Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas
Abstract
Cancers may be composed of multiple populations of submodal clones sharing the same initiating genetic lesions, followed by the acquisition of divergent genetic hits. Intra-tumour genetic heterogeneity has profound implications for cancer clinical management. To determine the extent of intra-tumour genetic heterogeneity in breast cancers, and whether the morphological diversity of breast cancers is underpinned by divergent genetic aberrations, we analysed the genomic profiles of microdissected, morphologically distinct components of six metaplastic breast carcinomas, tumours characterized by the presence of morphological areas with divergent differentiation. Each morphologically distinct component was separately microdissected and subjected to high-resolution microarray-based comparative genomic hybridization. Each component was also analysed by immunohistochemistry and in situ hybridization. Clonal relationship between the distinct components was tested by TP53 sequencing and human androgen receptor (HUMARA) X-chromosome inactivation assay. In the majority of cases, all morphologically distinct components from each case were clonal and displayed remarkably similar genetic profiles. In two cases, however, morphologically distinct components harboured specific genetic aberrations. In an adenosquamous carcinoma, the differences were such that only 20% of the genome harboured similar copy number changes. The squamous component displayed EGFR gene amplification, EGFR over-expression and lack of expression of hormone receptors, whereas the lobular component displayed the reverse pattern. The components of a biphasic spindle cell carcinoma harboured similar gains, losses, amplifications of 9p23 and 17q12 (HER2) and identical TP53 mutations, suggesting that these were relatively early events in the development of this tumour; however, each component displayed divergent focal amplifications. Importantly, the metastatic deposit of this case, despite harbouring a TP53 mutation identical to that found in the primary tumour, harboured additional specific focal amplifications. This proof-of-principle study provides direct evidence of intra-tumour genetic heterogeneity in breast cancers, and shows that in some cases morphological diversity may be underpinned by distinct genetic aberrations.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Incidents also occur in lesions, and a clonal origin does not exclude heterogeneity within a lesion as demonstrated for breast and other cancers.
“Incidents also occur in lesions, and a clonal origin does not exclude heterogeneity within a lesion as demonstrated for breast (257) and other (258, 259) cancers.”
From Pathogenesis of endometriosis: The genetic/epigenetic theory (2019) · cites this paper as [257]
Cites
Elston, C. W., & Ellis, I. O. (1991) · Histopathology · doi:10.1111/j.1365-2559.1991.tb00229.x · Cited by 6,181 · see citing works
Wolff, A. C., Hammond, M. E., Schwartz, J. N., Hagerty, K. L., Allred, D. C., Côté, R. J., Dowsett, M., Fitzgibbons, P. L., Hanna, W. M., Langer, A. S., et al. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.09.2775 · Cited by 4,406 · see citing works
Nielsen, T. O., Hsu, F. D., Jensen, K. C., Cheang, M. C. U., Karaca, G., Hu, Z., Hernandez‐Boussard, T., Livasy, C., Cowan, D., Dressler, L. G., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-0220 · Cited by 2,665 · see citing works
Cancer as an evolutionary and ecological process
Merlo, L. M. F., Pepper, J. W., Reid, B. J., & Maley, C. C. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2013 · Cited by 1,690 · see citing works
Molecular Definition of Breast Tumor Heterogeneity
Shipitsin, M. V., Campbell, L. L., Argani, P., Weremowicz, S., Bloushtain-Qimron, N., Yao, J., Nikolskaya, T., Serebryiskaya, T., Beroukhim, R., Hu, M., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.01.013 · Cited by 1,347 · see citing works
Heterogeneity in Cancer: Cancer Stem Cells versus Clonal Evolution
Shackleton, M. J., Quintana, E., Fearon, E. R., & Morrison, S. J. (2009) · Cell · doi:10.1016/j.cell.2009.08.017 · Cited by 1,152 · see citing works
Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers
Sakai, W., Swisher, E. M., Karlan, B. Y., Agarwal, M. K., Higgins, J., Friedman, C., Villegas, E., Jacquemont, C., Farrugia, D. J., Couch, F. J., et al. (2008) · Nature · doi:10.1038/nature06633 · Cited by 1,086 · see citing works
Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution
Shah, S. P., Morin, R. D., Khattra, J. S., Prentice, L., Pugh, T. J., Burleigh, A., Delaney, A. D., Gelmon, K. A., Guliany, R., Senz, J., et al. (2009) · Nature · doi:10.1038/nature08489 · Cited by 1,063 · see citing works
Resistance to therapy caused by intragenic deletion in BRCA2
Edwards, S. L., Brough, R., Lord, C. J., Natrajan, R., Vatcheva, R., Levine, D. A., Boyd, J., Reis-Filho, J. S., & Ashworth, A. (2008) · Nature · doi:10.1038/nature06548 · Cited by 1,011 · see citing works
Self-citationSelf-renewal and solid tumor stem cells
Al‐Hajj, M., & Clarke, M. F. (2004) · Oncogene · doi:10.1038/sj.onc.1207947 · Cited by 911 · see citing works
Hennessy, B. T., Gonzalez-Angulo, A. M., Stemke‐Hale, K., Gilcrease, M. Z., Krishnamurthy, S., Lee, J., Fridlyand, J., Şahin, A. A., Agarwal, R., Joy, C., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3441 · Cited by 874 · see citing works
Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic Leukemia
Mullighan, C. G., Phillips, L. A., Su, X., Ma, J., Miller, C. B., Shurtleff, S. A., & Downing, J. R. (2008) · Science · doi:10.1126/science.1164266 · Cited by 806 · see citing works
Heinrich, M. C., Maki, R. G., Corless, C. L., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.7461 · Cited by 797 · see citing works
Breast cancer: origins and evolution
Polyák, K. (2007) · Journal of Clinical Investigation · doi:10.1172/jci33295 · Cited by 703 · see citing works
Schmidt‐Kittler, O., Ragg, T., Daskalakis, A., Granzow, M., Ahr, A., Blankenstein, T. J. F., Kaufmann, M., Diebold, J., Arnholdt, H., Müller, P. E., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1331931100 · Cited by 631 · see citing works
Therapeutic implications of cancer stem cells
Al‐Hajj, M., Becker, M. W., Wicha, M. S., Weissman, I. L., & Clarke, M. F. (2003) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2003.11.007 · Cited by 561 · see citing works
Weigelt, B., Horlings, H. M., Kreike, B., Hayes, M., Hauptmann, M., Wessels, L. F. A., de Jong, D., van de Vijver, M. J., Veer, L. V., & Peterse, J. L. (2008) · The Journal of Pathology · doi:10.1002/path.2407 · Cited by 560 · see citing works
Self-citationMolecular evolution of breast cancer
Simpson, P. T., Reis-Filho, J. S., Gale, T., & Lakhani, S. R. (2005) · The Journal of Pathology · doi:10.1002/path.1691 · Cited by 520 · see citing works
Self-citationImplications of the cancer stem-cell hypothesis for breast cancer prevention and therapy.
Kakarala, M., & Wicha, M. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.16.3931 · Cited by 417 · see citing works
Roots and stems: stem cells in cancer
Polyák, K., & Hahn, W. C. (2006) · Nature Medicine · doi:10.1038/nm1379 · Cited by 379 · see citing works
Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond
Ladanyi, M., & Pao, W. J. (2008) · Modern Pathology · doi:10.1038/modpathol.3801018 · Cited by 365 · see citing works
Flier, J., Boorsma, D. M., van Beek, P. J., Nieboer, C., Stoof, T. J., Willemze, R., & Tensen, C. P. (2001) · The Journal of Pathology · doi:10.1002/1096-9896(200108)194:4 · Cited by 362 · see citing works
Metaplastic breast carcinomas are basal‐like tumours
Reis-Filho, J. S., Milanezi, F., Steele, D., et al. (2006) · Histopathology · doi:10.1111/j.1365-2559.2006.02467.x · Cited by 341 · see citing works
Self-citationNovel patterns of genome rearrangement and their association with survival in breast cancerPreprint
Hicks, J. B., Krasnitz, A., Lakshmi, B. V., Navin, N. E., Riggs, M. G., Leibu, E., Esposito, D., Alexander, J., Troge, J. E., Grubor, V. D., et al. (2006) · Genome Research · doi:10.1101/gr.5460106 · Cited by 320 · see citing works
Tan, D. S. P., Marchiò, C., Jones, R. L., Savage, K., Smith, I. E., Dowsett, M., & Reis-Filho, J. S. (2007) · Breast Cancer Research and Treatment · doi:10.1007/s10549-007-9756-8 · Cited by 318 · see citing works
Self-citationEpithelial to mesenchymal transition and breast cancer
Tomaskovic‐Crook, E., Thompson, E. W., & Thiery, J. P. (2009) · Breast Cancer Research · doi:10.1186/bcr2416 · Cited by 317 · see citing works
EGFR amplification and lack of activating mutations in metaplastic breast carcinomas
Reis‐Filho, J., Pinheiro, C. M., Lambros, M., et al. (2006) · The Journal of Pathology · doi:10.1002/path.2004 · Cited by 266 · see citing works
Self-citationMetaplastic breast carcinomas are basal-like breast cancers: a genomic profiling analysis
Weigelt, B., Kreike, B., & Reis-Filho, J. S. (2008) · Breast Cancer Research and Treatment · doi:10.1007/s10549-008-0197-9 · Cited by 224 · see citing works
Self-citationWalker, M., Patel, K., & Stappenbeck, T. (2008) · The Journal of Pathology · doi:10.1002/path.2474 · Cited by 215 · see citing works
Godin-Heymann, N., Ulkus, L., Brannigan, B. W., McDermott, U., Lamb, J. A., Maheswaran, S., Settleman, J. E., & Haber, D. A. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-2387 · Cited by 206 · see citing works
Marchiò, C., Lambros, M. B. K., Gugliotta, P., di Cantogno, L. V., Botta, C., Pasini, B., Tan, D. S. P., Mackay, A. G., Fenwick, K., Tamber, N., et al. (2009) · The Journal of Pathology · doi:10.1002/path.2574 · Cited by 202 · see citing works
Self-citationTorres, L., Ribeiro, F. R., Pandis, N., Andersen, J. A., Heim, S., & Teixeira, M. R. (2006) · Breast Cancer Research and Treatment · doi:10.1007/s10549-006-9317-6 · Cited by 187 · see citing works
Reis-Filho, J. S., Simpson, P. T., Jones, C., et al. (2005) · The Journal of Pathology · doi:10.1002/path.1806 · Cited by 182 · see citing works
Self-citationResolving the resolution of array CGH
Coe, B. P., Ylstra, B., Carvalho, B. G., Meijer, G. A., MacAulay, C. E., & Lam, W. L. (2007) · Genomics · doi:10.1016/j.ygeno.2006.12.012 · Cited by 179 · see citing works
Detection and analysis of mammary gland stem cells
Stingl, J. (2009) · Journal of Pathology · doi:10.1002/path.2457 · Cited by 170 · see citing works
Tiling Path Genomic Profiling of Grade 3 Invasive Ductal Breast Cancers
Natrajan, R., Lambros, M. B. K., Rodríguez-Pinilla, S. M., Moreno‐Bueno, G., Tan, D. S. P., Marchiò, C., Vatcheva, R., Rayter, S., Mahler-Araujo, B. M., Fulford, L. G., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-1878 · Cited by 170 · see citing works
Self-citationSimpson, P. T., Reis‐Filho, J., Lambros, M., et al. (2008) · The Journal of Pathology · doi:10.1002/path.2358 · Cited by 169 · see citing works
Self-citationGenetic divergence in the clonal evolution of breast cancer.
Fujii, H., Marsh, C., Cairns, P., et al. (1996) · PubMed · Cited by 166 · see citing works
PPM1D Is a Potential Therapeutic Target in Ovarian Clear Cell Carcinomas
Tan, D. S. P., Lambros, M. B. K., Rayter, S., Natrajan, R., Vatcheva, R., Gao, Q., Marchiò, C., Geyer, F. C., Savage, K., Parry, S., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2403 · Cited by 165 · see citing works
Self-citationMiddleton, L. P. (2006) · Breast Diseases A Year Book Quarterly · doi:10.1016/s1043-321x(06)80501-1 · Cited by 160 · see citing works
Genomic and immunophenotypical characterization of pure micropapillary carcinomas of the breast
Marchiò, C., Iravani, M., Natrajan, R., et al. (2008) · The Journal of Pathology · doi:10.1002/path.2368 · Cited by 157 · see citing works
Self-citationNatrajan, R., Weigelt, B., Mackay, A. G., Geyer, F. C., Grigoriadis, A. E., Tan, D. S. P., Jones, C., Lord, C. J., Vatcheva, R., Rodríguez-Pinilla, S. M., et al. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0501-3 · Cited by 153 · see citing works
Self-citationGenomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines
Arriola, E., Marchiò, C., Tan, D. S. P., Drury, S., Lambros, M. B. K., Natrajan, R., Rodríguez-Pinilla, S. M., Mackay, A. G., Tamber, N., Fenwick, K., et al. (2008) · Laboratory Investigation · doi:10.1038/labinvest.2008.19 · Cited by 151 · see citing works
Self-citationBreast Cancer Stem Cells and Intrinsic Subtypes: Controversies Rage On
Nakshatri, H., Srour, E. F., & Badve, S. (2009) · Current Stem Cell Research & Therapy · doi:10.2174/157488809787169110 · Cited by 125 · see citing works
Lien, H., Lin, C., Mao, T., Kuo, S., Hsiao, C.-H., & Huang, C. (2004) · The Journal of Pathology · doi:10.1002/path.1624 · Cited by 123 · see citing works
Gunnarsson, R., Staaf, J., Jansson, M., et al. (2008) · Genes Chromosomes and Cancer · doi:10.1002/gcc.20575 · Cited by 115 · see citing works
Robanus-Maandag, E. C., Bosch, C. A. J., Kristel, P., Hart, A. A. M., Faneyte, I. F., Nederlof, P. M., Peterse, J. L., & van de Vijver, M. J. (2003) · The Journal of Pathology · doi:10.1002/path.1385 · Cited by 93 · see citing works
Analysis of the progression of fibroepithelial tumours of the breast by PCR‐based clonality assay
Kuijper, A., Buerger, H., Simon, R., Schaefer, K., Croonen, A., Boecker, W., van der Wall, E., & van Diest, P. J. (2002) · The Journal of Pathology · doi:10.1002/path.1161 · Cited by 92 · see citing works
Armstrong, A. B., Wang, M., Eble, J. N., et al. (2008) · Modern Pathology · doi:10.1038/modpathol.2008.176 · Cited by 88 · see citing works
Lambros, M. B. K., Simpson, P. T., Jones, C., Natrajan, R., Westbury, C., Steele, D., Savage, K., Mackay, A. G., Schmitt, F. C., Ashworth, A., et al. (2006) · Laboratory Investigation · doi:10.1038/labinvest.3700390 · Cited by 87 · see citing works
Self-citationESR1 gene amplification in breast cancer: a common phenomenon?
Reis-Filho, J. S., Drury, S., Lambros, M. B. K., et al. (2008) · Nature Genetics · doi:10.1038/ng0708-809b · Cited by 86 · see citing works
Self-citationCottu, P. H., Asselah, J., Lae, M. E., et al. (2008) · Annals of Oncology · doi:10.1093/annonc/mdn021 · Cited by 82 · see citing works
Tan, D. S. P., Lambros, M. B. K., Natrajan, R., & Reis-Filho, J. S. (2007) · Laboratory Investigation · doi:10.1038/labinvest.3700593 · Cited by 75 · see citing works
Self-citationMarchiò, C., Iravani, M., Natrajan, R., et al. (2009) · The Journal of Pathology · doi:10.1002/path.2572 · Cited by 75 · see citing works
Self-citationA high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines
Mackay, A. G., Tamber, N., Fenwick, K., et al. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-008-0296-7 · Cited by 64 · see citing works
Self-citationBenetkiewicz, M., Piotrowski, A., de Ståhl, T. D., Jankowski, M., Bała, D., Hoffman, J., Śrutek, E., Laskowski, R., Zegarski, W., & Dumanski, J. (2006) · International Journal of Oncology · doi:10.3892/ijo.29.4.935 · Cited by 33 · see citing works
Cooper, M., Li, S.-Q., Bhardwaj, T., Rohan, T. E., & Kandel, R. A. (2004) · Clinical Chemistry · doi:10.1373/clinchem.2003.025221 · Cited by 22 · see citing works
Reduced Incidence of Persistent Chromosome Aberrations in Mice Irradiated at Low Dose Rates
Nowell̀, P. C., & Cole, L. J. (1963) · Science · doi:10.1126/science.141.3580.524 · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Pathogenesis of endometriosis: The genetic/epigenetic theory
Koninckx, P. R., Ussia, A., Adamyan, L., Wattiez, A., Gomel, V., & Martin, D. C. (2019) · Fertility and Sterility · doi:10.1016/j.fertnstert.2018.10.013 · Cited by 427 · see citing works
- Authors
- Geyer, F. C., Weigelt, B., Natrajan, R., Lambros, M. B., de Biase, D., Vatcheva, R., Savage, K., Mackay, A., Ashworth, A., & Reis‐Filho, J. S.
- Affiliations
- Institute of Cancer Research (GB)
- Cancer Research UK (GB)
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2010-01-22
- Volume
- 220
- Issue
- 5
- Pages
- 562-573
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- OpenAlex
- W2012751102
- Cited by
- 233
- References
- 58
- Citations by year
- 2025: 7 · 2024: 26 · 2023: 18 · 2022: 6 · 2021: 14 · 2020: 11 · 2019: 7 · 2018: 10 · 2017: 19 · 2016: 12 · 2015: 12 · 2014: 18 · 2013: 12 · 2012: 23
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Pathology (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- Cancer Research UK
- National Institute for Health and Care Research
- Breakthrough Cancer Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Breast Lesions and Carcinomas
- Keywords
- metaplastic breast carcinoma, clonal relatedness, adenosquamous carcinoma, sarcomatoid carcinoma, EGFR amplification, TP53 mutation, focal amplification, copy number alterations, metastatic deposits, tumor heterogeneity
- MeSH terms
- Breast Neoplasms, Chromosome Aberrations, Female, Humans, Metaplasia, Mutation, Phenotype, Neoplastic Stem Cells, Cluster Analysis, Genes, p53, In Situ Hybridization, Evolution, Molecular, Reverse Transcriptase Polymerase Chain Reaction, Microdissection, Comparative Genomic Hybridization
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
