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

Abstract

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. 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.

Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients

“…Observed frequencies of these mutations are not inconsistent with those in the general population. For example, the frequency of BRCA1 pathogenic variants in healthy non-Finnish European controls in gnomAD is 0.38% (81 of 21,384) compared to 0.25% in our cohort 23 .…”

Risk of invasive breast cancer in relatives of patients with breast carcinoma in situ: a prospective cohort study

“…Similar genetic variants have been shown to predispose to increased risk of both in situ and invasive breast cancer [26]. A study among Japanese women found a similar prevalence of high penetrance BRCA1/2 variants in women with invasive and breast carcinoma in situ [27].…”

Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer

“…In patients with nonclonally related recurrences, the major question is what factors constituted the basis of risk in these women who developed two clonally different cancers in the same breast over time. We can speculate that such cases may be due to genetic predisposition as there is clear evidence that the known invasive breast cancer predisposition genes and polymorphisms also predispose to DCIS, particularly ER+ DCIS 16 , 17 . However, the limited data on rare germline variants in this study does not support this theory.…”