Family history and breast cancer susceptibility : clinical and molecular studies

Sammanfattning: 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 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. 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. 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. 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. 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. Three polymorphisms in the estrogen receptor