Family history and breast cancer susceptibility : clinical and molecular studies

<p>Apart from gender, family history is the most important risk factor for breast cancer. In 5-10 % of the cases there is a family history pattern of an autosomal dominant disease and there is also a familial clustering of breast cancer associated with a more modest increased risk of the disease. Mutations in the known high risk genes BRCA1, BRCA2 and p53 account for less than 25% of the familial risk for breast cancer, while the remainder remain genetically unexplained despite a large effort in research. A polygenic model has been proposed to best explain the residual familial breast cancer risk and also to contribute to sporadic breast cancer susceptibility in interaction with environmental factors.</p><p>In order to further elucidate the impact of genetic susceptibility for familial and sporadic breast cancer, a population-basect-cohort of 489 breast cancer patients from southern Stockholm was collected. For all patients, information on family history, clinical data and 5 years follow-up was retrieved. In addition, a riskcohort of 350 non-BRCA1/2 familial patients from the Stockholm region were used for these studies.</p><p>In total 32% of the patients in the population-based cohort reported a family history of breast cancer and 10% was defined a high-risk familial group. There was no relation between family history and age of onset, hormonal background, tumour characteristics, treatment or prognosis.</p><p>The population-based cohort was screened for mutations in BRCA I (exon 11). Two mutations.(< 1 %) were detected, both in cases with a family history of both breast and ovarian cancer.</p><p>Sporadic (n=313) and familial (n=387) breast cancer cases and controls (n=760) were screened for the rare truncating variant, CHEK2 1100delC, which has previously been shown to be associated with familial and unselected breast cancer. Of the familial patients 2.3% carried the variant compared to 0.7% of the controls. The prevalence was not increased in sporadic patients (0.3%), The variant seemed to influence age at onset, with a lower mean age in carriers than in non-carriers.</p><p>Analysis of a common single single nucleotide polymorphism orphism, C975G, in the estrogen In receptor a (ESR1) gene in 288 sporadic, 197 low risk and 191 high risk non BRCA1/2 familial breast cancer suggested a protective effect of the variant allele in high-risk familial breast cancer compared to controls. No association was seen in low risk familial or sporadic cases.</p><p>Three polymorphisms in the estrogen receptor â (ESR2) gene were analysed for association wi h familial and sporadic breast cancer. In total 723 breast cancer cases were genotyped, 323 sporadic cases and 400 non-BRCA1/2 familial cases. There was no overall significant difference in genotype distribution but one common haplotype .pc, G-A-G, was associated with an increased risk of sporadic breast cancer indicating a role for ER,â in breast cancer susceptibility.</p><h3>List of scientific papers</h3><p>I. Margolin S, Johansson H, Rutqvist LE, Lindblom A, Fornander T (2006). Family History, and Impact on Clinical Presentation and Prognosis, in a Population-based Breast Cancer Cohort from the Stockholm County. Fam Cancer. [Accepted] <br><a href="https://pubmed.ncbi.nlm.nih.gov/16858627">https://pubmed.ncbi.nlm.nih.gov/16858627</a><br><br> </p><p>II. Margolin S, Werelius B, Fornander T, Lindblom A (2004). BRCA1 mutations in a population-based study of breast cancer in Stockholm County. Genet Test. 8(2): 127-32. <br><a href="https://pubmed.ncbi.nlm.nih.gov/15345109">https://pubmed.ncbi.nlm.nih.gov/15345109</a><br><br> </p><p>III. Margolin S, Eiberg H, Lindblom A, Bisgaard ML (2006). CHEK2 1100delC in Swedish familial and sporadic breast cancer. [Submitted]</p><p>IV. Skoglund J, Margolin S, Zhou XL, Maguire P, Werelius B, Lindblom A (2006). The estrogen receptor alpha C975G variant in familial and sporadic breast cancer: a case-control study. Anticancer Res. 26(48): 3077-81. <br><a href="https://pubmed.ncbi.nlm.nih.gov/16886637">https://pubmed.ncbi.nlm.nih.gov/16886637</a><br><br></p><p>V. Maguire P, Margolin S, Skoglund J, Sun XF, Gustafsson JA, Borresen-Dale AL, Lindblom A (2005). Estrogen Receptor Beta (ESR2) Polymorphisms in Familial and Sporadic Breast Cancer. Breast Cancer Res Treat. 94(2): 145-52. <br><a href="https://pubmed.ncbi.nlm.nih.gov/16261413">https://pubmed.ncbi.nlm.nih.gov/16261413</a><br><br> </p>