Genetic studies in familial non-BRCA breast cancer

• Family history is an important risk factor for breast cancer, the presence of breast cancer in a first degree relative in general nearly doubles the risk and the risk increases with the number of affected relatives. Pathogenic mutations in BRCA1, BRCA2 and other high- and moderate risk-genes account for 25% of the familial risk for breast cancer. About 180 low-risk variants explain an additional 18% of the excess familial risk. The remainder of the genetic contribution to familial breast cancer is unexplained. A polygenic model, where pathogenic mutations with differential impact together confer an increased risk for breast cancer, has been suggested. The aim of this thesis has been to study and better understand how breast cancer is inherited and to identify underlying genetic factors that contribute to the risk in familial breast cancer without pathogenic mutations in BRCA1 or BRCA2 (non-BRCA families). In paper I tumour spectrum was investigated in our cohort of non-BRCA families with at least 2 cases of breast cancer and one case of other tumour type in first-, second degree relatives or first cousins. Distribution of tumour types, other than breast cancer, was compared with the distribution in Sweden in two reference years. We found an overrepresentation of endometrial cancer in the non-BRCA families with a 6.36 % proportion (CI 4.67–8.2) compared to the proportion in the general population in the reference years 1970 (3.07 %) and 2010 (2.64 %). The main finding of the study was the strong support for a breast- and endometrial cancer syndrome, which is a first step towards detecting new susceptibility variants. In paper II we investigated if breast cancer prognosis is affected by parent-of-origin in our cohort of non-BRCA families. A difference in prognosis may indicate an influence of a genetic mechanism that produces inter-lineage effects, such as genomic imprinting. No significant difference in overall or recurrence-free survival between maternal and paternal inheritance of breast cancer was observed with HRs of 0.99 (95% CI=0.54 to 1.80) and 1.22 (95% CI=0.78 to 1.92) respectively. An interesting finding in paper II was the predominance of maternally inherited cases, which indicates that parent-of-origin may not have an effect on breast cancer prognosis, but rather the risk of being affected. The protein truncating mutation CHEK2*1100delC is a moderate-risk variant associated with a 2-3 fold increased risk of developing breast cancer, but the risk is considerably higher in carriers with a family history. The individual risk for breast cancer in carriers of CHEK2*1100delC is thereby difficult to predict. In paper III we performed whole-exome sequencing in cases of CHEK2*1100delC carriers in search of genetic variants that may modify breast cancer risk in this patient group. All non-synonymous mutations were evaluated and 11 candidate alleles were selected and tested in a validation. No CHEK2 specific modifier could be identified though, as none of the variants showed significant difference in allele frequency in CHEK2*1100delC carriers compared to controls. Continuous studies of genetic modifiers are of importance to improve breast cancer risk prediction for CHEK2*1100delC carriers.

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