G2Cdb::Human Disease report

Disease id
D00000057
Name
Prostate cancer
Nervous system disease
no

Genes (3)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002235 CTNNB1
catenin (cadherin-associated protein), beta 1, 88kDa
Y (11921277) Single nucleotide polymorphism (SNP) Y
G00002235 CTNNB1
catenin (cadherin-associated protein), beta 1, 88kDa
Y (9635571) Microinsertion (MI) Y
G00002164 IRS1
insulin receptor substrate 1
Y (15678496) Single nucleotide polymorphism (SNP) Y
G00000031 HRAS
v-Ha-ras Harvey rat sarcoma viral oncogene homolog
Y (8336750) Unknown (?) Y

References

  • Prostate cancer risk and IRS1, IRS2, IGF1, and INS polymorphisms: strong association of IRS1 G972R variant and cancer risk.

    Neuhausen SL, Slattery ML, Garner CP, Ding YC, Hoffman M and Brothman AR

    Department of Medicine, Division of Epidemiology, University of California Irvine, Irvine, CA 92697-7550, USA. sneuhaus@uci.edu

    Background: As cellular proliferation is central to the carcinogenic process, pathways that regulate proliferation may be important. Therefore, genes in the insulin and the insulin-like growth factor signaling pathways are plausible candidates for susceptibility genes for prostate cancer. We hypothesized that functional polymorphisms in INS, IRS1, IRS2, and IGF1 may be associated with prostate cancer.

    Methods: We studied 199 incident prostate cancer cases and 267 age-matched controls. Genotyping was performed for the INS +1127 Ins-PstI, IRS1 G972R, IRS2 G1079D, and the IGF1 CA-repeat polymorphisms. Outcomes were prostate cancer, Gleason score, and AJCC stage.

    Results: The IRS1 G972R GR/RR genotypes were associated with a significant 2.8-fold increased risk for prostate cancer (95% CI 1.5-5.1, P = 0.0007). The other variants were not significantly associated with prostate cancer. The IRS1 G972R GR/RR genotypes were also significantly associated with more advanced Gleason score (P = 0.001) and AJCC stage (P = 0.004).

    Conclusions: These results support a role of the insulin and/or insulin-like growth factor pathways in the etiology of prostate cancer.

    Funded by: NCI NIH HHS: R01CA46269, R01CA48998

    The Prostate 2005;64;2;168-74

  • APC/CTNNB1 (beta-catenin) pathway alterations in human prostate cancers.

    Gerstein AV, Almeida TA, Zhao G, Chess E, Shih IeM, Buhler K, Pienta K, Rubin MA, Vessella R and Papadopoulos N

    Department of Pathology, Institute of Cancer Genetics, Columbia University, New York, New York, USA.

    Genetic alterations serve as beacons for the involvement of specific pathways in tumorigenesis. It was previously shown that 5% of prostate tumors harbor CTNNB1 mutations, suggesting that this tumor type may involve a deregulated APC/CTNNB1 pathway. To explore this possibility further, we searched for mutations in genes implicated in this pathway in 22 samples that included cell lines, xenografts, and primary tumors. We identified seven alterations: two in CTNNB1, three in APC, and two in hTRCP1 (also known as BTRC) which controls the degradation of CTNNB1. Alterations in the CTNNB1 regulatory domain, APC, and hTRCP1 were mutually exclusive, consistent with their equivalent effects on CTNNB1 stability. These results suggest that CTNNB1 signaling plays a critical role in the development of a significant fraction of prostate cancers. Moreover, they provide the first evidence that hTRCP1 plays a role in human neoplasia.

    Genes, chromosomes & cancer 2002;34;1;9-16

  • Beta-catenin mutations in human prostate cancer.

    Voeller HJ, Truica CI and Gelmann EP

    Division of Hematology/Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC 20007-2197, USA.

    Beta-catenin plays essential roles in both intercellular adhesion and signal transduction. As a signaling molecule, beta-catenin supplies an activating domain to the T-cell factor/lymphoid enhancer-binding factor family of DNA-binding proteins and activates gene transcription. Posttranslational stabilization of beta-catenin, leading to elevated protein levels and constitutive gene activation, has been proposed as an important step in oncogenesis. Stabilization of beta-catenin can occur through mutation to highly conserved amino acids encoded in exon 3 of the beta-catenin gene (CTNNB1). To determine whether this pathway of malignant transformation is important in prostate cancer, we analyzed 104 prostate cancer tissue specimens, 4 prostate cancer cell lines, and 3 prostate tumor xenografts for activating mutations in exon 3 of CTNNB1. Mutations were detected in 5 of the 104 prostate cancer tissue samples. Four of the five mutations involved serine or threonine residues implicated in the degradation of beta-catenin. A fifth tumor had a mutation at codon 32, changing a highly conserved aspartic acid to a tyrosine. Mutational analysis of multiple regions from several tumor samples showed that the beta-catenin mutations were present focally and therefore may occur during tumor progression.

    Funded by: NCI NIH HHS: P30-CA-51008

    Cancer research 1998;58;12;2520-3

  • An association between the risk of cancer and mutations in the HRAS1 minisatellite locus.

    Krontiris TG, Devlin B, Karp DD, Robert NJ and Risch N

    Department of Medicine, Tufts University School of Medicine, Boston, MA.

    Background: The role of mutations in protooncogenes and their regulatory sequences in the pathogenesis of cancer is under close scrutiny. Minisatellites are unstable repetitive sequences of DNA that are present throughout the human genome. The highly polymorphic HRAS1 minisatellite locus just downstream from the protooncogene H-ras-1 consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. We previously observed an association of the rare mutant alleles with many forms of cancer, and we undertook the present study to pursue this observation further.

    Methods: We conducted a case-control study, typing 736 HRAS1 alleles from patients with cancer and 652 from controls by Southern blotting of leukocyte DNA. We also carried out a meta-analysis of this study and 22 other published studies, estimating the relative risk of cancer (such as bladder, breast, or colorectal cancer) when one of the rare HRAS1 alleles was present.

    Results: Both the present case-control study (odds ratio, 1.83; 95 percent confidence interval, 1.28 to 2.67; P = 0.002) and the present study combined with our previous study (odds ratio, 2.07; 95 percent confidence interval, 1.47 to 2.92; P < 0.001), as well as the meta-analysis of all 23 studies (odds ratio, 1.93; 95 percent confidence interval, 1.63 to 2.30; chi-square = 57.58; P < 0.001), replicated our original finding and demonstrated a significant association of rare HRAS1 alleles with cancer. We found significant associations for four types of cancer: carcinomas of the breast, colorectum, and urinary bladder and acute leukemia. We also identified suggestive but not statistically significant associations for cancers of the lung and prostate and for non-Hodgkin's lymphoma.

    Conclusions: Mutant alleles of the HRAS1 minisatellite locus represent a major risk factor for common types of cancer. Although the relative risk associated with the presence of one rare allele is moderate, the aggregate prevalence of one rare allele is moderate, the aggregate prevalence of this class of mutant alleles implies an extremely important attributable risk: 1 in 11 cancers of the breast, colorectum, and bladder.

    Funded by: NCI NIH HHS: CA-45052

    The New England journal of medicine 1993;329;8;517-23

Literature (4)

Pubmed - human_disease

  • Beta-catenin mutations in human prostate cancer.

    Voeller HJ, Truica CI and Gelmann EP

    Division of Hematology/Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC 20007-2197, USA.

    Beta-catenin plays essential roles in both intercellular adhesion and signal transduction. As a signaling molecule, beta-catenin supplies an activating domain to the T-cell factor/lymphoid enhancer-binding factor family of DNA-binding proteins and activates gene transcription. Posttranslational stabilization of beta-catenin, leading to elevated protein levels and constitutive gene activation, has been proposed as an important step in oncogenesis. Stabilization of beta-catenin can occur through mutation to highly conserved amino acids encoded in exon 3 of the beta-catenin gene (CTNNB1). To determine whether this pathway of malignant transformation is important in prostate cancer, we analyzed 104 prostate cancer tissue specimens, 4 prostate cancer cell lines, and 3 prostate tumor xenografts for activating mutations in exon 3 of CTNNB1. Mutations were detected in 5 of the 104 prostate cancer tissue samples. Four of the five mutations involved serine or threonine residues implicated in the degradation of beta-catenin. A fifth tumor had a mutation at codon 32, changing a highly conserved aspartic acid to a tyrosine. Mutational analysis of multiple regions from several tumor samples showed that the beta-catenin mutations were present focally and therefore may occur during tumor progression.

    Funded by: NCI NIH HHS: P30-CA-51008

    Cancer research 1998;58;12;2520-3

  • An association between the risk of cancer and mutations in the HRAS1 minisatellite locus.

    Krontiris TG, Devlin B, Karp DD, Robert NJ and Risch N

    Department of Medicine, Tufts University School of Medicine, Boston, MA.

    Background: The role of mutations in protooncogenes and their regulatory sequences in the pathogenesis of cancer is under close scrutiny. Minisatellites are unstable repetitive sequences of DNA that are present throughout the human genome. The highly polymorphic HRAS1 minisatellite locus just downstream from the protooncogene H-ras-1 consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. We previously observed an association of the rare mutant alleles with many forms of cancer, and we undertook the present study to pursue this observation further.

    Methods: We conducted a case-control study, typing 736 HRAS1 alleles from patients with cancer and 652 from controls by Southern blotting of leukocyte DNA. We also carried out a meta-analysis of this study and 22 other published studies, estimating the relative risk of cancer (such as bladder, breast, or colorectal cancer) when one of the rare HRAS1 alleles was present.

    Results: Both the present case-control study (odds ratio, 1.83; 95 percent confidence interval, 1.28 to 2.67; P = 0.002) and the present study combined with our previous study (odds ratio, 2.07; 95 percent confidence interval, 1.47 to 2.92; P < 0.001), as well as the meta-analysis of all 23 studies (odds ratio, 1.93; 95 percent confidence interval, 1.63 to 2.30; chi-square = 57.58; P < 0.001), replicated our original finding and demonstrated a significant association of rare HRAS1 alleles with cancer. We found significant associations for four types of cancer: carcinomas of the breast, colorectum, and urinary bladder and acute leukemia. We also identified suggestive but not statistically significant associations for cancers of the lung and prostate and for non-Hodgkin's lymphoma.

    Conclusions: Mutant alleles of the HRAS1 minisatellite locus represent a major risk factor for common types of cancer. Although the relative risk associated with the presence of one rare allele is moderate, the aggregate prevalence of one rare allele is moderate, the aggregate prevalence of this class of mutant alleles implies an extremely important attributable risk: 1 in 11 cancers of the breast, colorectum, and bladder.

    Funded by: NCI NIH HHS: CA-45052

    The New England journal of medicine 1993;329;8;517-23

Pubmed - other

  • Prostate cancer risk and IRS1, IRS2, IGF1, and INS polymorphisms: strong association of IRS1 G972R variant and cancer risk.

    Neuhausen SL, Slattery ML, Garner CP, Ding YC, Hoffman M and Brothman AR

    Department of Medicine, Division of Epidemiology, University of California Irvine, Irvine, CA 92697-7550, USA. sneuhaus@uci.edu

    Background: As cellular proliferation is central to the carcinogenic process, pathways that regulate proliferation may be important. Therefore, genes in the insulin and the insulin-like growth factor signaling pathways are plausible candidates for susceptibility genes for prostate cancer. We hypothesized that functional polymorphisms in INS, IRS1, IRS2, and IGF1 may be associated with prostate cancer.

    Methods: We studied 199 incident prostate cancer cases and 267 age-matched controls. Genotyping was performed for the INS +1127 Ins-PstI, IRS1 G972R, IRS2 G1079D, and the IGF1 CA-repeat polymorphisms. Outcomes were prostate cancer, Gleason score, and AJCC stage.

    Results: The IRS1 G972R GR/RR genotypes were associated with a significant 2.8-fold increased risk for prostate cancer (95% CI 1.5-5.1, P = 0.0007). The other variants were not significantly associated with prostate cancer. The IRS1 G972R GR/RR genotypes were also significantly associated with more advanced Gleason score (P = 0.001) and AJCC stage (P = 0.004).

    Conclusions: These results support a role of the insulin and/or insulin-like growth factor pathways in the etiology of prostate cancer.

    Funded by: NCI NIH HHS: R01CA46269, R01CA48998

    The Prostate 2005;64;2;168-74

  • APC/CTNNB1 (beta-catenin) pathway alterations in human prostate cancers.

    Gerstein AV, Almeida TA, Zhao G, Chess E, Shih IeM, Buhler K, Pienta K, Rubin MA, Vessella R and Papadopoulos N

    Department of Pathology, Institute of Cancer Genetics, Columbia University, New York, New York, USA.

    Genetic alterations serve as beacons for the involvement of specific pathways in tumorigenesis. It was previously shown that 5% of prostate tumors harbor CTNNB1 mutations, suggesting that this tumor type may involve a deregulated APC/CTNNB1 pathway. To explore this possibility further, we searched for mutations in genes implicated in this pathway in 22 samples that included cell lines, xenografts, and primary tumors. We identified seven alterations: two in CTNNB1, three in APC, and two in hTRCP1 (also known as BTRC) which controls the degradation of CTNNB1. Alterations in the CTNNB1 regulatory domain, APC, and hTRCP1 were mutually exclusive, consistent with their equivalent effects on CTNNB1 stability. These results suggest that CTNNB1 signaling plays a critical role in the development of a significant fraction of prostate cancers. Moreover, they provide the first evidence that hTRCP1 plays a role in human neoplasia.

    Genes, chromosomes & cancer 2002;34;1;9-16

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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