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\u2009years

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

doi:10.1186/s13058-019-1143-y

Christos Petridis, Anca Mera + Show 11 more

Open Access

https://doi.org/10.1186/s13058-019-1143-y

Copy DOI

Abstract

IntroductionDuctal 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.MethodsAfter 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.ResultsCase-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.ConclusionsThis 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.

Highlights

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
One study of almost 40,000 women suggested that the familial relative risk of DCIS may be greater than that of invasive breast cancer [10], but this was not confirmed in the Million Women Study, which showed a similar association with family history for DCIS and Invasive ductal cancer (IDC) [8]
We report the frequency of rare variants in five known breast cancer predisposition genes (BRCA2, BRCA1, TP53, CHEK2 and PALB2) in 655 cases of pure DCIS with no invasive disease in women diagnosed before the age of 50

Summary

Introduction

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. Ductal carcinoma in situ (DCIS) is considered a non-obligate precursor of invasive breast cancer of ductal/no special type (IDC) as many IDCs have evidence of associated DCIS at presentation [1, 2] and the two components have similar genetic changes, suggesting that in the majority of cases the invasive component has arisen from the DCIS [3]. Most non-genetic risk factors for breast cancer have similar associations with DCIS and IDC, again supporting the notion that DCIS is a precursor of invasive cancer [7, 8]. One study of almost 40,000 women suggested that the familial relative risk of DCIS may be greater than that of invasive breast cancer [10], but this was not confirmed in the Million Women Study, which showed a similar association with family history for DCIS and IDC [8]

Objectives

Methods

Results

Discussion

Conclusion