Genetic modifiers of CHEK2-associated and familial breast cancer

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

In Western countries lifetime risk of breast cancer is about 10%; one in every ten women will develop the disease. Susceptibility mutations and positive family history increase the risk. For example, a woman with a mutation in one of the high-risk genes, BRCA1 or BRCA2, has about 70% lifetime risk, but for a BRCA1/2-carrier woman with an affected first-degree relative the risk is even higher. This study focused on two recurrent breast cancer predisposing CHEK2 variants. C.1100delC is a moderate penetrance mutation associated with about 20% lifetime risk in general population, but with upwards of 30% risk in breast cancer families. On the contrary, P.(I157T) is a low penetrance variant without clinical applicability alone. This study aimed to clarify, whether common genetic variation could be used in risk stratification of CHEK2 mutation carriers or women with positive family history of breast cancer. Further aims included investigating the applicability of CHEK2 mutations in patient prognosis estimation and characterization of the molecular profiles of breast tumors from carriers of CHEK2 mutations. Genome-wide association analyses have identified multiple common genetic variants, which account for individual variation in breast cancer risk. The effects associated with these variants can be summarized into a polygenic risk score (PRS). In collaboration with the Breast Cancer Association Consortium (BCAC), we have investigated the synergistic breast cancer risk conferred by CHEK2 c.1100delC and a PRS of 75 variants. Furthermore, using data from 52 Finnish breast cancer families, we have evaluated the applicability of the PRS for genetic counseling of Finnish women with positive family history of breast cancer. Our analyses indicate that PRS could be used in identifying some CHEK2 carriers and women with positive family history, whose lifetime risk exceeds the 30-40% threshold for intensive screening and prevention. C.1100delC has been suggested to be associated with poor prognosis after breast cancer diagnosis. According to our analyses based on the BCAC data, there is a significant difference in the survival of breast cancer patients carrying the two CHEK2 mutations: c.1100delC is a marker for poor prognosis, whereas the survival of p.(I157T) carriers does not differ from patients without any CHEK2 mutations. The characterization of breast tumors from patients carrying either c.1100delC or p.(I157T) suggested a novel hypothesis that the two mutations may have different roles in the development of breast cancer. The genetic instability and mutability caused by germline c.1100delC appears to be a central factor driving the breast cancer progression. On the contrary, p.(I157T) carrier breast cancers may often have a CHEK2-independent origin, and p.(I157T) is only a factor accelerating the cancer progression.
Original languageEnglish
Supervisors/Advisors
  • Nevanlinna, Heli, Supervisor
  • Greco, Dario, Supervisor
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-4503-1
Electronic ISBNs978-951-51-4504-8
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • Breast Neoplasms
  • +genetics
  • Genes, BRCA2
  • Genes, BRCA1
  • BRCA1 Protein
  • Checkpoint Kinase 2
  • Genetic Predisposition to Disease
  • Risk Assessment
  • Genome-Wide Association Study
  • Penetrance
  • Prognosis
  • Genetic Markers
  • Female
  • 3123 Gynaecology and paediatrics
  • 3111 Biomedicine
  • 1184 Genetics, developmental biology, physiology
  • 3122 Cancers

Cite this

@phdthesis{e878b44de16b48a5a1d74677826b8d52,
title = "Genetic modifiers of CHEK2-associated and familial breast cancer",
abstract = "In Western countries lifetime risk of breast cancer is about 10{\%}; one in every ten women will develop the disease. Susceptibility mutations and positive family history increase the risk. For example, a woman with a mutation in one of the high-risk genes, BRCA1 or BRCA2, has about 70{\%} lifetime risk, but for a BRCA1/2-carrier woman with an affected first-degree relative the risk is even higher. This study focused on two recurrent breast cancer predisposing CHEK2 variants. C.1100delC is a moderate penetrance mutation associated with about 20{\%} lifetime risk in general population, but with upwards of 30{\%} risk in breast cancer families. On the contrary, P.(I157T) is a low penetrance variant without clinical applicability alone. This study aimed to clarify, whether common genetic variation could be used in risk stratification of CHEK2 mutation carriers or women with positive family history of breast cancer. Further aims included investigating the applicability of CHEK2 mutations in patient prognosis estimation and characterization of the molecular profiles of breast tumors from carriers of CHEK2 mutations. Genome-wide association analyses have identified multiple common genetic variants, which account for individual variation in breast cancer risk. The effects associated with these variants can be summarized into a polygenic risk score (PRS). In collaboration with the Breast Cancer Association Consortium (BCAC), we have investigated the synergistic breast cancer risk conferred by CHEK2 c.1100delC and a PRS of 75 variants. Furthermore, using data from 52 Finnish breast cancer families, we have evaluated the applicability of the PRS for genetic counseling of Finnish women with positive family history of breast cancer. Our analyses indicate that PRS could be used in identifying some CHEK2 carriers and women with positive family history, whose lifetime risk exceeds the 30-40{\%} threshold for intensive screening and prevention. C.1100delC has been suggested to be associated with poor prognosis after breast cancer diagnosis. According to our analyses based on the BCAC data, there is a significant difference in the survival of breast cancer patients carrying the two CHEK2 mutations: c.1100delC is a marker for poor prognosis, whereas the survival of p.(I157T) carriers does not differ from patients without any CHEK2 mutations. The characterization of breast tumors from patients carrying either c.1100delC or p.(I157T) suggested a novel hypothesis that the two mutations may have different roles in the development of breast cancer. The genetic instability and mutability caused by germline c.1100delC appears to be a central factor driving the breast cancer progression. On the contrary, p.(I157T) carrier breast cancers may often have a CHEK2-independent origin, and p.(I157T) is only a factor accelerating the cancer progression.",
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author = "Muranen, {Taru A.}",
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year = "2018",
language = "English",
isbn = "978-951-51-4503-1",
series = "Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis",
publisher = "Helsingin yliopisto",
number = "61/2018",
address = "Finland",

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Genetic modifiers of CHEK2-associated and familial breast cancer. / Muranen, Taru A.

Helsinki : Helsingin yliopisto, 2018. 94 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Genetic modifiers of CHEK2-associated and familial breast cancer

AU - Muranen, Taru A.

N1 - M1 - 94 s. + liitteet

PY - 2018

Y1 - 2018

N2 - In Western countries lifetime risk of breast cancer is about 10%; one in every ten women will develop the disease. Susceptibility mutations and positive family history increase the risk. For example, a woman with a mutation in one of the high-risk genes, BRCA1 or BRCA2, has about 70% lifetime risk, but for a BRCA1/2-carrier woman with an affected first-degree relative the risk is even higher. This study focused on two recurrent breast cancer predisposing CHEK2 variants. C.1100delC is a moderate penetrance mutation associated with about 20% lifetime risk in general population, but with upwards of 30% risk in breast cancer families. On the contrary, P.(I157T) is a low penetrance variant without clinical applicability alone. This study aimed to clarify, whether common genetic variation could be used in risk stratification of CHEK2 mutation carriers or women with positive family history of breast cancer. Further aims included investigating the applicability of CHEK2 mutations in patient prognosis estimation and characterization of the molecular profiles of breast tumors from carriers of CHEK2 mutations. Genome-wide association analyses have identified multiple common genetic variants, which account for individual variation in breast cancer risk. The effects associated with these variants can be summarized into a polygenic risk score (PRS). In collaboration with the Breast Cancer Association Consortium (BCAC), we have investigated the synergistic breast cancer risk conferred by CHEK2 c.1100delC and a PRS of 75 variants. Furthermore, using data from 52 Finnish breast cancer families, we have evaluated the applicability of the PRS for genetic counseling of Finnish women with positive family history of breast cancer. Our analyses indicate that PRS could be used in identifying some CHEK2 carriers and women with positive family history, whose lifetime risk exceeds the 30-40% threshold for intensive screening and prevention. C.1100delC has been suggested to be associated with poor prognosis after breast cancer diagnosis. According to our analyses based on the BCAC data, there is a significant difference in the survival of breast cancer patients carrying the two CHEK2 mutations: c.1100delC is a marker for poor prognosis, whereas the survival of p.(I157T) carriers does not differ from patients without any CHEK2 mutations. The characterization of breast tumors from patients carrying either c.1100delC or p.(I157T) suggested a novel hypothesis that the two mutations may have different roles in the development of breast cancer. The genetic instability and mutability caused by germline c.1100delC appears to be a central factor driving the breast cancer progression. On the contrary, p.(I157T) carrier breast cancers may often have a CHEK2-independent origin, and p.(I157T) is only a factor accelerating the cancer progression.

AB - In Western countries lifetime risk of breast cancer is about 10%; one in every ten women will develop the disease. Susceptibility mutations and positive family history increase the risk. For example, a woman with a mutation in one of the high-risk genes, BRCA1 or BRCA2, has about 70% lifetime risk, but for a BRCA1/2-carrier woman with an affected first-degree relative the risk is even higher. This study focused on two recurrent breast cancer predisposing CHEK2 variants. C.1100delC is a moderate penetrance mutation associated with about 20% lifetime risk in general population, but with upwards of 30% risk in breast cancer families. On the contrary, P.(I157T) is a low penetrance variant without clinical applicability alone. This study aimed to clarify, whether common genetic variation could be used in risk stratification of CHEK2 mutation carriers or women with positive family history of breast cancer. Further aims included investigating the applicability of CHEK2 mutations in patient prognosis estimation and characterization of the molecular profiles of breast tumors from carriers of CHEK2 mutations. Genome-wide association analyses have identified multiple common genetic variants, which account for individual variation in breast cancer risk. The effects associated with these variants can be summarized into a polygenic risk score (PRS). In collaboration with the Breast Cancer Association Consortium (BCAC), we have investigated the synergistic breast cancer risk conferred by CHEK2 c.1100delC and a PRS of 75 variants. Furthermore, using data from 52 Finnish breast cancer families, we have evaluated the applicability of the PRS for genetic counseling of Finnish women with positive family history of breast cancer. Our analyses indicate that PRS could be used in identifying some CHEK2 carriers and women with positive family history, whose lifetime risk exceeds the 30-40% threshold for intensive screening and prevention. C.1100delC has been suggested to be associated with poor prognosis after breast cancer diagnosis. According to our analyses based on the BCAC data, there is a significant difference in the survival of breast cancer patients carrying the two CHEK2 mutations: c.1100delC is a marker for poor prognosis, whereas the survival of p.(I157T) carriers does not differ from patients without any CHEK2 mutations. The characterization of breast tumors from patients carrying either c.1100delC or p.(I157T) suggested a novel hypothesis that the two mutations may have different roles in the development of breast cancer. The genetic instability and mutability caused by germline c.1100delC appears to be a central factor driving the breast cancer progression. On the contrary, p.(I157T) carrier breast cancers may often have a CHEK2-independent origin, and p.(I157T) is only a factor accelerating the cancer progression.

KW - Breast Neoplasms

KW - +genetics

KW - Genes, BRCA2

KW - Genes, BRCA1

KW - BRCA1 Protein

KW - Checkpoint Kinase 2

KW - Genetic Predisposition to Disease

KW - Risk Assessment

KW - Genome-Wide Association Study

KW - Penetrance

KW - Prognosis

KW - Genetic Markers

KW - Female

KW - 3123 Gynaecology and paediatrics

KW - 3111 Biomedicine

KW - 1184 Genetics, developmental biology, physiology

KW - 3122 Cancers

M3 - Doctoral Thesis

SN - 978-951-51-4503-1

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - Helsingin yliopisto

CY - Helsinki

ER -

Muranen TA. Genetic modifiers of CHEK2-associated and familial breast cancer. Helsinki: Helsingin yliopisto, 2018. 94 p. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 61/2018).