Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans

Abstract

IntroductionToll-like receptor 9 (TLR9) is an innate immune system DNA-receptor that regulates tumor invasion and immunity in vitro. Low tumor TLR9 expression has been associated with poor survival in Caucasian patients with triple negative breast cancer (TNBC). African American (AA) patients with TNBC have worse prognosis than Caucasians but whether this is due to differences in tumor biology remains controversial. We studied the prognostic significance of tumor Toll like receptor-9 (TLR9) protein expression among African American (AA) triple negative breast cancer (TNBC) patients. Germline TLR9 variants in European Americans (EAs) and AAs were investigated, to determine their contribution to AA breast cancer risk.MethodsTLR9 expression was studied with immunohistochemistry in archival tumors. Exome Variant Server and The Cancer Genome Atlas were used to determine the genetic variation in the general EA and AA populations, and AA breast cancer cases. Minor allele frequencies (MAFs) were compared between EAs (n = 4300), AAs (n = 2203), and/or AA breast cancer cases (n = 131).ResultsThirty-two TLR9 variants had a statistically significant MAF difference between general EAs and AAs. Twenty-one of them affect a CpG site. Rs352140, a variant previously associated with protection from breast cancer, is more common in EAs than AAs (p = 2.20E-16). EAs had more synonymous alleles, while AAs had more rare coding alleles. Similar analyses comparing AA breast cancer cases with AA controls did not reveal any variant class differences; however, three previously unreported TLR9 variants were associated with late onset breast cancer. Although not statistically significant, rs352140 was observed less frequently in AA cases compared to controls. Tumor TLR9 protein expression was not associated with prognosis.ConclusionsTumor TLR9 expression is not associated with prognosis in AA TNBC. Significant differences were detected in TLR9 variant MAFs between EAs and AAs. They may affect TLR9 expression and function. Rs352140, which may protect from breast cancer, is 1.6 X more common among EAs. These findings call for a detailed analysis of the contribution of TLR9 to breast cancer pathophysiology and health disparities.

Greater Survival Improvement in African American vs. Caucasian Women with Hormone Negative Breast Cancer

“…The lower improvement in the Caucasian population with the same disease category may indicate that in fact, a limit of effectiveness of treatment for hormone receptor negative disease has been reached with current therapies and that African American patients are catching up to these limits. It is entirely possible that the bridging of disparities in survival in this subpopulation may reach a limit with current therapy due to reported biological differences responsible for more aggressive behavior of hormone negative cancer in African American women (55)(56)(57)(58)(59). Nevertheless, our study is the first to demonstrate that African Americans with ER-and PR-disease benefitted significantly more than Caucasians with ER-and PR-disease in the 21 st century.…”

Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis

“…Perhaps our most exciting finding is the observed racial differences in mtDNA, especially with aggressive clinical phenotypes. Genome-wide association studies have identified susceptible genetic variants for sarcoidosis among African Americans [44], and racial differences in innate immunity have been demonstrated, particularly in TLR9 polymorphisms related to breast cancer [45] and infectious granulomas [46], and in TLR9 expression in systemic lupus erythematosus [47]. An association between TLR9 and sarcoidosis has been reported [48], although racial differences have not been explored.…”

Toll-Like Receptors Gene Polymorphism and Susceptibility to Cancer Development

“…In a comparison study of African American (AA) and European American (EA) breast cancer patients, the association of rs352140 was investigated. It was found that rs352140 SNP, located at the CpG site, has a protective effect that is 1.6X more common in EA compared to AA [71]. In contrast, Etokebe et al found no association of rs352140 with breast cancer among 130 case samples of Croatian patients [72].…”