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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

Research output: Contribution to journalArticle

Christos Petridis, Iteeka Arora, Vandna Shah, Anargyros Megalios, Charlotte Moss, Anca Mera, Angela Clifford, Sarah E Pinder, Ian Tomlinson, Rebecca Roylance, Michael A Simpson, Elinor J Sawyer

Original languageEnglish
JournalBreast Cancer Research
Publication statusAccepted/In press - 16 Apr 2019

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Abstract

Introduction: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer and approximately 20% of screen-detected tumors 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 peripheral blood, Access Array technology (Fluidigm) was used to amplify all exons of these six 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 1,611 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 x10-10) and CHEK2 (OR = 8.04, 95%CI 2.93-22.05, P = 9.0 x10-6), with weaker associations with PALB2 (P = 0.003), BRCA1 (P = 0.007) and TP53 (P = 0.02). For estrogen 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 age of 50 and 40 respectively.
Conclusions: This study has shown that breast tumorigenesis 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.

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