4 research outputs found
Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation
Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495–45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13–1.18; p = 8.35 × 10−30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER−) breast cancer (lead SNP rs6864776: per-a allele OR ER− = 1.10; 95% CI 1.05–1.14; p conditional = 1.44 × 10−12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09–1.15; p conditional = 1.12 × 10−05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis
Immunohisto(cyto)chemistry: an old time classic tool driving modern oncological therapies
In the era of precision medicine
immunohistochemistry (IHC) and immunocytochemistry
(ICC) share some of the highlights in personalized
treatment. Survival data obtained from clinical trials
shape the cut-offs and IHC scoring that serve as
recommendations for patient selection both for targeted
and conventional therapies. Assessment of Estrogen and
Progesterone Receptors along with HER2 status has
been among the first approved immunostaining assays
revolutionizing breast cancer treatment. Similarly, ALK
positivity predicts the efficacy of ALK inhibitors in
patients with non-small cell lung cancer (NSCLC). In
recent years, Programmed Death Ligand 1 (PD-L1) IHC
assays have been approved as companion or
complimentary diagnostic tools predicting the response
to checkpoint inhibitors. Anti-PD-L1 and anti-PD-1
monoclonal antibodies have inaugurated a new period in
the treatment of advanced cancers, but the path to
approval of these biomarkers is filled with
immunohistochemical challenges. The latter brings to
the fore the significance of molecular pathology as a hub
between basic and clinical research. Besides, novel
markers are translated into routine practice, suggesting
that we are at the beginning of a new exciting period.
Unraveling the molecular mechanisms involved in
cellular homeostasis unfolds biomarkers with greater
specificity and sensitivity. The introduction of GL13
(SenTraGor®) for the detection of senescent cells in
archival material, the implementation of key players of
stress response pathways and the development of
compounds detecting common mutant P53 isoforms in
dictating oncological treatments are paradigms for
precision oncology
Bacterial genotoxins induce T cell senescence
Several types of pathogenic bacteria produce genotoxins that induce DNA damage in host cells. Accumulating evidence suggests that a central function of these genotoxins is to dysregulate the host's immune response, but the underlying mechanisms remain unclear. To address this issue, we investigated the effects of the most widely expressed bacterial genotoxin, the cytolethal distending toxin (CDT), on T cells—the key mediators of adaptive immunity. We show that CDT induces premature senescence in activated CD4 T cells in vitro and provide evidence suggesting that infection with genotoxin-producing bacteria promotes T cell senescence in vivo. Moreover, we demonstrate that genotoxin-induced senescent CD4 T cells assume a senescence-associated secretory phenotype (SASP) which, at least partly, is orchestrated by the ATM-p38 signaling axis. These findings provide insight into the immunomodulatory properties of bacterial genotoxins and uncover a putative link between bacterial infections and T cell senescence
Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers
10.1016/j.ajhg.2013.01.002American Journal of Human Genetics924489-503AJHG