Target Proteins for Breast Cancer Risk | Genomics
A recently published study analyzed Genome-wide association studies (GWAS) summary statistics for breast cancer among European-ancestry individuals in the Breast Cancer Association Consortium (BCAC), which consisted of three datasets: iCOGS, OncoArray, and other GWAS. The study also acquired GWAS summary statistics for five intrinsic-like subtypes of breast cancer. The researchers used protein prediction models to analyze the association between genetically predicted protein levels and overall breast cancer risk. As a result, they identified proteins associated with breast cancer risk, conducted association analyses by intrinsic-like subtype, and performed conditional analyses adjusted for index variants.
Breast cancer is the most common cancer in women, accounting for 16% of all female cancers, and genome-wide association studies have identified genetic variants associated with breast cancer risk. While studies have identified potential target genes in these loci (specific locations on the human genome where genetic variations or mutations have been identified and found to be associated with an increased risk of developing breast cancer), they have primarily focused on mRNA levels without considering protein translation and post-translational modification. However, blood protein levels can be influenced by genetic variants. And recent studies have developed genetic prediction models for circulating protein levels.
By using these models, researchers investigated the association between genetically predicted protein levels and breast cancer risk in European-ancestry individuals in the Breast Cancer Association Consortium.
Genomic and Proteomic Data Analysis
A recently published study analyzed Genome-wide association studies (GWAS) summary statistics for breast cancer among European-ancestry individuals in the Breast Cancer Association Consortium (BCAC), which consisted of three datasets: iCOGS, OncoArray, and other GWAS. The study also acquired GWAS summary statistics for five intrinsic-like subtypes of breast cancer. The researchers used protein prediction models to analyze the association between genetically predicted protein levels and overall breast cancer risk. As a result, they identified proteins associated with risk, conducted association analyses by intrinsic-like subtype, and performed conditional analyses adjusted for index variants.
The study also investigated the association between higher risk and the genetically predicted expression levels of encoding genes. Therefore, the authors used RNA sequencing data from whole blood samples and female breast mammary tissue samples collected from European-ancestry participants in the Gene-tissue Expression project. Association analyses of predicted gene expression with cancer risk were performed using the S-PrediXcan tool.
Blood Proteins Associated with Breast Cancer: Study Identifies Potential Targets for Improved Screening and Treatment
Let's go trough the researchers' findings: 22 blood proteins at 19 regions showed an association with overall breast cancer risk. Of these proteins, nine were encoded by genes located at least 500kb away from any GWAS-identified risk variants. Additionally, genetically predicted protein levels of PARK7, RSPO3, and A4GALT were associated with cancer risk at a Bonferroni-correction level of P <4.37×10-5. The study also found that the identified proteins were likely the target proteins of risk variants identified in previous GWAS of breast cancer.
Most of the identified proteins for overall breast cancer also showed a significant association with luminal A breast cancer. In contrast, proteins GSTM1, GSTM3, GSTM4, and KDELC2 showed a strong association with triple-negative breast cancer. The study also evaluated the associations of genetically predicted mRNA expression levels of the identified proteins with risk. In result, it found significant associations for 13 genes using blood models and eight genes using breast tissue models.
Identification of 30 Blood Proteins Associated with Breast Cancer Risk, including 9 Unrelated to Previous Risk Variants
The study aimed to identify blood proteins associated with breast cancer risk. Therefore, 1,180 SOMAmers for 1,142 unique proteins in 133,384 cases and 113,789 controls of European-ancestry women were analyzed. The study identified 30 blood proteins significantly associated with risk. These include nine proteins encoded by genes located more than 500kb away from any of the risk variants identified previously. Moreover, it provided evidence for ten proteins as the likely target proteins of risk loci identified in previous GWAS studies. It also found that low expression of GSTM genes is associated with an increased risk of breast cancer. The study has several limitations, including the limited number of evaluated SOMAmers and the focus on European-ancestry individuals.
At a Glance
Identification of 22 blood proteins associated with overall breast cancer risk
9 of the identified proteins were encoded by genes not previously linked to risk variants
Significant association between genetically predicted protein levels of PARK7, RSPO3, and A4GALT with cancer risk
Identified proteins likely target proteins of risk variants identified in previous GWAS studies
Association of specific proteins with different breast cancer subtypes, including GSTM1, GSTM3, GSTM4, and KDELC2 with triple-negative breast cancer.