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

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

doi:10.1186/s13058-019-1143-y

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

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

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

223 Downloads (Pure)

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.

Original language	English
Article number	58
Number of pages	10
Journal	Breast Cancer Research
Volume	21
Issue number	1
DOIs	https://doi.org/10.1186/s13058-019-1143-y
Publication status	Published - 6 May 2019

Keywords

Germline variants
BRCA2
CHEK2
PALB2
BRCA1
TP53
Ductal carcinoma in situ

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s13058-019-1143-yLicence: Creative Commons: Attribution (CC BY)

Christos_Petridis_et_al_Frequency_of_pathogenic_germline_variants_in_BRCA1,_BRCA2,_PALB2,_CHEK2_and_TP53_in_ductal_carcinoma_Breast_Cancer_Research_2019
Checked for eligibility: 23/05/2019
Final published version, 753 KBLicence: Creative Commons: Attribution (CC BY)

Cite this

Petridis, C., Arora, I., Shah, V., Megalios, A., Moss, C., Mera, A., Clifford, A., Gillett, C., Pinder, S. E., Tomlinson, I., Roylance, R., Simpson, M. A., & Sawyer, E. J. (2019). 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. Breast Cancer Research, 21(1), Article 58. https://doi.org/10.1186/s13058-019-1143-y

@article{15adc89ee8a74e0b8612858b97cb6b6f,

title = "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.",

keywords = "Germline variants, BRCA2, CHEK2, PALB2, BRCA1, TP53, Ductal carcinoma in situ",

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

year = "2019",

month = may,

day = "6",

doi = "10.1186/s13058-019-1143-y",

language = "English",

volume = "21",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "Springer",

number = "1",

}

Petridis, C, Arora, I, Shah, V, Megalios, A, Moss, C, Mera, A, Clifford, A, Gillett, C, Pinder, SE, Tomlinson, I, Roylance, R, Simpson, MA & Sawyer, EJ 2019, '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', Breast Cancer Research, vol. 21, no. 1, 58. https://doi.org/10.1186/s13058-019-1143-y

TY - JOUR

T1 - 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

AU - Petridis, Christos

AU - Arora, Iteeka

AU - Shah, Vandna

AU - Megalios, Anargyros

AU - Moss, Charlotte

AU - Mera, Anca

AU - Clifford, Angela

AU - Gillett, Cheryl

AU - Pinder, Sarah E

AU - Tomlinson, Ian

AU - Roylance, Rebecca

AU - Simpson, Michael A

AU - Sawyer, Elinor J

PY - 2019/5/6

Y1 - 2019/5/6

N2 - 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.

AB - 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.

KW - Germline variants

KW - BRCA2

KW - CHEK2

KW - PALB2

KW - BRCA1

KW - TP53

KW - Ductal carcinoma in situ

U2 - 10.1186/s13058-019-1143-y

DO - 10.1186/s13058-019-1143-y

M3 - Article

C2 - 31060593

SN - 1465-5411

VL - 21

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 1

M1 - 58

ER -