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

Autor: Cheryl Gillett, Vandna Shah, Michael A. Simpson, Anca Mera, Angela Clifford, Iteeka Arora, Rebecca Roylance, Christos Petridis, Sarah E Pinder, Ian Tomlinson, Anargyros Megalios, Elinor J. Sawyer, Charlotte Moss
Rok vydání: 2019
Předmět:
Oncology
Germline variants
0302 clinical medicine
Gene Frequency
TP53
Family history
skin and connective tissue diseases
medicine.diagnostic_test
BRCA1 Protein
Age Factors
High-Throughput Nucleotide Sequencing
Middle Aged
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Penetrance
Risk factors for breast cancer
030220 oncology & carcinogenesis
Female
Research Article
Adult
medicine.medical_specialty
DNA Copy Number Variations
Genotype
PALB2
Breast Neoplasms
lcsh:RC254-282
03 medical and health sciences
Breast cancer
Internal medicine
Biomarkers
Tumor
medicine
Humans
neoplasms
CHEK2
Germ-Line Mutation
Genetic testing
BRCA2 Protein
business.industry
Ductal carcinoma in situ
Computational Biology
Ductal carcinoma
BRCA1
medicine.disease
BRCA2
Checkpoint Kinase 2
Carcinoma
Intraductal
Noninfiltrating
Case-Control Studies
Neoplasm Grading
Tumor Suppressor Protein p53
business
Zdroj: Petridis, C, Arora, I, Shah, V, Megalios, A, Moss, C, Mera, A, Clifford, A, Gillett, C, Pinder, S E, Tomlinson, I P, 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, vol. 21, no. 1 . https://doi.org/10.1186/s13058-019-1143-y
Breast Cancer Research : BCR
Breast Cancer Research, Vol 21, Iss 1, Pp 1-10 (2019)
Petridis, C, Arora, I, Shah, V, Megalios, A, Moss, C, Mera, A, Clifford, A, 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, vol. 21, 58 . https://doi.org/10.1186/s13058-019-1143-y
ISSN: 1465-542X
DOI: 10.1186/s13058-019-1143-y
Popis: 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.
Databáze: OpenAIRE
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