Absent Toll-like receptor-9 expression predicts poor prognosis in renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 9 (TLR9) is a cellular DNA-receptor whose activation with cognate ligands triggers an immune reaction, with increased production of inflammatory cytokines. The aim of this study was to examine the expression of TLR9 in renal cell carcinoma (RCC), which is generally renowned of its immunogenic nature. We also evaluated the prognostic value of TLR9 in RCC.</p> <p>Methods</p> <p>TLR9 expression in RCC was characterized with immunohistochemistry in a retrospective study population of 152 RCC patients who underwent renal surgery. The TLR9 staining intensity was compared with clinical parameters.</p> <p>Results</p> <p>Of the studied tumours, 112 (81%) exhibited cytoplasmic TLR9 immunostaining. No association was detected between cytoplasmic TLR9 immunoexpression intensity and stage, nuclear grade, histological subtype or tumour necrosis. Cytoplasmic TLR9 immunoexpression was, however, a marker of favourable RCC specific survival both in univariate analysis and in multivariate regression model.</p> <p>Conclusions</p> <p>We conclude that TLR9 expression is an independent prognostic marker of RCC and the absence of TLR9 expression is related to poorer prognosis in RCC.</p

Comparison of allele counts between AA cases and controls for different variant classes.

<p>Comparison of allele counts between AA cases and controls for different variant classes.</p

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

<div><p>Introduction</p><p>Toll-like receptor 9 (TLR9) is an innate immune system DNA-receptor that regulates tumor invasion and immunity <i>in vitro</i>. 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 <i>TLR9</i> variants in European Americans (EAs) and AAs were investigated, to determine their contribution to AA breast cancer risk.</p><p>Methods</p><p>TLR9 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).</p><p>Results</p><p>Thirty-two <i>TLR9</i> 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 <i>TLR9</i> 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.</p><p>Conclusions</p><p>Tumor TLR9 expression is not associated with prognosis in AA TNBC. Significant differences were detected in <i>TLR9</i> 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.</p></div

Comparison of allele counts between ethnicities for different variant classes.

<p>Comparison of allele counts between ethnicities for different variant classes.</p

Variants with a statistically significant MAF in EAs.

<p>Variants with a statistically significant MAF in EAs.</p

Patient outcomes stratified by tumor TLR9 expression status.

<p>a) Breast cancer recurrence probability stratified by median tumor TLR9 expression status, b) survival probability stratified by ipsilateral breast cancer (IBTR) and tumor TLR9 expression status and c) breast cancer specific-survival probability stratified by tumor TLR9 expression status (n = 43).</p

Comparison of allele counts between AA cases and controls for different variant classes.

<p>Comparison of allele counts between AA cases and controls for different variant classes.</p

Variants with a statistically significant MAF in AAs.

<p>Variants with a statistically significant MAF in AAs.</p