Breast cancer risk is a perfect example of a multifactorial trait –– which these GEITP pages have continued to scrutinize and underscore importance. I still recall discovery of the BRCA1 gene (1994) when it was declared “THE breast cancer risk gene.” And within the year, the BRCA2 gene was identified. And some of us insisted “things might be much more complicated than what sees on the surface.” And they are. Now virtually everyone agrees that breast cancer risk is affected by rare coding single-nucleotide variants (SNVs) in susceptibility genes (i.e. BRCA1 and BRCA2) and hundreds if not thousands of common mostly non-coding SNVs. And most of the genetic contribution to breast cancer risk remains unknown.
In the attached report, authors describe results of a genome-wide association study (GWAS) of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. They identified 65 new loci that are associated with overall breast cancer risk at P <5.0 x 10–8. The majority of credible-risk single-nucleotide variants in these loci fall into distant regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, authors showed a strong overlap between candidate target genes and somatic driver genes ("somatic" = DNA in the body other than sperm or ovum DNA) in breast tumors. They also found that the heritability (proportion of total variation between individuals in a given population that reflects genetic variation) of breast cancer –– due to all SNVs in regulatory modules was enriched 2– to 5-fold, relative to the genome-wide average, with strong enrichment for particular transcription-factor-binding sites. These data provide further insight into genetic susceptibility to breast cancer risk and (although emphasizing the "increasing complexity" every time another larger cohort is studied by GWAS), perhaps these studies will improve the use of genetic risk scores for individualized screening and prevention of breast cancer. Nature 2 Nov 2o17; 551: 92–94