Investigation on the genetic susceptibility and causes of breast cancer onset age provide novel insights into early-onset breast cancer aetiology — The Association Specialists
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  3. Investigation on the genetic susceptibility and causes of breast cancer onset age provide novel insights into early-onset breast cancer aetiology

Investigation on the genetic susceptibility and causes of breast cancer onset age provide novel insights into early-onset breast cancer aetiology (24176)

Shuhan Peng 1 , Vicki Jackson 2 , Karen Alpen 1 , Melissa Southey 3 , Shuai Li 1
  1. Centre of Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, Australia
  2. Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  3. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC, Australia

Background:

Although over 200 common genetic variants have been found to be associated with breast cancer risk, these variants largely explain the genetic susceptibility to later-onset disease. A substantial familial risk of early-onset breast cancer (EOBC) remains unexplained. We aimed to investigate the genetic susceptibility and causal risk factors for breast cancer onset age (BCA) to provide insights into the aetiology of EOBC.

Methods:

We performed a multi-ancestry GWAS of BCA adjusting for index event bias in 130,531 breast cancer patients (median BCA: 56). For ~50,000 traits, we conducted: (1) linkage disequilibrium score regression (LDSC) and genomic network analysis to estimate genetic correlations with BCA; and (2) two-sample Mendelian randomisation (MR) and mediation analysis to assess their causal associations.

Results:

BCA had a SNP-based heritability of 3.7% (95%CI: 2.69%, 4.73%). We identified nine susceptibility loci, explaining 9.2% of the heritability. The strongest association was for CHEK2 gene (beta=-1.70; 95%CI: -2.17, -1.23). All loci have been associated previously with breast cancer risk. LDSC found 39 genetically correlated traits (FDR<0.05), with mother’s age at death showing the strongest positive correlation (rg=0.50; 95% CI: 0.29, 0.66) and knee joint operation the strongest negative correlation (rg=-0.47; 95% CI: -0.68, -0.20). MR analyses identified 22 traits (eight positive), two with robust evidence. Four traits including age at first childbirth (AFB), parental longevity, college/university completion and years of schooling were identified by both analyses, all showing positive correlations/associations. AFB mediated the causal associations of education attainment. Consistently, the genetic correlation between educational attainment and BCA became null after conditioning on AFB.

Conclusions:

We identified multiple genetic loci and causal risk factors for BCA, with valuable insights into the aetiology of EOBC. Our findings imply that the rising incidence of EOBC is unlikely to be driven by the delayed AFB and increased educational attainment in young women.