Germline mutations in the ribonuclease L gene in families showing linkage with HPC1

Carpten, John D.; Nupponen, Nina N.; Isaacs, Sarah D.; Sood, Raman; Robbins, Christiane M.; Xu, Jianfeng; Faruque, Mezbah U.; Moses, Tracy; Ewing, Charles M.; Gillanders, Elizabeth M.; Hu, Ping; Bujnovszky, Piroska; Makałowska, Izabela; Baffoe-Bonnie, Agnes; Faith, Dennis; Smith, Jeffrey R.; Stephan, Dietrich A.; Wiley, Kathleen E.; Brownstein, Michael J.; Gildea, Derek; Kelly, Brian; Jenkins, Robert B.; Hostetter, Galen; Matikainen, Mika; Schleutker, Johanna; Klinger, Kathy; Connors, Timothy D.; Xiang, Ying; Wang, Z.; Marzo, Angelo De; Papadopoulos, Nickolas; Kallioniemi, Olli; Burk, Robert D.; Meyers, Deborah A.; Grönberg, Henrik; Meltzer, Paul S.; Silverman, Robert H.; Bailey-Wilson, Joan E.; Walsh, Patrick C.; Isaacs, William B.; Trent, Jeffrey M.

doi:10.1038/ng823

Cited by 467 publications

(321 citation statements)

References 21 publications

Supporting

Mentioning

308

Contrasting

Unclassified

Order By: Relevance

“…RNase L was initially proposed to be a candidate tumor suppressor by us and Peter Lengyel based on its involvement in the antiproliferative activity of IFN and on the location of RNASEL at chromosome 1q25, a region deleted or rearranged in some breast cancers [89][90][91]. However, specific evidence of a role for RNase L in the suppression of cancer had to wait almost 10 years, until the long sought, hereditary prostate cancer 1 (HPC1) was mapped to the RNase L gene by the group of Jeff Trent [92]. Several germline mutations or variants in HPC1/RNASEL have been observed in hereditary prostate cancer [92][93][94][95] (reviewed in ref.…”

Section: The Role Of Rnase L In Hereditary Prostate Cancer and Discovmentioning

confidence: 99%

“…However, specific evidence of a role for RNase L in the suppression of cancer had to wait almost 10 years, until the long sought, hereditary prostate cancer 1 (HPC1) was mapped to the RNase L gene by the group of Jeff Trent [92]. Several germline mutations or variants in HPC1/RNASEL have been observed in hereditary prostate cancer [92][93][94][95] (reviewed in ref. [96]), including a common (35% allelic frequency) missense variant of RNase L, in which a G to A transition at nucleotide position 1385 (G1385A) results in a glutamine instead of arginine at amino acid position 462 (R462Q).…”

Section: The Role Of Rnase L In Hereditary Prostate Cancer and Discovmentioning

confidence: 99%

“…The RNase L "Q" variant had a 3-fold decrease in catalytic activity compared to the wild-type enzyme [95,97]. Although several genetic and epidemiologic studies support the involvement of RNASEL (and notably the R462Q variant) in prostate cancer etiology [92][93][94][95], others did not [98][99][100], suggesting that either population differences or environmental factors such as infections may modulate the impact of RNASEL on prostatic carcinogenesis.…”

Section: The Role Of Rnase L In Hereditary Prostate Cancer and Discovmentioning

confidence: 99%

See 2 more Smart Citations

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

View full text Add to dashboard Cite

The antiviral and antitumor actions of interferons are caused, in part, by a remarkable regulated RNA cleavage pathway known as the 2-5A/RNase L system. 2′-5′ linked oligoadenylates (2-5A) are produced from ATP by interferon-inducible synthetases. 2-5A activates pre-existing RNase L, resulting in the cleavage of RNAs within single-stranded regions. Activation of RNase L by 2-5A leads to an antiviral response, although precisely how this happens is a subject of ongoing investigations. Recently, RNase L was identified as the hereditary prostate cancer 1 gene. That finding has led to the discovery of a novel human retrovirus, XMRV. My scientific journey through the 2-5A system recounts some of the highlights of these efforts. Knowledge gained from studies on the 2-5A system could have an impact on development of therapies for important viral pathogens and cancer.Keywords 2-5A; RNase L; interferon; cancer; virus Background on the 2-5A/RNase L systemOver the past thirty-years, investigations into the mechanisms of interferon (IFN) action have elucidated how antiviral innate immunity operates within and between mammalian cells. The focus of my work over this period has been, and continues to be, probing the biology and biochemistry of the 2-5A/RNase L system, and studying its roles in health and disease. My scientific journey, from basic research to clinical studies, are summarized in this monograph. The 2-5A/RNase L system is one the principal pathways by which IFNs suppress viral infections. Exposure of cells to IFNs induces expression of genes that result in an "antiviral state". Type I IFNs bind to the IFN-α receptor 1 (IFNAR1) and IFNAR2 polypeptide chains on cell surfaces initiating JAK-STAT signaling to the IFN stimulated genes (ISGs) [1]. Included among over a hundred different ISGs are genes encoding 2-5A synthetases (OAS) [2,3]. The OAS genes are a family of ISGs that function in the 2-5A/RNase L system (Fig. 1). In humans there are three functional OAS genes (OAS1-3), resulting in 8 to 10 OAS isoforms due to alternative mRNA splicing [4]. In mice, in addition to OAS2 and OAS3 there are 7 separate OAS1 genes, including OAS1b, the flavivirus resistance gene (Flv r ] [5][6][7][8]. When stimulated by dsRNA, the functional OAS proteins produce a series of short 5′-phosphorylated, 2′,5′-linked oligoadenylates collectively referred to as 2-5A [p x 5′A(2′p5′A) n ; x = 1-3; n≥2] from ATP [9]. The first molecular clone for an OAS was obtained by Michel Revel's lab [10]. Biochemical characterization of OAS proteins by Ara Hovanessian's lab [11][12][13][14] and Ganes Sen's lab [15][16][17][18][19] and a crystal structure by Rune Hartmann and Vivien Yee (in collaboration with Ganes Sen and Just Justesen) [20] have led to functional and structural insight into the OAS family of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, type...

show abstract

Section: The Role Of Rnase L In Hereditary Prostate Cancer and Discovmentioning

confidence: 99%

Section: The Role Of Rnase L In Hereditary Prostate Cancer and Discovmentioning

confidence: 99%

Section: The Role Of Rnase L In Hereditary Prostate Cancer and Discovmentioning

confidence: 99%

See 1 more Smart Citation

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

View full text Add to dashboard Cite

show abstract

“…9 The role of the ''2 0 -5 0 A-system'' in the control of cellular growth suggests that defects in this pathway could result in reduced immunity to virus infections and cancer. 10 The first evidence implicating RNASEL as a tumor suppressor gene was the recent identification of this gene as the candidate for the hereditary prostate cancer 1 (HPC1) gene by Carpten et al 11 They identified the RNASEL nonsense mutation Glu265X that segregated with the disease in one prostate cancer family. This same mutation has been identified in further prostate cancer families, although not always with evidence of segregation with the disease.…”

mentioning

confidence: 99%

RNASEL germline variants are associated with pancreatic cancer

Bartsch

Fendrich

Slater

et al. 2005

Intl Journal of Cancer

View full text Add to dashboard Cite

The RNASEL (encoding ribonuclease L) gene Glu265X mutation has been implicated in familial prostate cancer, and an association between the RNASEL Arg462Gln variant and sporadic and familial prostate cancer, has also been suggested. Because prostate cancer occurs in some familial pancreatic cancer families, we evaluated the role of the RNASEL gene variants Glu265X and Arg462Gln in the etiology of pancreatic cancer. Exon 2 of the RNASEL gene was directly sequenced in the germline of 36 familial and 75 sporadic pancreatic cancer patients and in 108 controls. The Glu265X mutation was identified in one (2.8%) familial and one (1.3%) sporadic pancreatic cancer case, but not in any of the controls. Arg462Gln variants were identified in 61 (56%) controls and in 55 (73%) sporadic pancreatic cancer cases with 8 (7%) and 12 (16%) homozygotes, respectively (p 5 0.009). For homozygous carriers the increased risk for pancreatic cancer was 3.5 (odds ratio [OR] 5 3.53, 95% confidence interval [CI] 5 1.11-11.46, p 5 0.03). The population attributable fraction (PAF) was 38.7% (95% CI 5 0.08-0.80). In familial pancreatic cancer no association between Arg462Gln genotypes and pancreatic cancer risk was evident. In sporadic pancreatic cancer there were no significant differences between Arg462Gln genotypes regarding clinical characteristics. In familial pancreatic cancer, however, patients with Arg462Gln variants had more aggressive tumors with more high grade cancers (OR 5 15.40, p 5 0.009) and more distant metastases (OR 5 7.00, p 5 0.04) than patients with the wild-type genotype. Our results suggest that RNASEL variants Glu265X and Arg462Gln may contribute to the tumorigenesis of sporadic and familial pancreatic cancer, which has to be proven in large scale studies. ' 2005 Wiley-Liss, Inc.Key words: RNASEL; familial pancreatic cancer; sporadic pancreatic cancer Pancreatic cancer (PC) is the fifth leading cause of cancer death in Western countries with an overall 5-year survival rate of <5%. 1 The genetic basis of pancreatic cancer is complex and seems to involve multiple susceptibility genes. Epidemiological data suggest that dominant susceptibility genes may be responsible for about 3% of all pancreatic cancer cases. 2,3 BRCA2 germline mutations have been identified in 4.9% and 7.3% of apparently sporadic PC cases 4,5 and about 17% of and familial pancreatic cancer (FPC) cases, 6,7 respectively. There is also some evidence that mutations in CDKN2a, PRSS1, Mismatch-Repair and Fanconi anaemia genes predispose to PC, but the contribution of these genes to PC tumorigenesis is considered to be small. 8 The major underlying gene defect(s) of FPC are still unknown.The RNASEL (2 0 -5 0 oligoisoadenylate-synthetase dependent) gene located at chromosome 1q24-q25 plays a causal role in cell death by viral and non-viral stimuli and represents an important fragment of the apoptosis cascade. 9 The role of the ''2 0 -5 0 A-system'' in the control of cellular growth suggests that defects in this pathway could result in reduced immunity to virus...

show abstract

“…Many susceptibility genes for prostate cancer exist, and HPCX and RNASEL have been reported. 7,8 A genetic linkage study showed an association between familial risk of brain and prostate cancers and the 1p36 chromosome locus. 9 In previous studies on the effects of lipoproteins on prostate cancer proliferation and migration, we found that remnant lipoprotein or high-density lipoprotein exerted proliferative effects on PC-3 and DU-145 prostate cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Role of squalene synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer

Fukuma

Matsui

Koike

et al. 2012

Prostate Cancer Prostatic Dis

View full text Add to dashboard Cite

BACKGROUND:We previously conducted a genome-wide linkage analysis of Japanese nuclear families affected with prostate cancer and showed that the susceptibility to prostate cancer was closely linked to D8S550 at 8p23. The role of farnesyl diphosphate farnesyltransferase (FDFT1), which is located under the peak marker D8S550 at 8p23, and squalene synthase, the enzyme encoded by FDFT1, in prostate cancer was studied. METHODS: The association among common variants of FDFT1 with prostate cancer risk, the promoter activities of FDFT1 with different genotypes and the effects of inhibition of squalene synthase were studied, and the FDFT1 transcript levels of human prostate samples were quantified. RESULTS: The A allele of rs2645429 was significantly associated with prostate cancer risk in a Japanese familial prostate cancer population. Rs2645429 was located in the promoter region of FDFT1, and the AA genotype showed significantly increased promoter activity. The knockdown of FDFT1 mRNA expression or squalene synthase inhibition led to a significant decrease in prostate cancer cell proliferation. Additionally, human prostate cancer specimens expressed significantly higher levels of FDFT1 mRNA compared with noncancerous specimens. Finally, aggressive cancers showed higher transcript levels. CONCLUSIONS: FDFT1 and its encoded enzyme, squalene synthase, may play an important role in prostate cancer development and its aggressive phenotypes.

show abstract

Germline mutations in the ribonuclease L gene in families showing linkage with HPC1

Cited by 467 publications

References 21 publications

A scientific journey through the 2-5A/RNase L system

A scientific journey through the 2-5A/RNase L system

RNASEL germline variants are associated with pancreatic cancer

Role of squalene synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer

Contact Info

Product

Resources

About