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Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer, and approximately 20% of screen-detected tumours are pure DCIS. Most risk factors for breast cancer have similar associations with DCIS and IDC; however, there is limited data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in DCIS and which women with DCIS should be referred for genetic screening.  The aim of this study was to assess the frequency of germline variants in  BRCA2 ,  BRCA1 ,  CHEK2 ,  PALB2  and  TP53  in DCIS in women aged less than 50 years of age.    Methods  After DNA extraction from the peripheral blood, Access Array technology (Fluidigm) was used to amplify all exons of these five known breast cancer predisposition genes using a custom made targeted sequencing panel in 655 cases of pure DCIS presenting in women under the age of 50 years together with 1611 controls.    Results  Case-control analysis revealed an excess of pathogenic variants in  BRCA2  (OR = 27.96, 95%CI 6.56–119.26,  P  = 2.0 × 10 −10 ) and  CHEK2  (OR = 8.04, 95%CI 2.93–22.05,  P  = 9.0 × 10 −6 ), with weaker associations with  PALB2  ( P  = 0.003),  BRCA1  ( P  = 0.007) and  TP53  ( P  = 0.02). For oestrogen receptor (ER)-positive DCIS the frequency of pathogenic variants was 9% under the age of 50 (14% with a family history of breast cancer) and 29% under the age of 40 (42% with a family history of breast cancer). For ER-negative DCIS, the frequency was 9% (16% with a family history of breast cancer) and 8% (11% with a family history of breast cancer) under the ages of 50 and 40, respectively.    Conclusions  This study has shown that breast tumourigenesis in women with pathogenic variants in  BRCA2 ,  CHEK2 ,  PALB2 ,  BRCA1  and  TP53  can involve a DCIS precursor stage and that the focus of genetic testing in DCIS should be on women under the age of 40 with ER-positive DCIS.    Electronic supplementary material  The online version of this article (10.1186/s13058-019-1143-y) contains supplementary material, which is available to authorized users.

breast cancer research

Frequency of pathogenic germline variants in BRCA1, BRCA2, PALB2, CHEK2 and TP53 in ductal carcinoma in situ diagnosed in women under the age of 50 years