Breast cancer is the most common cancer among women in the United States, accounting for 15% of all new cancer cases. An estimated 15% to 30% of breast cancer cases are heritable or due to underlying genetic transmission, but the genetic alterations accounting for these breast cancers are not fully defined . Mutations in dominant high and moderate penetrance breast cancer susceptibility genes, such as BRCA1, BRCA2, PALB2, ATM, and CHEK2 have been identified in 5% of breast cancer cases in the general population and only 30%-40% of cases associated with a family history of breast cancer .Over the last decade, efforts to explain the missing heritability of breast cancer have focused on discovery of other moderate and high-risk genes as well as identification of common genetic variants. Investigations of common variants by genome-wide association studies (GWAS) have successfully identified many genetic loci that are associated with breast cancer risk, and explain up to 18% heritability, suggesting that breast cancer is a complex, polygenic disease. Early investigations of common genetic risk factors for breast cancer focused on candidate gene and candidate variant studies using hundreds of breast cancer cases and unaffected controls. The majority of candidate variants associated with breast cancer in these studies have subsequently failed replication and have therefore been excluded as risk factors for breast cancer . Only a coding variant (D302H) in the caspase 8 gene (CASP8) has consistently shown associations with breast cancer, and ongoing studies have recently identified multiple independent risk–associated signals in this locus (Soon after the groundbreaking publication by Easton and colleagues, additional evidence quickly accumulated implicating the FGFR2 locus in breast cancer risk . A study by CGEMS showed an increased risk of breast cancer associated with rs1219648 (in high LD with rs2981582) and a related haplotype in FGFR2 in Caucasian postmenopausal women (11). In addition, the FGFR2 rs2981582 SNP was more strongly associated with ER-positive than ER-negative disease, and was associated with increased risk of breast cancer among BRCA2 mutation carriers. The Collaborative Oncologic Gene-environment Study (COGS) was a multi-consortium initiative to study prostate, ovarian, and breast cancer using a customized iSelect SNP genotyping array from Illumina (iCOGS) in which more than 200,000 SNPs were tested in each sample. In 2013, Michailidou and colleagues reported on the evaluation of 199,961 SNPs across 52,675 breast cancer cases and 49,436 controls from BCAC (22). At that time, 27 breast cancer risk loci had already been identified. Twenty-three of the 27 loci were replicated in COGS, 3 were more weakly associated with breast cancer risk, and 1 SNP was not included on the iCOGS genotyping array. In addition, 41 new breast cancer susceptibility loci were identified, bringing the total number of breast cancer susceptibility loci to 68. Thirteen of the newly identified SNPs were more strongly associated with ER-positive breast cancer, while one SNP was associated with ER-negative breast cancer. The 68 susceptibility SNPs were estimated to account for approximately 14% of familial relative risk (risk of breast cancer in first-degree relatives of women with breast cancer).

By 2015, 79 breast cancer susceptibility loci had been published, and 71 of these were confirmed in a 2015 meta-analysis including the COGS data from BCAC and 11 additional GWAS . The meta-analysis included 62,533 breast cancer cases and 60,976 controls. Using the 1000 Genomes Project, which catalogues a haplotype map for 38 million SNPs, genotypes were imputed for approximately 11.6 million SNPs, with imputation r2 > 0.3, that had not been included on the original arrays. After excluding SNPs within 500 kb of previously identified SNPs, 15 new breast cancer susceptibility loci were identified.

General Surgery: Open Access journal is heartening researchers to submit relevant research works within the scope of the journal. Author may submit their manuscripts at https://www.pulsus.com/submissions/general-surgery-open-access.html .

Regards,

Richard Potvin

Editorial team

General Surgery: Open Access