Association of genetic variants with breast cancer intrinsic subtypes and splice variants of the fibroblast growth factor receptor 2 in a South African population

Abstract

African populations are more genetically diverse than other groups, but there is a paucity of information about breast carcinomas. South Africa uses immunohistochemistry (IHC) rather than multiparameter genomic assays, such as PAM50, to classify tumors. Genome-wide association studies have shown variants in fibroblast growth factor receptor 2 (FGFR2) are associated with breast cancer, but this has not been examined in black, African women. This thesis investigated intrinsic subtypes; the effects of four FGFR2 single nucleotide polymorphisms (SNPs), and FGFR2 mRNA expression and splice variants associated with breast cancer subtypes. In a cohort of 378 breast cancer patients, we investigated the concordance between tumor samples classified by IHC and PAM50. The SNPs rs2981582, rs35054928, rs2981578 and rs11200014 were examined in 1001 patients with, and 1005 participants without, cancer. The FGFR2 mRNA expression and IIIb and IIIc isoforms were examined using cBioPortal, TCGA Splice Seq and TSVdb databases. Statistical analyses were performed using STATA v14.2. This study was approved by the Human Research Ethics Committee of the University of the Witwatersrand (clearance certificate no M161116).

IHC classified patients as estrogen receptor-positive (77.45%), progesterone receptor-positive (70.56%), and epidermal growth factor receptor 2 (HER2)-positive (32.28%). These results, together with ki67, were used as surrogates for intrinsic subtyping, and showed 7% IHC-A-clinical, 73% IHC-B-clinical, 5% IHC-HER2-clinical and 15% triple negative (TNBC). PAM50 gave 19% luminal-A, 32% luminal-B, 24% HER2-enriched and 25% basal-like. Concordance was highest between basal-like and TNBC and lowest between luminal-A and IHC-A. There was no association with the SNPS, rs2981582, rs35054928, rs2981578 and rs11200014, and breast cancer in the black, South African population. However, rs2981578 was associated with invasive lobular carcinoma (ILC) and HER2-positive breast cancer was associated with rs11200014. ILC and ER-positive cancers were associated with higher FGFR2, while TNBC or HER2-positive breast cancers were associated with lower FGFR2. The IIIb isoform was prevalent in ER- positive breast cancer and IIIc prevalent in HER2-positive breast cancer. Genetic information from the black South African population can improve understanding of breast cancer in our population. We suggest that the cutoff for Ki67 be changed to 20-25% to better reflect the luminal subtype classifications. Lobular carcinoma is associated with rs2981578, and HER2-postive carcinoma is associated with rs11200014. Increased levels of FGFR2 mRNA and IIIb isoforms are associated with ER-positive breast cancer, while lower levels of FGFR2 and higher IIIc isoforms are associated with HER2 and TNBC