Prediction of BRCA1 and BRCA2 mutation status using post-irradiation assays of lymphoblastoid cell lines is compromised by inter-cell-line phenotypic variability

Lovelock, Paul K., Wong, Ee Ming, Sprung, Carl N., Marsh, Anna, Hobson, Karen, French, Juliet D., Southey, Melissa, kConFab Investigators, Sculley, Tom, Pandeya, Nirmala, Brown, Melissa A., Chenevix-Trench, Georgia, Spurdle, Amanda B. and McKay, Michael J. (2007) Prediction of BRCA1 and BRCA2 mutation status using post-irradiation assays of lymphoblastoid cell lines is compromised by inter-cell-line phenotypic variability. Breast Cancer Research and Treatment, 104 3: 257-266. doi:10.1007/s10549-006-9415-5


Author Lovelock, Paul K.
Wong, Ee Ming
Sprung, Carl N.
Marsh, Anna
Hobson, Karen
French, Juliet D.
Southey, Melissa
kConFab Investigators
Sculley, Tom
Pandeya, Nirmala
Brown, Melissa A.
Chenevix-Trench, Georgia
Spurdle, Amanda B.
McKay, Michael J.
Title Prediction of BRCA1 and BRCA2 mutation status using post-irradiation assays of lymphoblastoid cell lines is compromised by inter-cell-line phenotypic variability
Formatted title
Prediction of BRCA1 and BRCA2 mutation status using post-irradiation assays of lymphoblastoid cell lines is compromised by inter-cell-line phenotypic variability
Journal name Breast Cancer Research and Treatment   Check publisher's open access policy
ISSN 0167-6806
1573-7217
Publication date 2007-09-01
Year available 2007
Sub-type Article (original research)
DOI 10.1007/s10549-006-9415-5
Volume 104
Issue 3
Start page 257
End page 266
Total pages 10
Place of publication New York, NY, U.S.A.
Publisher Springer New York
Collection year 2008
Language eng
Subject C1
270299 Genetics not elsewhere classified
730108 Cancer and related disorders
Formatted abstract
Background and purpose: Assays to determine the pathogenicity of unclassified sequence variants in disease-associated genes include the analysis of lymphoblastoid cell lines (LCLs). We assessed the ability of several assays of LCLs to distinguish carriers of germline BRCA1 and BRCA2 gene mutations from mutation-negative controls to determine their utility for use in a diagnostic setting.

Materials and methods: Post-ionising radiation cell viability and micronucleus formation, and telomere length were assayed in LCLs carrying BRCA1 or BRCA2 mutations, and in unaffected mutation-negative controls.

Results: Post-irradiation cell viability and micronucleus induction assays of LCLs from individuals carrying pathogenic BRCA1 mutations, unclassified BRCA1 sequence variants or wildtype BRCA1 sequence showed significant phenotypic heterogeneity within each group. Responses were not consistent with predicted functional consequences of known pathogenic or normal sequences. Telomere length was also highly heterogeneous within groups of LCLs carrying pathogenic BRCA1 or BRCA2 mutations, and normal BRCA1 sequences, and was not predictive of mutation status.

Conclusion: Given the significant degree of phenotypic heterogeneity of LCLs after γ-irradiation, and the lack of association with BRCA1 or BRCA2 mutation status, we conclude that the assays evaluated in this study should not be used as a means of differentiating pathogenic and non-pathogenic sequence variants for clinical application. We suggest that a range of normal controls must be included in any functional assays of LCLs to ensure that any observed differences between samples reflect the genotype under investigation rather than generic inter-individual variation.
Keyword Oncology
lymphoblastoid
Cell lines
BRCA2
Post-IR metabolism
Epstein-Barr virus
Induced micronucleus frequencies
Peripheral-blood lymphocytes
Breast-cancer families
Mutagen sensitivity
Missense mutations
DNA-damage
Chromosomal radiosensitivity
Ionizing-radiation
Gene-expression
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 5 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 5 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Mon, 17 Mar 2008, 21:45:34 EST by Darryl Greensill on behalf of School of Chemistry & Molecular Biosciences