Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations
Abstract CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-02-01
|
| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-024-00508-x |
| _version_ | 1797276044067078144 |
|---|---|
| author | Higinio Dopeso Andrea M. Gazzo Fatemeh Derakhshan David N. Brown Pier Selenica Sahar Jalali Arnaud Da Cruz Paula Antonio Marra Edaise M. da Silva Thais Basili Laxmi Gusain Lorraine Colon-Cartagena Shirin Issa Bhaloo Hunter Green Chad Vanderbilt Steffi Oesterreich Anne Grabenstetter M. Gabriela Kuba Dara Ross Dilip Giri Hannah Y. Wen Hong Zhang Edi Brogi Britta Weigelt Fresia Pareja Jorge S. Reis-Filho |
| author_facet | Higinio Dopeso Andrea M. Gazzo Fatemeh Derakhshan David N. Brown Pier Selenica Sahar Jalali Arnaud Da Cruz Paula Antonio Marra Edaise M. da Silva Thais Basili Laxmi Gusain Lorraine Colon-Cartagena Shirin Issa Bhaloo Hunter Green Chad Vanderbilt Steffi Oesterreich Anne Grabenstetter M. Gabriela Kuba Dara Ross Dilip Giri Hannah Y. Wen Hong Zhang Edi Brogi Britta Weigelt Fresia Pareja Jorge S. Reis-Filho |
| author_sort | Higinio Dopeso |
| collection | DOAJ |
| description | Abstract CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC. |
| first_indexed | 2024-03-07T15:21:39Z |
| format | Article |
| id | doaj.art-2bcd7e3ff5014c2e98a7bf5bd912578b |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-07T15:21:39Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-2bcd7e3ff5014c2e98a7bf5bd912578b2024-03-05T17:33:54ZengNature Portfolionpj Precision Oncology2397-768X2024-02-018111110.1038/s41698-024-00508-xGenomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterationsHiginio Dopeso0Andrea M. Gazzo1Fatemeh Derakhshan2David N. Brown3Pier Selenica4Sahar Jalali5Arnaud Da Cruz Paula6Antonio Marra7Edaise M. da Silva8Thais Basili9Laxmi Gusain10Lorraine Colon-Cartagena11Shirin Issa Bhaloo12Hunter Green13Chad Vanderbilt14Steffi Oesterreich15Anne Grabenstetter16M. Gabriela Kuba17Dara Ross18Dilip Giri19Hannah Y. Wen20Hong Zhang21Edi Brogi22Britta Weigelt23Fresia Pareja24Jorge S. Reis-Filho25Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Surgery, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pharmacology & Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of MedicineDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterAbstract CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC.https://doi.org/10.1038/s41698-024-00508-x |
| spellingShingle | Higinio Dopeso Andrea M. Gazzo Fatemeh Derakhshan David N. Brown Pier Selenica Sahar Jalali Arnaud Da Cruz Paula Antonio Marra Edaise M. da Silva Thais Basili Laxmi Gusain Lorraine Colon-Cartagena Shirin Issa Bhaloo Hunter Green Chad Vanderbilt Steffi Oesterreich Anne Grabenstetter M. Gabriela Kuba Dara Ross Dilip Giri Hannah Y. Wen Hong Zhang Edi Brogi Britta Weigelt Fresia Pareja Jorge S. Reis-Filho Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations npj Precision Oncology |
| title | Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations |
| title_full | Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations |
| title_fullStr | Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations |
| title_full_unstemmed | Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations |
| title_short | Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations |
| title_sort | genomic and epigenomic basis of breast invasive lobular carcinomas lacking cdh1 genetic alterations |
| url | https://doi.org/10.1038/s41698-024-00508-x |
| work_keys_str_mv | AT higiniodopeso genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT andreamgazzo genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT fatemehderakhshan genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT davidnbrown genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT pierselenica genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT saharjalali genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT arnauddacruzpaula genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT antoniomarra genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT edaisemdasilva genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT thaisbasili genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT laxmigusain genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT lorrainecoloncartagena genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT shirinissabhaloo genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT huntergreen genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT chadvanderbilt genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT steffioesterreich genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT annegrabenstetter genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT mgabrielakuba genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT daraross genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT dilipgiri genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT hannahywen genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT hongzhang genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT edibrogi genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT brittaweigelt genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT fresiapareja genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations AT jorgesreisfilho genomicandepigenomicbasisofbreastinvasivelobularcarcinomaslackingcdh1geneticalterations |