Cancer development is often associated with the lack of specific and efficient recognition of tumor cells by the immune system. Natural killer (NK) cells are lymphocytes of the innate immune system ...that participate in the elimination of tumors. We report the identification of a tumor cell surface molecule that binds NKp30, a human receptor which triggers antitumor NK cell cytotoxicity and cytokine secretion. This previously unannotated gene belongs to the B7 family and, hence, was designated B7-H6. B7-H6 triggers NKp30-mediated activation of human NK cells. B7-H6 was not detected in normal human tissues but was expressed on human tumor cells, emphasizing that the expression of stress-induced self-molecules associated with cell transformation serves as a mode of cell recognition in innate immunity.
Members of the CD28 family play important roles in regulating T‐cell functions and share a common gene structure profile. We have identified VSTM3 as a protein whose gene structure matches that of ...the other CD28 family members. This protein (also known as TIGIT and WUCAM) has been previously shown to affect immune responses and is expressed on NK cells, activated and memory T cells, and Tregs. The nectin‐family proteins CD155 and CD112 serve as counter‐structures for VSTM3, and CD155 and CD112 also bind to the activating receptor CD226 on T cells and NK cells. Hence, this group of interacting proteins forms a network of molecules similar to the well‐characterized CD28–CTLA‐4–CD80–CD86 network. In the same way that soluble CTLA‐4 can be used to block T‐cell responses, we show that soluble Vstm3 attenuates T‐cell responses in vitro and in vivo. Moreover, animals deficient in Vstm3 are more sensitive to autoimmune challenges indicating that this new member of the CD28 family is an important regulator of T‐cell responses.
The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of ...inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.
The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods ...for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10−12) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046–0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027–0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.
Abstract
Members of the B7-CD28 family play critical roles in the response of T cells. We have identified the transmembrane protein Vstm3 as a member of the CD28 family based on gene structure. It ...has two immunoreceptor tyrosine inhibitory motifs in its cytoplasmic domain and is expressed on NK cells and a subset of T cells. Antibodies against VSTM3 antagonize multiple aspects of T cell activation including proliferation and cytokine production indicating it plays an inhibitory role in T cell activation. We have also identified two counter-structures for this protein, the previously identified proteins CD155 and CD112, which are expressed on activated antigen presenting cells. CD155 and CD112 also bind to the activating receptor CD226 and hence this extended family of interacting proteins forms a network of molecules similar to the well characterized CD28-CTLA4-CD80-CD86 network. A soluble form of Vstm3 binds to CD155 and CD112 and disrupts their ability to trigger an activating response through CD226, and hence antagonizes immune responses in vitro and in vivo. On the other hand, an antibody that specifically blocks Vstm3 interaction with CD155 and CD112 tends to enhance T cell responses in vitro and in vivo. Finally, mice that lack Vstm3 are more sensitive to the development of autoimmune diseases. Our data indicate that this novel member of the CD28 family negatively regulates T cell responses.
Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in
...HOXB13
was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking
HOXB13
in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %),
P
= 9.9 × 10
−8
odds ratio 4.42 (95 % confidence interval 2.56–7.64). A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (
P
= 6.5 × 10
−6
). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the
HOXB13
G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.
Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease.
To detect new genetic variants associated with PCa, ...capitalizing on the role of family history and more aggressive PCa.
A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls.
Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls.
Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa.
Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease.
Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.
Family history of prostate cancer (PCa) is a well-known risk factor. By capitalizing on affected men with a strong family history of disease or with more aggressive disease, we identified 10 novel genes, with eight of these primarily associated with aggressive PCa.
Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better ...characterise the contribution of variants in
,
,
and
, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK.
Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four
algorithms.
Truncating variants in
(OR=4.69, 95% CI 2.27 to 9.68),
(OR=3.26; 95% CI 1.82 to 6.46) and
(OR=3.11; 95% CI 2.15 to 4.69), but not
(OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in
and
were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in
were associated with similar risks for both subtypes. There was also some evidence that missense variants in
,
and
may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect.
Truncating variants in
are associated with a higher risk of BC than those in
or
. A substantial risk of BC due to truncating
variants can be excluded.
Genes regulated by breast cancer risk alleles identified through genome-wide association studies (GWAS) may harbor rare coding risk alleles.
We sequenced the coding regions for 38 genes within 500 kb ...of 38 lead GWAS SNPs in 13,538 breast cancer cases and 5,518 controls.
Truncating variants in these genes were rare, and were not associated with breast cancer risk. Burden testing of rare missense variants highlighted 5 genes with some suggestion of an association with breast cancer, although none met the multiple testing thresholds:
, and
. Six common alleles in
(two), and
(three) were associated at the
< 0.0001 significance level, but these likely reflect linkage disequilibrium with causal regulatory variants.
There was no evidence that rare coding variants in these genes confer substantial breast cancer risks. However, more modest effect sizes could not be ruled out.
We tested the hypothesis that rare variants in 38 genes near breast cancer GWAS loci may mediate risk. These variants do not appear to play a major role in breast cancer heritability.
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