Genetic polymorphisms, IGF-1, and oral contraceptive use in women from high-risk breast cancer families

Maria Henningson

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Breast cancer is the most common cancer among Swedish women, affecting more than 7000 women each year. About 5-10% of all breast cancers are hereditary, with a monogenic inheritance pattern, but only 2-4% are explained by germline mutations in BRCA1 or BRCA2. BRCA1/BRCA2 mutation carriers have a 60-80% risk of developing breast cancer. Further, a large proportion of the breast cancers that are clustered in families are not associated with known disease-causing mutations. Those cases are likely to be explained by different combinations of low-penetrance genetic polymorphisms and exposure to other risk factors such as lifestyle, hormones, and high insulin-like growth factor 1 (IGF-1) levels. Such factors are also likely to influence the penetrance among high-risk women. Knowledge of which combinations of risk factors are important for the identification of women with high risk for early-onset breast cancer would allow more individualized risk assessments. For example, the absence of the common IGF1 19 CA-repeat allele in combination with oral contraceptive (OC) use has been associated with high IGF-1 levels. The aim of this thesis was to study genetic and non-genetic risk factors in women from high-risk breast cancer families.
In paper I, the variant allele (A2) of a SNP (rs743572) in the CYP17 gene was associated with short menstrual cycles and early OC use. The A2 allele was also more common among non-mutation carriers from BRCA1/2 mutation families.
In paper II, the absence of the common IGF1 19 CA-repeat allele was more common among BRCA1 mutation carriers than among non-carriers from BRCA1 families. This result confirms a previous finding of a smaller study.
In paper III, a three-way interaction between homozygous deletions of the GSTM1 and GSTT1 genes and OC use on IGF-1 levels was observed. Women who were lacking one, but not both, genes had the highest IGF-1 levels during OC use compared to OC users with either both genes deleted or both genes intact.
In paper IV, rare IGF1 diplotypes were associated with the absence of the common IGF1 19 CA-repeat allele, and they were more common among BRCA1 mutation carriers than other women from high-risk families. Rare diplotypes were also associated with breast cancer risk among all women and with an earlier age at first diagnosis of breast cancer among BRCA1 mutation carriers.
In conclusion, associations between genetic polymorphisms and other breast cancer risk factors need to be considered in future studies to understand their importance for breast cancer development and to improve current risk prediction models.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Breastcancer-genetics
Supervisors/Advisors
  • Jernström, Helena, Supervisor
  • Olsson, Håkan, Supervisor
  • Jönsson, Göran B, Supervisor
Award date2010 Nov 9
Publisher
ISBN (Print)978-91-86671-08-2
Publication statusPublished - 2010

Bibliographical note

Defence details

Date: 2010-11-09
Time: 09:00
Place: Segerfalk Lecture Hall, Wallenberg Neuroscience Center, Lund

External reviewer(s)

Name: Karlsson, Per
Title: Docent
Affiliation: Oncology, Institute of Clinical Sciences, the Sahlgrenska Academy, University of Gothenburg, Sweden

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Subject classification (UKÄ)

  • Cancer and Oncology

Keywords

  • familial breast cancer
  • premenopausal women
  • htSNP
  • GSTP1
  • polymorphism
  • BRCA1
  • BRCA2
  • IGF-1
  • oral contraceptives
  • CYP17
  • GSTT1
  • GSTM1

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