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Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1–14 per bre...

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Autores principales: Forsberg, Lars A., Rasi, Chiara, Pekar, Gyula, Davies, Hanna, Piotrowski, Arkadiusz, Absher, Devin, Razzaghian, Hamid Reza, Ambicka, Aleksandra, Halaszka, Krzysztof, Przewoźnik, Marcin, Kruczak, Anna, Mandava, Geeta, Pasupulati, Saichand, Hacker, Julia, Prakash, K. Reddy, Dasari, Ravi Chandra, Lau, Joey, Penagos-Tafurt, Nelly, Olofsson, Helena M., Hallberg, Gunilla, Skotnicki, Piotr, Mituś, Jerzy, Skokowski, Jaroslaw, Jankowski, Michal, Śrutek, Ewa, Zegarski, Wojciech, Tiensuu Janson, Eva, Ryś, Janusz, Tot, Tibor, Dumanski, Jan P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579338/
https://www.ncbi.nlm.nih.gov/pubmed/26430163
http://dx.doi.org/10.1101/gr.187823.114
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author Forsberg, Lars A.
Rasi, Chiara
Pekar, Gyula
Davies, Hanna
Piotrowski, Arkadiusz
Absher, Devin
Razzaghian, Hamid Reza
Ambicka, Aleksandra
Halaszka, Krzysztof
Przewoźnik, Marcin
Kruczak, Anna
Mandava, Geeta
Pasupulati, Saichand
Hacker, Julia
Prakash, K. Reddy
Dasari, Ravi Chandra
Lau, Joey
Penagos-Tafurt, Nelly
Olofsson, Helena M.
Hallberg, Gunilla
Skotnicki, Piotr
Mituś, Jerzy
Skokowski, Jaroslaw
Jankowski, Michal
Śrutek, Ewa
Zegarski, Wojciech
Tiensuu Janson, Eva
Ryś, Janusz
Tot, Tibor
Dumanski, Jan P.
author_facet Forsberg, Lars A.
Rasi, Chiara
Pekar, Gyula
Davies, Hanna
Piotrowski, Arkadiusz
Absher, Devin
Razzaghian, Hamid Reza
Ambicka, Aleksandra
Halaszka, Krzysztof
Przewoźnik, Marcin
Kruczak, Anna
Mandava, Geeta
Pasupulati, Saichand
Hacker, Julia
Prakash, K. Reddy
Dasari, Ravi Chandra
Lau, Joey
Penagos-Tafurt, Nelly
Olofsson, Helena M.
Hallberg, Gunilla
Skotnicki, Piotr
Mituś, Jerzy
Skokowski, Jaroslaw
Jankowski, Michal
Śrutek, Ewa
Zegarski, Wojciech
Tiensuu Janson, Eva
Ryś, Janusz
Tot, Tibor
Dumanski, Jan P.
author_sort Forsberg, Lars A.
collection PubMed
description Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1–14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.
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spelling pubmed-45793382015-10-01 Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer Forsberg, Lars A. Rasi, Chiara Pekar, Gyula Davies, Hanna Piotrowski, Arkadiusz Absher, Devin Razzaghian, Hamid Reza Ambicka, Aleksandra Halaszka, Krzysztof Przewoźnik, Marcin Kruczak, Anna Mandava, Geeta Pasupulati, Saichand Hacker, Julia Prakash, K. Reddy Dasari, Ravi Chandra Lau, Joey Penagos-Tafurt, Nelly Olofsson, Helena M. Hallberg, Gunilla Skotnicki, Piotr Mituś, Jerzy Skokowski, Jaroslaw Jankowski, Michal Śrutek, Ewa Zegarski, Wojciech Tiensuu Janson, Eva Ryś, Janusz Tot, Tibor Dumanski, Jan P. Genome Res Research Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1–14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer. Cold Spring Harbor Laboratory Press 2015-10 /pmc/articles/PMC4579338/ /pubmed/26430163 http://dx.doi.org/10.1101/gr.187823.114 Text en © 2015 Forsberg et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research
Forsberg, Lars A.
Rasi, Chiara
Pekar, Gyula
Davies, Hanna
Piotrowski, Arkadiusz
Absher, Devin
Razzaghian, Hamid Reza
Ambicka, Aleksandra
Halaszka, Krzysztof
Przewoźnik, Marcin
Kruczak, Anna
Mandava, Geeta
Pasupulati, Saichand
Hacker, Julia
Prakash, K. Reddy
Dasari, Ravi Chandra
Lau, Joey
Penagos-Tafurt, Nelly
Olofsson, Helena M.
Hallberg, Gunilla
Skotnicki, Piotr
Mituś, Jerzy
Skokowski, Jaroslaw
Jankowski, Michal
Śrutek, Ewa
Zegarski, Wojciech
Tiensuu Janson, Eva
Ryś, Janusz
Tot, Tibor
Dumanski, Jan P.
Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
title Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
title_full Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
title_fullStr Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
title_full_unstemmed Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
title_short Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
title_sort signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579338/
https://www.ncbi.nlm.nih.gov/pubmed/26430163
http://dx.doi.org/10.1101/gr.187823.114
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