Single and Multivariate Associations of <i>MSR1, ELAC2</i>, and <i>RNASEL</i> with Prostate Cancer in an Ethnic Diverse Cohort of Men

Beuten, Joke; Gelfond, Jonathan; Franke, Jennifer L.; Shook, Stacey; Johnson‐Pais, Teresa L.; Thompson, Ian M.; Leach, Robin J.

doi:10.1158/1055-9965.epi-09-0864

Cited by 45 publications

(35 citation statements)

References 51 publications

(57 reference statements)

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“…These genomic samples, isolated from whole blood using the QIAamp DNA blood maxi kit (Qiagen), were a part of a cohort that has been previously used to assess risk for PCa using various genetic markers (21). To determine the genomic status, the primers 5Ј-ACCCCTGCTCTGTGGGAGAGT-3Ј (forward) and 5Ј-AGGATCAGGAGGGGCATCCAAGGTGC-3Ј (reverse) were used to amplify a 570-bp region.…”

Section: Methodsmentioning

confidence: 99%

SIGLEC12, a Human-specific Segregating (Pseudo)gene, Encodes a Signaling Molecule Expressed in Prostate Carcinomas

Mitra

Banda

Altheide

et al. 2011

Journal of Biological Chemistry

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The primate SIGLEC12 gene encodes one of the CD33-related Siglec family of signaling molecules in immune cells. We had previously reported that this gene harbors a human-specific missense mutation of the codon for an Arg residue required for sialic acid recognition. Here we show that this R122C mutation of the Siglec-XII protein is fixed in the human population, i.e. it occurred prior to the origin of modern humans. Additional mutations have since completely inactivated the SIGLEC12 gene in some but not all humans. The most common inactivating mutation with a global allele frequency of 58% is a single nucleotide frameshift that markedly shortens the open reading frame. Unlike other CD33-related Siglecs that are primarily found on immune cells, we found that Siglec-XII protein is expressed not only on some macrophages but also on various epithelial cell surfaces in humans and chimpanzees. We also found expression on certain human prostate epithelial carcinomas and carcinoma cell lines. This expression correlates with the presence of the nonframeshifted, intact SIGLEC12 allele. Although SIGLEC12 allele status did not predict prostate carcinoma incidence, restoration of expression in a prostate carcinoma cell line homozygous for the frameshift mutation induced altered regulation of several genes associated with carcinoma progression. These stably transfected Siglec-XII-expressing prostate cancer cells also showed enhanced growth in nude mice. Finally, monoclonal antibodies against the protein were internalized by Siglec-XII-expressing prostate carcinoma cells, allowing targeting of a toxin to such cells. Polymorphic expression of Siglec-XII in humans thus has implications for prostate cancer biology and therapeutics.Sialic acids (Sias) 5 are nine-carbon backbone sugar molecules typically found at terminal positions of glycan chains in Deuterostomes (vertebrates and some "higher" invertebrates), making them potentially important in recognition events (1-3). One class of intrinsic Sia recognition proteins in vertebrates are Siglecs (sialic acid-binding immunoglobulin-like lectins). Siglecs are single-pass transmembrane proteins, with a Siabinding site in the extracellular N-terminal Ig-like V-set domain (4 -9). Such V-set domains are followed by one or more C2-set Ig-like domains. Siglecs can signal through one or more tyrosine-based signaling motif(s) in the cytoplasmic tail (5,8,9).CD33-related Siglecs (CD33rSiglecs) are encoded by a subset of SIGLEC genes clustered on chromosome 19 in humans and chimpanzees. They are homologous in sequence and typically expressed on immune cells (10). Analyses of genomic SIGLEC sequences across humans, chimpanzees, baboons, rats, and mice showed that CD33rSiglecs are evolving rapidly (11). This is particularly pronounced in the Sia-recognizing V-set domain, suggesting that this domain is under the greatest selection pressure (11)(12)(13)(14).This study focuses on Siglec-12 (formerly Siglec-L1). We have shown previously that human Siglec-12 has an Arg 3 Cys (R122C) substitution m...

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Section: Methodsmentioning

confidence: 99%

SIGLEC12, a Human-specific Segregating (Pseudo)gene, Encodes a Signaling Molecule Expressed in Prostate Carcinomas

Mitra

Banda

Altheide

et al. 2011

Journal of Biological Chemistry

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“…8p deletion typically involves extended areas or even the entire 8p arm, with several putative tumor suppressor genes which are located in this region. [17][18][19][20][21][22][23][24] Some breast cancer studies found associations between 8p deletions and advanced tumor stage, [25][26][27] highgrade, 28 metastatic growth, 25,27,29 familial breast cancer risk, 30 and poor prognosis, 25,27,29,31 but these associations could not be confirmed by others. 14,[32][33][34][35][36][37][38][39] To better understand the clinical relevance of 8p deletions in breast cancer, including association to tumor grade, pathological tumor stage, patient survival, hormone receptor status, and amplifications of HER2, MYC and CCND1, we analyzed more than 2,100 breast cancers with clinical follow-up data.…”

Section: Introductionmentioning

confidence: 99%

8p deletion is strongly linked to poor prognosis in breast cancer

Lebok

Mittenzwei

Kluth

et al. 2015

Cancer Biology & Therapy

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Deletions of chromosome 8p occur frequently in breast cancers, but analyses of its clinical relevance have been limited to small patient cohorts and provided controversial results. A tissue microarray with 2,197 breast cancers was thus analyzed by fluorescence in-situ hybridization using an 8p21 probe in combination with a centromere 8 reference probe. 8p deletions were found in 50% of carcinomas with no special type, 67% of papillary, 28% of tubular, 37% of lobular cancers and 56% of cancers with medullary features. Deletions were always heterozygous. 8p deletion was significantly linked to advanced tumor stage (P < 0.0001), high-grade (P < 0.0001), high tumor cell proliferation (Ki67 Labeling Index; P < 0.0001), and shortened overall survival (P < 0.0001). For example, 8p deletion was seen in 32% of 290 grade 1, 43% of 438 grade 2, and 65% of 427 grade 3 cancers. In addition, 8p deletions were strongly linked to amplification of MYC (P < 0.0001), HER2 (P < 0.0001), and CCND1 (p D 0.001), but inversely associated with ER receptor expression (p D 0.0001). Remarkably, 46.5% of 8p-deleted cancers harbored amplification of at least one of the analyzed genes as compared to 27.5% amplifications in 8p-non-deleted cancers (P < 0.0001). In conclusion, 8p deletion characterizes a subset of particularly aggressive breast cancers. As 8p deletions are easy to analyze, this feature appears to be highly suited for future DNA based prognostic breast cancer panels. The strong link of 8p deletion with various gene amplifications raises the possibility of a role for regulating genomic stability.

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“…9,14,15 Many variants 15 described in this gene, such as Arg462Gln, have been found to be associated with sporadic prostate cancer risk among Caucasians and African Americans. 16 However, the same variant (R462Q or Arg462Gln) has been found with decreased familial prostate cancer risk in a Japanese population with the Gln/Gln genotype.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 A study in African Americans and Hispanic Caucasians has concluded that RNASEL genetic variants have a role in prostate cancer risk. 6 The main genetic variants described are missense mutations (R462Q and D541E), the stop mutation (E265X) 7 and other variants such as 471delAAAG, 8 G265X, M1I 9 and I97L. 10 These studies describe results in Caucasian (from northern Europe), Jewish, African and American populations.…”

Section: Introductionmentioning

confidence: 99%

Predictive value in the analysis of RNASEL genotypes in relation to prostate cancer

Álvarez-Cubero

Entrala

Fernandez-Rosado

et al. 2011

Prostate Cancer Prostatic Dis

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BACKGROUND:We would like to compare the different RNASEL genotypes with the stage of the cancer using parameters such as PSA levels, Gleason score and T-stage, and to develop a clinical protocol for the monitoring of the disease for trying a better evolution of the patient. METHODS:A total of 231 patients with sporadic prostate cancer and 100 of controls were genotyped in RNASEL gene by sequencing the exons 1 and 3. A survey of clinical information was collected by a specialist following the Helsinki protocol. All patients and controls were interviewed by a researcher and signed their informed consent to participation in the study, which was approved by Ethics Committee of the hospital. The genetic information was processed and collected with an ABI PRISM Genetic Analyser 3130 using SeqScape software v.2.6. All the patients were analysed by comparing the genetic and clinical data. w 2 -tests, Monte Carlo, Fisher tests and contigency tables were performed using SPSS v.15.0 and ARLEQUIN v.3.5 software on patient population.RESULTS: Significant differences were found only between patients and controls in D541E, R461Q and I97L genotypes, the remainder of the variants did not seem relevant to our population in contrast to other populations, such as north-Caucasians, Afro Americans and Ashkenazi Jews. The genotypes associated with the worst prognoses are G/G in D541E, A/A in R462Q and A/G in I97L. The controls were included in our study to determine an approximation of the genotype in our population compared with the patients, but they did not account for the statistical process. CONCLUSIONS:The genetic profile of patients with this cancer combined with other parameters could be used as a prognosis factor in deciding to give more radical and frequent treatments, depending on personal genotype.

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Single and Multivariate Associations of MSR1, ELAC2, and RNASEL with Prostate Cancer in an Ethnic Diverse Cohort of Men

Cited by 45 publications

References 51 publications

SIGLEC12, a Human-specific Segregating (Pseudo)gene, Encodes a Signaling Molecule Expressed in Prostate Carcinomas

SIGLEC12, a Human-specific Segregating (Pseudo)gene, Encodes a Signaling Molecule Expressed in Prostate Carcinomas

8p deletion is strongly linked to poor prognosis in breast cancer

Predictive value in the analysis of RNASEL genotypes in relation to prostate cancer

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