Research IndicatorsGraph generated 26 August 2015 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 26 August, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: ARL11 (cancer-related)
Prostate cancer (PCa) is a heterogeneous trait for which several susceptibility loci have been implicated by genome-wide linkage and association studies. The genomic region 13q14 is frequently deleted in tumour tissues of both sporadic and familial PCa patients and is consequently recognised as a possible locus of tumour suppressor gene(s). Deletions of this region have been found in many other cancers. Recently, we showed that homozygous carriers for the T442C variant of the ARLTS1 gene (ADP-ribosylation factor-like tumour suppressor protein 1 or ARL11, located at 13q14) are associated with an increased risk for both unselected and familial PCa. Furthermore, the variant T442C was observed in greater frequency among malignant tissue samples, PCa cell lines and xenografts, supporting its role in PCa tumourigenesis. In this study, 84 PCa cases and 15 controls were analysed for ARLTS1 expression status in blood-derived RNA. A statistically significant (p = 0.0037) decrease of ARLTS1 expression in PCa cases was detected. Regulation of ARLTS1 expression was analysed with eQTL (expression quantitative trait loci) methods. Altogether fourteen significant cis-eQTLs affecting the ARLTS1 expression level were found. In addition, epistatic interactions of ARLTS1 genomic variants with genes involved in immune system processes were predicted with the MDR program. In conclusion, this study further supports the role of ARLTS1 as a tumour suppressor gene and reveals that the expression is regulated through variants localised in regulatory regions.
ARLTS1 is a recently characterized tumor suppressor gene at 13q14.3, a region frequently deleted in both sporadic and hereditary prostate cancer (PCa). ARLTS1 variants, especially Cys148Arg (T442C), increase susceptibility to different cancers, including PCa. In this study the role of Cys148Arg substitution was investigated as a risk factor for PCa using both genetic and functional analysis. Cys148Arg genotypes and expression of the ARLTS1 were explored in a large set of familial and unselected PCa cases, clinical tumor samples, xenografts, prostate cancer cell lines and benign prostatic hyperplasia (BPH) samples. The frequency of the variant genotype CC was significantly higher in familial (OR = 1.67, 95% CI = 1.08-2.56, P = 0.019) and unselected patients (OR = 1.52, 95% CI = 1.18-1.97, P = 0.001) and the overall risk was increased (OR = 1.54, 95% CI = 1.20-1.98, P = 0.0007). Additional analysis with clinicopathological data revealed an association with an aggressive disease (OR = 1.28, 95% CI = 1.05-∞, P = 0.02). The CC genotype of the Cys148Arg variant was also contributing to the lowered ARLTS1 expression status in lymphoblastoid cells from familial patients. In addition significantly lowered ARLTS1 expression was observed in clinical tumor samples compared to BPH samples (P = 0.01). The ARLTS1 co-expression signature based on previously published microarray data was generated from 1587 cancer samples confirming the low expression of ARLTS1 in PCa and showed that ARLTS1 expression was strongly associated with immune processes. This study provides strong confirmation of the important role of ARLTS1 Cys148Arg variant as a contributor in PCa predisposition and a potential marker for aggressive disease outcome.
BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium.
METHODS: CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family.
RESULTS: None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value < 0.05 in EPICOLON stage 1 [rs698 in ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive), rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive), rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant), and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1.12, 95% CI = 1.00-1.25, P-value = 0.04, log-additive 0, 1, 2 alleles) and borderline significant for rs698 and rs2102302. The rs3803185 variant was not significantly associated with CRC risk in an external cohort (MCC-Spain), but it still showed some borderline significance in the pooled analysis of both cohorts (OR = 1.08, 95% CI = 0.98-1.18, P-value = 0.09, log-additive 0, 1, 2 alleles).
CONCLUSIONS: ARL11, ADH1C, GALNTL2 and IL6 genetic variants may have an effect on CRC risk. Further validation and meta-analyses should be undertaken in larger CRC studies.
Yang XY, Yu H, Peng ZLInvolvement of ARLTS1 in chemotherapy and apoptosis in ovarian cancer cell line.
Arch Gynecol Obstet. 2011; 284(5):1241-6 [PubMed
] Related Publications
PURPOSE: Recent evidence suggests that ADP-ribosylation factor-like tumor suppressor gene 1(ARLTS1) may act as a tumor suppressor gene. However, its role in tumor chemotherapy remains unclear. The aim of this study is to investigate the effects of ARLTS1 gene in regulation of chemosensitivity in ovarian cystadenocarcinoma cell line SKOV3.
METHODS: We stably expressed wild-type (wt) ARLTS1 and empty vector (neo) in SKOV3 cells. Chemosensitivity test was carried out with four chemotherapeutic agents. Cell proliferation, cycle kinetics and apoptosis were evaluated by MTT assay and flow cytometry. Apoptosis-related proteins caspase-3 and bcl-2 were determined by Western blot analysis.
RESULTS: The proliferation of wtARLTS1 clones was more dramatically inhibited by all the cytotoxic agents than parental cells (P < 0.05). Increased sensitivity to chemotherapy by two to threefolds was detected in wtARLTS1 cells. The rate of apoptosis in wtARLTS1 was 60.2% treated with DDP (10× peak plasma concentration, PPC), which was dramatically higher than that of neo and parental cells (P is 0.017 and 0.020, respectively). Expression of caspase-3 and bcl-2 in parental cells declined modestly when treated with DDP, while in wtARLTS1 clones the expression of caspase-3 and bcl-2 levels declined more dramatically and become undetectable at lower DDP doses (P = 0.023 and <0.001, respectively).
CONCLUSION: Our findings suggested that ARLTS1 may facilitate chemosensitivity in ovarian cancer cells by acting synergistic with chemotherapeutic agents to induce the apoptosis signaling pathway and regulate apoptosis-related proteins.
Akisik E, Yazici H, Dalay NARLTS1, MDM2 and RAD51 gene variations are associated with familial breast cancer.
Mol Biol Rep. 2011; 38(1):343-8 [PubMed
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Genetic factors that contribute to the risk of breast cancer are largely not known and association studies have revealed several genes with low penetrance risk alleles for breast cancer. Analysis of these genes may provide important information on the risk factors affecting carcinogenesis. Variations in the ARLTS1, RAD51 and MDM2 genes have been associated with increased risk of different cancer types but for breast cancer the results are not consistent. In this study we investigated the role of the allelic variants in candidate genes acting in the tumor suppressor, DNA repair and p53 pathways as risk factors for familial breast cancer in 147 patients displaying characteristics of familial disease. Presence of the polymorphic variants were investigated by amplification of the corresponding regions and restriction fragment length polymorphism analysis. Genotype and allele frequencies in the patients were significantly different for all three variants. Our results indicate that the polymorphic variants might affect individual susceptibility towards breast cancer.
Bartsch DK, Langer P, Habbe N, et al.Clinical and genetic analysis of 18 pancreatic carcinoma/melanoma-prone families.
Clin Genet. 2010; 77(4):333-41 [PubMed
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Families with both melanoma and pancreatic cancer are extremely rare and some are affected with the autosomal dominant inherited familial atypical multiple mole melanoma-pancreatic cancer (FAMMM-PC) syndrome. The phenotypic and genotypic expressions of such pancreatic cancer-melanoma prone families are not well defined. The National Case Collection of Familial Pancreatic Cancer of the Deutsche Krebshilfe includes 110 pancreatic cancer families, 18 of which (16%) show an association of pancreatic cancer and melanoma. These 18 families were analysed regarding their phenotype and the prevalence of germline mutations in the candidate genes CDKN2A, BRCA2, CHEK2, NOD2, ARL11 and Palladin (PALLD). There were two types of families: five families with the FAMMM-PC phenotype and 13 PC/melanoma families without the multiple mole phenotypes (PCMS). The prevalences of PC and melanoma in the two types of families were similar. The prevalence of other tumour types, especially breast carcinoma, was higher (11%) in PCMS- than in FAMMM-PC families (2.4%, p = 0.02). CDKN2A mutations were identified in 2 of 18 (11%) PCMS families. A cosegregating BRCA2 mutation was detected in one PCMS family without breast cancer. None of the reported germline mutations in the NOD2, Palladin, ARL11 or CHEK2 genes were detected in either type of family. In conclusion, families with an accumulation of PC and melanoma show a large variety of phenotypic expression, which is not always consistent with the FAMMM-PC phenotype. More PC/melanoma-prone families need to be analysed to clarify whether such families represent variations of the FAMMM-PC syndrome or two distinct hereditary cancer syndromes.
Yang XY, Yu H, Xi MR, et al.Association of the ARLTS1 variants with familial ovarian cancer risk in China.
Int J Gynecol Cancer. 2009; 19(4):585-90 [PubMed
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ARLTS1 has been identified in chromosome 13q14 as a tumor suppressor gene of the adenosine diphosphate-ribosylation factor family with pro-apoptotic characteristics. The ARLTS1 mutation Trp149Stop and Cys148Arg have been shown to be associated with familial cancers, but limited information is available regarding the impact of ARLTS1 variants on familial ovarian cancer (OC). The aim of this study was to evaluate the ARLTS1 genetic variants associated with familial OC risk in China. We genotyped 85 OC patients with family ovarian/breast history, 80 sporadic OC patients, and 120 controls from general population by denaturing high-performance liquid chromatography screening analysis followed by direct sequencing of the conspicuous polymerase chain reaction products. ARLTS1 Cys148Arg revealed a significant association with an increased risk of familial OC compared with both sporadic cases and controls in a dose-dependent manner (P = 0.0031 and 0.012, respectively). In the clinical-pathological study, our results support previous data in demonstrating that familial OC was associated with younger age at diagnosis (49.7 years vs 53.3 years; P = 0.014), higher proportion of tumors of advanced stages (81.2% vs 67.5%; P = 0.033), and higher rates of serous adenocarcinomas (76.4% vs 53.8%; P = 0.028) compared with sporadic OC cases. To investigate the association between genetic variants of ARLTS1 and the clinical-pathological characteristics of familial OC, we identified a significantly higher proportion of serous adenocarcinoma (55/67, 82.1%) and higher rates of advanced stage tumors (88.1% vs 55.6%; P = 0.004) in ARLTS1 Cys148Arg carriers. We showed a significantly increased risk of familial OC for ARLTS1 Cys148Arg variant, which indicate that ARLTS1 may play a role in familial OC.
Yendamuri S, Trapasso F, Calin GAARLTS1 - a novel tumor suppressor gene.
Cancer Lett. 2008; 264(1):11-20 [PubMed
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ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) is a member of the ARF family of the Ras superfamily of small GTPases that are known to be involved in multiple regulatory pathways altered in human carcinogenesis. Here, we review recent work that has provided insights into the role of this small gene as an emerging player in both familial and sporadic cancers of several histotypes. ARLTS1 is a low penetrance gene that is primarily dysregulated in sporadic lung cancer by promoter hypermethylation. Two ARLTS1 polymorphisms are also associated with familial cancer risk. Down-regulation of ARLTS1 is seen in all lung cancer cell lines studied and in a significant proportion (37%) of primary lung tumors. Restoration of ARLTS1 expression in ARLTS1-deficient lung cancer cell lines by either demethylation or adenoviral transduction leads to apoptosis via caspase-dependent mechanisms. Furthermore, ARLTS1 re-expression induces an in vivo decreased tumor growth in preclinical models of lung cancer. Microarray analysis of gene expression patterns in cells transduced with ARLTS1 demonstrates that various pathways involved in cell survival, proliferation and development mediate its pro-apoptotic effects.
Recently, a nonsense alteration Trp149Stop in the ARLTS1 gene was found more frequently in familial cancer cases versus sporadic cancer patients and healthy controls. Here, the role of Trp149Stop or any other ARLTS1 germline variant was evaluated on breast, prostate, and colorectal cancer risk. The whole gene was screened for germline alterations in 855 familial cancer patients. The five observed variants were further screened in 1169 non-familial cancer patients as well as in 809 healthy population controls. The Trp149Stop was found at low frequencies (0.5-1.2%) in all patient subgroups versus 1.6% in controls, and the mutant allele did not co-segregate with disease status in families with multiple affected individuals. The CC genotype in the Cys148Arg variant was slightly more common among both familial and sporadic breast (odds ratio (OR), 1.48; 95% confidence interval (CI), 1.16-1.87; P=0.001) and prostate cancer patients (OR, 1.50; 95% CI, 1.13-1.99; P=0.005) when compared to controls. A novel ARLTS1 variant Gly65Val was found at higher frequency among familial prostate cancer patients (8 of 164, 4.9%) than in controls (13 of 809, 1.6%; OR, 3.14; 95% CI, 1.28-7.70, P=0.016). However, after adjusting for multiple testing, none of these results were still significant. No association was found with any of the variants and colorectal cancer risk. Our results suggest that Trp149Stop is not a predisposition allele in breast, prostate, or colorectal cancer in the Finnish population, and, while the Gly65Val variant may increase familial prostate cancer risk and the Cys148Arg change may affect both breast and prostate cancer risk, the evidence is not strong in these data.
Yendamuri S, Trapasso F, Ferracin M, et al.Tumor suppressor functions of ARLTS1 in lung cancers.
Cancer Res. 2007; 67(16):7738-45 [PubMed
] Related Publications
ARLTS1 is a newly characterized tumor suppressor gene located at chromosome 13q14.3 and involved in the pathogenesis of various types of tumors: two single-nucleotide polymorphisms, one of them responsible for protein truncation, were found statistically associated with familial malignancies, whereas DNA hypermethylation and genomic deletions have been identified as a mechanism of ARLTS1 down-regulation in sporadic cancers. We found that in a large portion of lung carcinomas (37%) and in all analyzed lung cancer cell lines, ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After its restoration by adenoviral transduction, ARLTS1-negative A549 and H1299 cells underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the ability of A549 and H1299 to form tumors in nude mice. Finally, we identified approximately 650 transcripts differentially expressed after restoration of ARLTS1 expression in A549 cells, suggesting that various pathways involved in cell survival, proliferation, signaling, and development mediate the effects of wild-type ARLTS1 in a lung cancer system.
Castellví-Bel S, Castells A, de Cid R, et al.Association of the ARLTS1 Cys148Arg variant with sporadic and familial colorectal cancer.
Carcinogenesis. 2007; 28(8):1687-91 [PubMed
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ARLTS1 was recently identified in chromosome 13q14 as a tumor suppressor gene of the ADP-ribosylation factor family with pro-apoptotic characteristics. Additionally, one of its genetic variants (W149X) was hypothesized to be a polymorphism associated with familial cancer. We performed a large case-control association study within the EPICOLON project aimed at evaluating the sporadic and familial colorectal cancer (CRC) risk associated with ARLTS1 genetic variants. Whereas P131L and W149X did not seem to affect CRC risk, C148R did show, for the first time in CRC, statistically significant differences between cases and controls [odds ratio (OR) = 1.45, 95% confidence interval (95% CI) = 1.13-1.86, P = 0.003], sporadic cases and controls (OR = 1.59, 95% CI = 1.13-2.23, P = 0.007) and familial cases and controls (OR = 1.55, 95% CI = 1.10-2.19, P = 0.01) in agreement with a hypothetical moderate increase of the cancer risk linked to the C148R ARLTS1 variant, both in sporadic and familial CRC cases.
Petrocca F, Iliopoulos D, Qin HR, et al.Alterations of the tumor suppressor gene ARLTS1 in ovarian cancer.
Cancer Res. 2006; 66(21):10287-91 [PubMed
] Related Publications
ARLTS1 is a tumor suppressor gene initially described as a low-penetrance cancer gene: a truncated Trp149Stop (MUT) polymorphism is associated with general familial cancer aggregation and, particularly, high-risk familial breast cancer. DNA hypermethylation has been identified as a mechanism of ARLTS1 expression down-regulation in lung carcinomas and B-cell chronic lymphocytic leukemia. We found that, in the majority of ovarian carcinomas (61.5%) and in a significant proportion of ovarian and breast cancer cell lines (45%), ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After ARLTS1 restoration by adenoviral transduction, only the negative TOV-112 and the homozygously mutated (MUT) MCF7 cells, but not the OV-90 cells expressing a normal ARLTS1 product, underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the tumorigenic potential of TOV-112 in nude mice. On the contrary, the ARLTS1-MUT induced significantly lower levels of apoptosis in infected cells and reduced in vivo tumorigenesis only partially, supporting the hypothesis that Trp149Stop polymorphism is retained in the general population and predisposes to cancer because of a reduction, but not full loss, of normal ARLTS1 function.
Frank B, Meyer P, Boettger MB, et al.ARLTS1 variants and melanoma risk.
Int J Cancer. 2006; 119(7):1736-7 [PubMed
] Related Publications
Variants in the tumor suppressor gene ARLTS1 (ADP-ribosylation factor-like tumor-suppressor gene 1) have been shown to influence familial cancer risk. Both Cys148Arg and Trp149Stop were associated with an increased risk of familial or high-risk familial breast cancer, respectively. We studied the impact of these gene variants on melanoma risk, investigating 351 melanoma patients and 804 control subjects. While ARLTS1 Trp149Stop did not influence melanoma risk (OR = 0.83, 95% CI = 0.37-1.88, p = 0.65), Cys148Arg revealed a statistically significant association with an increased risk for heterozygous carriers (OR = 1.43, 95% CI = 1.05-1.95, p = 0.02). An additional risk enhancement, though statistically non-significant, was observed in individuals with multiple melanomas (OR = 2.33, 95% CI = 0.87-6.26, p = 0.08).
Sellick GS, Catovsky D, Houlston RSRelationship between ARLTS1 polymorphisms and risk of chronic lymphocytic leukemia.
Leuk Res. 2006; 30(12):1573-6 [PubMed
] Related Publications
ARLTS1, a member of the Ras superfamily and putative tumor-suppressor gene resides at chromosome 13q14, a region commonly deleted in hematopoietic and solid tumors. Previously, the truncating single nucleotide polymorphism (SNP) of ARLTS, G446A (W149X) has been reported to act as a multi-site tumor susceptibility allele. To explore the relationship between polymorphic variation in ARTLS1 and risk of chronic lymphocytic leukemia (CLL) we analyzed germline DNA from 413 cases and 471 healthy controls for W149X and five additional coding SNPs, S99S, P131L, L132L, C148R, and E164K. A high proportion of the cases were familial, thereby empowering detection of an association. None of the SNPs were individually significantly associated with risk of CLL and there was no evidence for epistatic interaction between loci. Our study does not support the postulate that variants of ARLTS1 influence the risk of CLL.
Masojć B, Mierzejewski M, Cybulski C, et al.Cancer Familial Aggregation (CFA) and G446A polymorphism in ARLTS1 gene.
Breast Cancer Res Treat. 2006; 99(1):59-62 [PubMed
] Related Publications
ARLTS1--a member of ADP-ribosylation factor family, is a newly described candidate tumour suppressor gene. Recent studies show that a nonsense polymorphism, G446A (Trp149Stop), in ARLTS1 gene is significantly more frequent in familial cancer cases than in sporadic cancer cases. This study presents analysis of the germ-line G446A polymorphism in the ARLTS1 gene among 1686 consecutively collected patients with breast cancer, prostate cancer, malignant melanoma, thyroid papillary cancer or laryngeal cancer in Poland. The G446A allele was present in 1.81% (9/497) breast cancer patients, 1.46% (5/343) prostate cancer patients, 1.76% (7/397) melanoma patients, 1.65% (3/182) thyroid papillary carcinoma patients and 2.68% (8/299) of laryngeal cancer patients. The frequency of this polymorphism in the control group was 1.45% (8/552). Differences in the frequency of the G446A polymorphism between case and control groups were not statistically significant. In addition, there was no significant difference in the number of Cancer Familial Aggregations (CFA) among breast, prostate, thyroid or laryngeal cancer cases harbouring the G446A polymorphism, when compared to the G446A negative cases. Interestingly out of the CFA melanoma cases, 4/6 (66.6%) were found to harbour the change compared to only 20.2% (69/341) sporadic melanoma cases. This difference was statistically significant (p = 0.02, OR = 7.8). The results of this study suggest that the G446A in ARLTS1 gene is probably not associated with an increased risk of sporadic breast cancer, prostate cancer, melanoma, thyroid papillary cancer or laryngeal cancer. Moreover, the G446A polymorphism is not significantly more frequent in CFA cases except for families in which the proband had melanoma. To confirm this result more cases of melanoma should be analysed.
Frank B, Hemminki K, Brenner H, et al.ARLTS1 variants and risk of colorectal cancer.
Cancer Lett. 2006; 244(2):172-5 [PubMed
] Related Publications
The Cys148Arg and Trp149Stop variants in the tumour suppressor gene ARLTS1 predispose to familial breast cancer, suggesting that these variants might also contribute to colorectal carcinogenesis. As the first to evaluate the association between Cys148Arg and Trp149Stop and colorectal cancer (CRC) risk, we genotyped 611 cases with CRC (including 77 cases with a first-degree family history) and 539 controls recruited from the German DACHS study. No significant differences in the genotype frequencies of Cys148Arg and Trp149Stop were observed between cases and controls. However, we showed a non-significant increased risk of familial CRC for both variants (OR=1.40 and 1.45), indicating a possible role of ARLTS1 in familial CRC.
Frank B, Hemminki K, Meindl A, et al.Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk.
Int J Cancer. 2006; 118(10):2505-8 [PubMed
] Related Publications
Recently, ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) has been identified as a tumor suppressor gene, playing a major role in apoptotic signaling. The ARLTS1 Trp149Stop mutation has been shown to predispose to general familial cancer and high-risk familial breast cancer (BC), provoking the attenuation of apoptotic function. We studied the impact of the ARLTS1 Pro131Leu and Cys148Arg variants on high-risk familial and familial BC risk, investigating 482 familial BC cases (including 305 high-risk cases) and 530 control individuals. Unlike ARLTS1 Pro131Leu, Cys148Arg revealed a significant association with an increased risk of high-risk familial BC (odds ratio (OR)=1.47, 95% confidence interval (95% CI)=1.04-2.06, p=0.03) in a dose-dependent manner (ptrend=0.007). The genotype distribution of Cys148Arg in familial cases was similar, indicating significance as well (OR=1.48, 95% CI=1.10-1.99, p=0.009; ptrend=0.003). On the basis of the small number of 46 cases, we additionally showed an association between the Trp149Stop mutation and an increased risk of bilateral BC (OR=4.11, 95% CI=1.27-13.31, p=0.011).
Calin GA, Trapasso F, Shimizu M, et al.Familial cancer associated with a polymorphism in ARLTS1.
N Engl J Med. 2005; 352(16):1667-76 [PubMed
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BACKGROUND: The finding of hemizygous or homozygous deletions at band 14 on chromosome 13 in a variety of neoplasms suggests the presence of a tumor-suppressor locus telomeric to the RB1 gene.
METHODS: We studied samples from 216 patients with various types of sporadic tumors or idiopathic pancytopenia, peripheral-blood samples from 109 patients with familial cancer or multiple cancers, and control blood samples from 475 healthy people or patients with diseases other than cancer. We performed functional studies of cell lines lacking ARLTS1 expression with the use of both the full-length ARLTS1 gene and a truncated variant.
RESULTS: We found a gene at 13q14, ARLTS1, a member of the ADP-ribosylation factor family, with properties of a tumor-suppressor gene. We analyzed 800 DNA samples from tumors and blood cells from patients with sporadic or familial cancer and controls and found that the frequency of a nonsense polymorphism, G446A (Trp149Stop), was similar in controls and patients with sporadic tumors but was significantly more common among patients with familial cancer than among those in the other two groups (P=0.02; odds ratio, 5.7; 95 percent confidence interval, 1.3 to 24.8). ARLTS1 was down-regulated by promoter methylation in 25 percent of the primary tumors we analyzed. Transfection of wild-type ARLTS1 into A549 lung-cancer cells suppressed tumor formation in immunodeficient mice and induced apoptosis, whereas transfection of truncated ARLTS1 had a limited effect on apoptosis and tumor suppression. Microarray analysis revealed that the wild-type and Trp149Stop-transfected clones had different expression profiles.
CONCLUSIONS: A genetic variant of ARLTS1 predisposes patients to familial cancer.