Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium

Taru A Muranen; Carl Blomqvist; Thilo Dörk; Anna Jakubowska; Päivi Heikkilä; Rainer Fagerholm; Dario Greco; Kristiina Aittomäki; Stig E Bojesen; Mitul Shah; Alison M Dunning; Valerie Rhenius; Per Hall; Kamila Czene; Judith S Brand; Hatef Darabi; Jenny Chang-Claude; Anja Rudolph; Børge G Nordestgaard; Fergus J Couch; Steven N Hart; Jonine Figueroa; Montserrat García-Closas; Peter A Fasching; Matthias W Beckmann; Jingmei Li; Jianjun Liu; Irene L Andrulis; Robert Winqvist; Katri Pylkäs; Arto Mannermaa; Vesa Kataja; Annika Lindblom; Sara Margolin; Jan Lubinski; Natalia Dubrowinskaja; Manjeet K Bolla; Joe Dennis; Kyriaki Michailidou; Qin Wang; Douglas F Easton; Paul D P Pharoah; Marjanka K Schmidt; Heli Nevanlinna

doi:10.1186/s13058-016-0758-5

Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium

Taru A Muranen, Carl Blomqvist, Thilo Dörk, Anna Jakubowska, Päivi Heikkilä, Rainer Fagerholm, Dario Greco, Kristiina Aittomäki, Stig E Bojesen, Mitul Shah, Alison M Dunning, Valerie Rhenius, Per Hall, Kamila Czene, Judith S Brand, Hatef Darabi, Jenny Chang-Claude, Anja Rudolph, Børge G Nordestgaard, Fergus J CouchSteven N Hart, Jonine Figueroa, Montserrat García-Closas, Peter A Fasching, Matthias W Beckmann, Jingmei Li, Jianjun Liu, Irene L Andrulis, Robert Winqvist, Katri Pylkäs, Arto Mannermaa, Vesa Kataja, Annika Lindblom, Sara Margolin, Jan Lubinski, Natalia Dubrowinskaja, Manjeet K Bolla, Joe Dennis, Kyriaki Michailidou, Qin Wang, Douglas F Easton, Paul D P Pharoah, Marjanka K Schmidt, Heli Nevanlinna

Institut for Klinisk Medicin

19 Citationer (Scopus)

Abstract

BACKGROUND: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers.

METHODS: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature.

RESULTS: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors.

CONCLUSIONS: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.

Originalsprog	Engelsk
Artikelnummer	98
Tidsskrift	Breast Cancer Research (Online)
Vol/bind	18
Antal sider	15
ISSN	1465-5411
DOI	https://doi.org/10.1186/s13058-016-0758-5
Status	Udgivet - 3 okt. 2016

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10.1186/s13058-016-0758-5Licens: CC BY

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Muranen, T. A., Blomqvist, C., Dörk, T., Jakubowska, A., Heikkilä, P., Fagerholm, R., Greco, D., Aittomäki, K., Bojesen, S. E., Shah, M., Dunning, A. M., Rhenius, V., Hall, P., Czene, K., Brand, J. S., Darabi, H., Chang-Claude, J., Rudolph, A., Nordestgaard, B. G., ... Nevanlinna, H. (2016). Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium. Breast Cancer Research (Online), 18, [98]. https://doi.org/10.1186/s13058-016-0758-5

Muranen, TA, Blomqvist, C, Dörk, T, Jakubowska, A, Heikkilä, P, Fagerholm, R, Greco, D, Aittomäki, K, Bojesen, SE, Shah, M, Dunning, AM, Rhenius, V, Hall, P, Czene, K, Brand, JS, Darabi, H, Chang-Claude, J, Rudolph, A, Nordestgaard, BG, Couch, FJ, Hart, SN, Figueroa, J, García-Closas, M, Fasching, PA, Beckmann, MW, Li, J, Liu, J, Andrulis, IL, Winqvist, R, Pylkäs, K, Mannermaa, A, Kataja, V, Lindblom, A, Margolin, S, Lubinski, J, Dubrowinskaja, N, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Easton, DF, Pharoah, PDP, Schmidt, MK & Nevanlinna, H 2016, 'Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium', Breast Cancer Research (Online), bind 18, 98. https://doi.org/10.1186/s13058-016-0758-5

@article{2439c42fcbe64e6eab6ffa763b52079b,

title = "Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium",

abstract = "BACKGROUND: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers.METHODS: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature.RESULTS: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors.CONCLUSIONS: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.",

author = "Muranen, {Taru A} and Carl Blomqvist and Thilo D{\"o}rk and Anna Jakubowska and P{\"a}ivi Heikkil{\"a} and Rainer Fagerholm and Dario Greco and Kristiina Aittom{\"a}ki and Bojesen, {Stig E} and Mitul Shah and Dunning, {Alison M} and Valerie Rhenius and Per Hall and Kamila Czene and Brand, {Judith S} and Hatef Darabi and Jenny Chang-Claude and Anja Rudolph and Nordestgaard, {B{\o}rge G} and Couch, {Fergus J} and Hart, {Steven N} and Jonine Figueroa and Montserrat Garc{\'i}a-Closas and Fasching, {Peter A} and Beckmann, {Matthias W} and Jingmei Li and Jianjun Liu and Andrulis, {Irene L} and Robert Winqvist and Katri Pylk{\"a}s and Arto Mannermaa and Vesa Kataja and Annika Lindblom and Sara Margolin and Jan Lubinski and Natalia Dubrowinskaja and Bolla, {Manjeet K} and Joe Dennis and Kyriaki Michailidou and Qin Wang and Easton, {Douglas F} and Pharoah, {Paul D P} and Schmidt, {Marjanka K} and Heli Nevanlinna",

year = "2016",

month = oct,

day = "3",

doi = "10.1186/s13058-016-0758-5",

language = "English",

volume = "18",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium

AU - Muranen, Taru A

AU - Blomqvist, Carl

AU - Dörk, Thilo

AU - Jakubowska, Anna

AU - Heikkilä, Päivi

AU - Fagerholm, Rainer

AU - Greco, Dario

AU - Aittomäki, Kristiina

AU - Bojesen, Stig E

AU - Shah, Mitul

AU - Dunning, Alison M

AU - Rhenius, Valerie

AU - Hall, Per

AU - Czene, Kamila

AU - Brand, Judith S

AU - Darabi, Hatef

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Nordestgaard, Børge G

AU - Couch, Fergus J

AU - Hart, Steven N

AU - Figueroa, Jonine

AU - García-Closas, Montserrat

AU - Fasching, Peter A

AU - Beckmann, Matthias W

AU - Li, Jingmei

AU - Liu, Jianjun

AU - Andrulis, Irene L

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Lubinski, Jan

AU - Dubrowinskaja, Natalia

AU - Bolla, Manjeet K

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - Wang, Qin

AU - Easton, Douglas F

AU - Pharoah, Paul D P

AU - Schmidt, Marjanka K

AU - Nevanlinna, Heli

PY - 2016/10/3

Y1 - 2016/10/3

N2 - BACKGROUND: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers.METHODS: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature.RESULTS: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors.CONCLUSIONS: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.

AB - BACKGROUND: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers.METHODS: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature.RESULTS: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors.CONCLUSIONS: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.

U2 - 10.1186/s13058-016-0758-5

DO - 10.1186/s13058-016-0758-5

M3 - Journal article

C2 - 27716369

SN - 1465-5411

VL - 18

JO - Breast Cancer Research

JF - Breast Cancer Research

M1 - 98

ER -

Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium

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