In:
Cancer Medicine, Wiley, Vol. 7, No. 4 ( 2018-04), p. 1349-1358
Abstract:
The prevalence of germ line mutations in non‐ BRCA 1/2 genes associated with hereditary breast cancer ( BC ) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA 1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes ( ATM , CDH 1 , CHEK 2 , NBN , PALB 2 , RAD 51C , RAD 51D, and TP 53 ). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK 2 gene (2.5%), followed by ATM (1.5%) and PALB 2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM ( OR : 3.63, 95% CI : 2.67–4.94), CDH 1 ( OR : 17.04, 95% CI : 3.54–82), CHEK 2 ( OR : 2.93, 95% CI : 2.29–3.75), PALB 2 ( OR : 9.53, 95% CI : 6.25–14.51), and TP 53 ( OR : 7.30, 95% CI : 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk ( OR :1.39, 95% CI : 0.73–2.64). Due to their low mutation prevalence, the RAD 51C and RAD 51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK 2 and TP 53 in BC index patients. Compared with the overall sample, only TP 53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK 2 , PALB 2, and TP 53 genes with bilateral BC . Both, ATM and CHEK 2 , were negatively associated with triple‐negative breast cancer ( TNBC ) and estrogen receptor ( ER )‐negative tumor phenotypes. A particularly high CHEK 2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 ( HER 2)‐positive tumors.
Type of Medium:
Online Resource
ISSN:
2045-7634
,
2045-7634
DOI:
10.1002/cam4.2018.7.issue-4
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2659751-2
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