Circulating tumor microemboli (CTMs) are clusters of cancer cells detached from solid tumors, whose study can reveal mechanisms underlying metastatization. As they frequently comprise unknown fractions of leukocytes, the analysis of copy number alterations (CNAs) is challenging. To address this, we titrated known numbers of leukocytes into cancer cells (MDA-MB-453 and MDA-MB-36, displaying high and low DNA content, respectively) generating tumor fractions from 0-100%. After low-pass sequencing, ichorCNA was identified as the best algorithm to build a linear mixed regression model for tumor fraction (TF) prediction. We then isolated 53 CTMs from blood samples of six early-stage breast cancer patients and predicted the TF of all clusters. We found that all clusters harbor cancer cells between 8 and 48%. Furthermore, by comparing the identified CNAs of CTMs with their matched primary tumors, we noted that only 31-71% of aberrations were shared. Surprisingly, CTM-private alterations were abundant (30-63%), whereas primary tumor-private alterations were rare (4-12%). This either indicates that CTMs are disseminated from further progressed regions of the primary tumor or stem from cancer cells already colonizing distant sites. In both cases, CTM-private mutations may inform us about specific metastasis-associated functions of involved genes that should be explored in follow-up and mechanistic studies.

Detection of genomically aberrant cells within circulating tumor microemboli (CTMs) isolated from early-stage breast cancer patients / M. Silvestri, C. Reduzzi, G. Feliciello, M. Vismara, T. Schamberger, C. Köstler, R. Motta, S. Calza, C. Ferraris, A. Vingiani, G. Pruneri, M.G. Daidone, C.A. Klein, B. Polzer, V. Cappelletti. - In: CANCERS. - ISSN 2072-6694. - 13:6(2021), pp. 1409.1-1409.20. [10.3390/cancers13061409]

Detection of genomically aberrant cells within circulating tumor microemboli (CTMs) isolated from early-stage breast cancer patients

A. Vingiani;G. Pruneri;
2021

Abstract

Circulating tumor microemboli (CTMs) are clusters of cancer cells detached from solid tumors, whose study can reveal mechanisms underlying metastatization. As they frequently comprise unknown fractions of leukocytes, the analysis of copy number alterations (CNAs) is challenging. To address this, we titrated known numbers of leukocytes into cancer cells (MDA-MB-453 and MDA-MB-36, displaying high and low DNA content, respectively) generating tumor fractions from 0-100%. After low-pass sequencing, ichorCNA was identified as the best algorithm to build a linear mixed regression model for tumor fraction (TF) prediction. We then isolated 53 CTMs from blood samples of six early-stage breast cancer patients and predicted the TF of all clusters. We found that all clusters harbor cancer cells between 8 and 48%. Furthermore, by comparing the identified CNAs of CTMs with their matched primary tumors, we noted that only 31-71% of aberrations were shared. Surprisingly, CTM-private alterations were abundant (30-63%), whereas primary tumor-private alterations were rare (4-12%). This either indicates that CTMs are disseminated from further progressed regions of the primary tumor or stem from cancer cells already colonizing distant sites. In both cases, CTM-private mutations may inform us about specific metastasis-associated functions of involved genes that should be explored in follow-up and mechanistic studies.
breast cancer; circulating tumor microemboli; copy number alteration; low-pass whole genome sequencing; metastatic dissemination; tumor fraction
Settore MED/06 - Oncologia Medica
Settore MED/08 - Anatomia Patologica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/939385
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