Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital

Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


  1. Association Between Breastfeeding and Ovarian Cancer Risk

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Long-term Somatic Disease Risk in Adult Danish Cancer Survivors

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Self-reported and genetically predicted coffee consumption and smoking in dementia: A Mendelian randomization study

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Epigenetic regulation of F2RL3 associates with myocardial infarction and latelet function

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Chronic lymphocytic leukaemia clones are detectable decades before diagnosis

    Publikation: Bidrag til tidsskriftLetterForskningpeer review

  5. Rare germline copy number variants (CNVs) and breast cancer risk

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Nasim Mavaddat
  • Leila Dorling
  • Sara Carvalho
  • Jamie Allen
  • Anna González-Neira
  • Renske Keeman
  • Manjeet K Bolla
  • Joe Dennis
  • Qin Wang
  • Thomas U Ahearn
  • Irene L Andrulis
  • Matthias W Beckmann
  • Sabine Behrens
  • Javier Benitez
  • Marina Bermisheva
  • Carl Blomqvist
  • Natalia V Bogdanova
  • Stig E Bojesen
  • Ignacio Briceno
  • Thomas Brüning
  • Nicola J Camp
  • Archie Campbell
  • Jose E Castelao
  • Jenny Chang-Claude
  • Stephen J Chanock
  • Georgia Chenevix-Trench
  • Hans Christiansen
  • Kamila Czene
  • Thilo Dörk
  • Mikael Eriksson
  • D Gareth Evans
  • Peter A Fasching
  • Jonine D Figueroa
  • Henrik Flyger
  • Marike Gabrielson
  • Manuela Gago-Dominguez
  • Jürgen Geisler
  • Graham G Giles
  • Pascal Guénel
  • Andreas Hadjisavvas
  • Eric Hahnen
  • Per Hall
  • Ute Hamann
  • Jaana M Hartikainen
  • Mikael Hartman
  • Reiner Hoppe
  • Anthony Howell
  • Anna Jakubowska
  • Audrey Jung
  • Elza K Khusnutdinova
  • Breast Cancer Association Consortium
Vis graf over relationer

Importance: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction.

Objective: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies.

Design, Setting, and Participants: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021.

Exposures: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.

Main Outcomes and Measures: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes.

Results: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger.

Conclusions and Relevance: The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

TidsskriftJAMA Oncology
Udgave nummer3
Sider (fra-til)e216744
StatusUdgivet - 1 mar. 2022

ID: 73387266