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Polymorphisms in DNA double-strand break repair genes: link with breast cancer susceptibility and in vitro chromosomal radiosensitivity.

Petra Willems (UGent)
(2009)
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Abstract
Breast cancer is one of the most common types of neoplasia in females in Western industrialised countries. In Belgium, breast cancer is the leading cause of death by cancer in females and the risk of being diagnosed with breast cancer before the age of 75 years in Belgium is 11.5 %. One of the strongest risk factors is a family history of the disease, indicating a genetic predisposition to breast cancer. However, only 6% of all breast cancer cases can be linked to monogenic, germline mutations in the breast cancer predisposing genes BRCA1, BRCA2, ATM, CHK2, PTEN and TP53. Epidemiological analyses suggest that the remaining breast cancer cases can be explained by a polygenic model that states that the combined effect of many individual weak genetic variants is responsible for an enhanced breast cancer risk. As enhanced in vitro chromosomal radiosensitivity is a hallmark for breast cancer and results from non‐ or misrepaired double strand breaks (DSBs), single nucleotide polymorphisms (SNPs) in DSB repair genes, could be involved in in vitro chromosomal radiosensitivity and genetic predisposition to breast cancer. Several population based case‐control studies have already shown a link between SNPs in DSB repair genes and breast cancer risk. Moreover, the breast is a selected micro‐environment, vulnerable to endogenous oxidative stress through hormone exposure. Especially oestrogen has attracted considerable attention, as it induces DSBs during its metabolism and may act as a complete carcinogen. In the studies presented in this thesis, we investigated whether SNPs in the core repair genes of DSBs are associated with an enhanced breast cancer susceptibility and/or in vitro chromosomal radiosensitivity. Genes from the two main DSB repair pathways were studied: Ku70, Ku80 and DNAPKCS of the non homologous end‐joining (NHEJ) pathway and RAD51, XRCC3, BRCA1 and BRCA2 of the homologous recombination (HR) pathway. The results demonstrate that the c.‐1310C>G SNP in the promoter region of Ku70 is significantly associated with breast cancer risk in an unselected patient population, comprising mainly of sporadic patients. Additionally, the combination of the variant “G” allele of this polymorphism with a hormonal breast cancer risk factor, reflecting susceptibility to oestrogen exposure, is associated with a more pronounced increase in breast cancer risk. The c.2099‐2408G>A SNP in Ku80 shows a positive association with breast cancer risk in a group of patients with a known or putative genetic predisposition to the disease. Both the c.‐1310C>G (Ku70) and c.2099‐2408G>A (Ku80) point‐variations can be considered risk alleles for breast cancer and they also show a positive association with chromosomal radiosensitivity. The combination of 2 or 4 putative high‐risk genotypes in RAD51 and XRCC3 resulted in a significant association with breast cancer risk in a patient population selected for a genetic predisposition, which is in agreement with the polygenic model for breast cancer initiation. Our results are also indicative of a modifying effect of SNPs in RAD51, XRCC3, BRCA1 and BRCA2 on breast cancer penetrance and phenotype in patients carrying a pathological mutation in BRCA1 or BRCA2. We also showed that the c.190T>C variation in the BRCA1 RING finger domain may induce modifications of the protein structure which could disrupt the BRCA1‐BARD1 interaction and hence predispose to breast cancer. The studies performed in the frame of this thesis contribute to the ongoing research concerning the genetic profiles associated with an enhanced breast cancer risk. A better understanding of the underlying genetic factors, responsible for breast cancer predisposition will improve our understanding of the mechanisms underlying breast cancer aetiology and this will influence the approach to breast cancer prevention and treatment.

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Citation

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MLA
Willems, Petra. “Polymorphisms in DNA Double-strand Break Repair Genes: Link with Breast Cancer Susceptibility and in Vitro Chromosomal Radiosensitivity.” 2009 : n. pag. Print.
APA
Willems, Petra. (2009). Polymorphisms in DNA double-strand break repair genes: link with breast cancer susceptibility and in vitro chromosomal radiosensitivity. Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium.
Chicago author-date
Willems, Petra. 2009. “Polymorphisms in DNA Double-strand Break Repair Genes: Link with Breast Cancer Susceptibility and in Vitro Chromosomal Radiosensitivity.” Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
Chicago author-date (all authors)
Willems, Petra. 2009. “Polymorphisms in DNA Double-strand Break Repair Genes: Link with Breast Cancer Susceptibility and in Vitro Chromosomal Radiosensitivity.” Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
Vancouver
1.
Willems P. Polymorphisms in DNA double-strand break repair genes: link with breast cancer susceptibility and in vitro chromosomal radiosensitivity. [Ghent, Belgium]: Ghent University. Faculty of Medicine and Health Sciences; 2009.
IEEE
[1]
P. Willems, “Polymorphisms in DNA double-strand break repair genes: link with breast cancer susceptibility and in vitro chromosomal radiosensitivity.,” Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium, 2009.
@phdthesis{3090712,
  abstract     = {{Breast cancer is one of the most common types of neoplasia in females in Western industrialised countries. In Belgium, breast cancer is the leading cause of death by cancer in females and the risk of being diagnosed with breast cancer before the age of 75 years in Belgium is 11.5 %. One of the strongest risk factors is a family history of the disease, indicating a genetic predisposition to breast cancer. However, only 6% of all breast cancer cases can be linked to monogenic, germline mutations in the breast cancer predisposing genes BRCA1, BRCA2, ATM, CHK2, PTEN and TP53. Epidemiological analyses suggest that the remaining breast cancer cases can be explained by a polygenic model that states that the combined effect of many individual weak genetic variants is responsible for an enhanced breast cancer risk. As enhanced in vitro chromosomal radiosensitivity is a hallmark for breast cancer and results from non‐ or misrepaired double strand breaks (DSBs), single nucleotide polymorphisms (SNPs) in DSB repair genes, could be involved in in vitro chromosomal radiosensitivity and genetic predisposition to breast cancer. Several population based case‐control studies have already shown a link between SNPs in DSB repair genes and breast cancer risk. Moreover, the breast is a selected micro‐environment, vulnerable to endogenous oxidative stress through hormone exposure. Especially oestrogen has attracted considerable attention, as it induces DSBs during its metabolism and may act as a complete carcinogen. In the studies presented in this thesis, we investigated whether SNPs in the core repair genes of DSBs are associated with an enhanced breast cancer susceptibility and/or in vitro chromosomal radiosensitivity. Genes from the two main DSB repair pathways were studied: Ku70, Ku80 and DNAPKCS of the non homologous end‐joining (NHEJ) pathway and RAD51, XRCC3, BRCA1 and BRCA2 of the homologous recombination (HR) pathway.
The results demonstrate that the c.‐1310C>G SNP in the promoter region of Ku70 is significantly associated with breast cancer risk in an unselected patient population, comprising mainly of sporadic patients. Additionally, the combination of the variant “G” allele of this polymorphism with a hormonal breast cancer risk factor, reflecting susceptibility to oestrogen exposure, is associated with a more pronounced increase in breast cancer risk. The c.2099‐2408G>A SNP in Ku80 shows a positive association with breast cancer risk in a group of patients with a known or putative genetic predisposition to the disease. Both the c.‐1310C>G (Ku70) and c.2099‐2408G>A (Ku80) point‐variations can be considered risk alleles for breast cancer and they also show a positive association with chromosomal radiosensitivity. The combination of 2 or 4 putative high‐risk genotypes in RAD51 and XRCC3 resulted in a significant association with breast cancer risk in a patient population selected for a genetic predisposition, which is in agreement with the polygenic model for breast cancer initiation. Our results are also indicative of a modifying effect of SNPs in RAD51, XRCC3, BRCA1 and BRCA2 on breast cancer penetrance and phenotype in patients carrying a pathological mutation in BRCA1 or BRCA2. We also showed that the c.190T>C variation in the BRCA1 RING finger domain may induce modifications of the protein structure which could disrupt the BRCA1‐BARD1 interaction and hence predispose to breast cancer. The studies performed in the frame of this thesis contribute to the ongoing research concerning the genetic profiles associated with an enhanced breast cancer risk. A better understanding of the underlying genetic factors, responsible for breast cancer predisposition will improve our understanding of the mechanisms underlying breast cancer aetiology and this will influence the approach to breast cancer prevention and treatment.}},
  author       = {{Willems, Petra}},
  language     = {{eng}},
  pages        = {{248}},
  publisher    = {{Ghent University. Faculty of Medicine and Health Sciences}},
  school       = {{Ghent University}},
  title        = {{Polymorphisms in DNA double-strand break repair genes: link with breast cancer susceptibility and in vitro chromosomal radiosensitivity.}},
  year         = {{2009}},
}