3   7 , Gema Moreno-Bueno  3   7   8 , María Gión  9 , José Perez-García  1   10   11   12 , Javier Cortés  1   3   10   11   12   13   14 , Bozena Smolkova  15 , José Palacios  16   17   18   19
Affiliations

CDH1 methylation analysis in invasive lobular breast carcinomas with and without gene mutation

Silvia González-Martínez et al. Virchows Arch. 2024 Aug.

Abstract

The proposed role of CDH1 (E-cadherin gene) methylation as a mechanism of gene inactivation in invasive lobular carcinoma (ILC) remains inconclusive. For many years, CDH1 promoter hypermethylation has been regarded as a mechanism for gene inactivation in ILC. However, this assumption has primarily relied on non-quantitative assays, which have reported CDH1 methylation frequencies ranging from 26 to 93% at CpG sites within the island region. Few studies employing quantitative methods and covering CpG island shores, regions of relatively low CpG density situated proximal to conventional promoter CpGs, have been conducted, revealing lower percentages of methylation ranging from 0 to 51%. Therefore, using the quantitative pyrosequencing method, we examined CDH1 methylation in the island region and shores in E-cadherin deficient ILC cases (15 with CDH1 mutation and 22 non-mutated), 19 cases of invasive breast carcinomas non-special type (IBC-NSTs), and five cases of usual ductal hyperplasia (UDH). Our analysis revealed CDH1 methylation frequencies ranging from 3 to 64%, with no significant increase in methylation levels in any group of ILCs (median = 12%) compared to IBC-NST (median = 15%). In addition, considering the poorly studied association between the number of tumor-infiltrating lymphocytes (TILs) and CDH1 methylation in breast cancer, we undertook a thorough analysis within our dataset. Our findings revealed a positive correlation between CDH1 methylation and the presence of TILs (r = 0.5; p-value < 0.05), shedding light on an aspect of breast cancer biology warranting further investigation. These findings challenge CDH1 methylation as a CDH1 inactivation mechanism in ILC and highlight TILs as a potential confounding factor in gene methylation.

Keywords: CDH1; Breast cancer; DNA methylation; Lobular carcinomas.

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Conflict of interest statement

Consulting/advisor: Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, Merck Sharp&Dohme, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Scorpion Therapeutics, Expres2ion Biotechnologies, Jazz Pharmatheuticals, Abbvie. Honoraria: Roche , Novartis , Eisai, Pfizer, Lilly, Merck Sharp&Dohme, Daiichi Sankyo, Astrazeneca, Gilead, Steamline Therapeutics. Research funding to the Institution: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Queen Mary University of London, IQVIA. Stock: MAJ3 Capital, Leuko (relative). Travel, accommodation, expenses: Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, Astrazeneca, Gilead, Merck Sharp&Dohme, Steamline. Patents: Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED. Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés.US 2019/ 0338368 A1. LICENSED

Figures

Fig. 1
Fig. 1
a DNA methylation status of sequenced CpGs sites aligning with the CDH1 gene. Grey boxes = data not available. b Violin plots depicting methylation data across each tumor subgroup within the respective region
Fig. 2
Fig. 2
a, b, c Correlation between CDH1 methylation frequency and percentage of TILs across N-shore, island, and S-shore regions. d Hematoxylin-eosin staining displaying the percentage of TILs (40%) in non-mutated ILC case number 11
See this image and copyright information in PMC

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