Heterogeneity of Circulating Tumor Cell-Associated Genomic Gains in Breast Cancer and Its Association with the Host Immune Response.

Autor:	Kanwar N; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Balde Z; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Nair R; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Dawe M; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Chen S; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada., Maganti M; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Atenafu EG; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Manolescu S; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada., Wei C; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Mao A; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada., Fu F; STTARR Innovation Centre, University Health Network, Toronto, Canada., Wang D; Biomarker Imaging Research Laboratory, Sunnybrook Research Institute, Toronto, Canada., Cheung A; Biomarker Imaging Research Laboratory, Sunnybrook Research Institute, Toronto, Canada., Yerofeyeva Y; Biomarker Imaging Research Laboratory, Sunnybrook Research Institute, Toronto, Canada., Peters R; Biomarker Imaging Research Laboratory, Sunnybrook Research Institute, Toronto, Canada., Liu K; Biomarker Imaging Research Laboratory, Sunnybrook Research Institute, Toronto, Canada., Desmedt C; Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium., Sotiriou C; Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium., Szekely B; 2nd Department of Pathology, Semmelweis University, Budapest, Hungary., Kulka J; 2nd Department of Pathology, Semmelweis University, Budapest, Hungary., McKee TD; STTARR Innovation Centre, University Health Network, Toronto, Canada., Hirano N; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.; Department of Immunology, University of Toronto, Toronto, Canada., Bartlett JMS; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Ontario Institute for Cancer Research, Toronto, Canada., Yaffe MJ; Biomarker Imaging Research Laboratory, Sunnybrook Research Institute, Toronto, Canada.; Ontario Institute for Cancer Research, Toronto, Canada., Bedard PL; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., McCready D; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Done SJ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. susan.done@uhn.ca.; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.; Laboratory Medicine Program, University Health Network, Toronto, Canada.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Dec 15; Vol. 81 (24), pp. 6196-6206. Date of Electronic Publication: 2021 Oct 28.
DOI:	10.1158/0008-5472.CAN-21-1079
Abstrakt:	Tumor cells that preferentially enter circulation include the precursors of metastatic cancer. Previously, we characterized circulating tumor cells (CTC) from patients with breast cancer and identified a signature of genomic regions with recurrent copy-number gains. Through FISH, we now show that these CTC-associated regions are detected within the matched untreated primary tumors of these patients (21% to 69%, median 55.5%, n = 19). Furthermore, they are more prevalent in the metastases of patients who died from breast cancer after multiple rounds of treatment (70% to 100%, median 93%, samples n = 41). Diversity indices revealed that higher spatial heterogeneity for these regions within primary tumors is associated with increased dissemination and metastasis. An identified subclone with multiple regions gained (MRG clone) was enriched in a posttreatment primary breast carcinoma as well as multiple metastatic tumors and local breast recurrences obtained at autopsy, indicative of a distinct early subclone with the capability to resist multiple lines of treatment and eventually cause death. In addition, multiplex immunofluorescence revealed that tumor heterogeneity is significantly associated with the degree of infiltration of B lymphocytes in triple-negative breast cancer, a subtype with a large immune component. Collectively, these data reveal the functional potential of genetic subclones that comprise heterogeneous primary breast carcinomas and are selected for in CTCs and posttreatment breast cancer metastases. In addition, they uncover a relationship between tumor heterogeneity and host immune response in the tumor microenvironment. SIGNIFICANCE: As breast cancers progress, they become more heterogeneous for multiple regions amplified in circulating tumor cells, and intratumoral spatial heterogeneity is associated with the immune landscape. (©2021 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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