Evidence for a Tumor Suppressor Gene Distal to BRCA1 in Prostate Cancer

Williams, B. Jill; Jones, Emma; Zhu, Xiao Lin; Steele, Matt; Stephenson, Robert A.; Rohr, L. Ralph; Brothman, Arthur R.

doi:10.1097/00005392-199602000-00101

Cited by 10 publications

(12 citation statements)

References 22 publications

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“…It may signify that the underlying molecular mechanisms involved in tumour initiation may follow an alternative pathway in inherited than sporadic CaP. Interestingly, allelic losses at 17q in CaP seem to target a region that lies distal to the BRCA1 gene, implicating a novel tumour suppressor gene, distinct from the BRCA1 gene, in CaP tumorigenesis (Williams et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel

et al. 2000

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Inherited predisposition occurs in 5–10% of all prostate cancer (CaP) patients, but the genes involved in conferring genetic susceptibility remain largely unknown. Several lines of evidence indicate that germline mutations in BRCA1 and BRCA2 might be associated with an increased risk for CaP. Three mutations in these two genes (185delAG and 5382InsC ( BRCA1 ) and 6174delT ( BRCA2 ) occur in about 2.5% of the general Ashkenazi population, and the 185delAG BRCA1 mutation, in up to 1% of non-Ashkenazi Jews. In order to assess the contribution of these germline mutations to prostate cancer in Jewish Israeli patients, we tested 174 unselected prostate cancer patients (95 of Ashkenazi origin) for these mutations by PCR amplification and modified restriction enzyme digests. Patient’s age range was 45–81 years (median 66), and in 24 (14.4%) the disease was diagnosed prior to 55 years of age. Nineteen (11%) and 12 (6.9%) patients had a first or second degree relative with CaP or breast cancer, respectively. Overall, five mutation carriers were detected: 2/152 (1.3%) 185delAG, 2/104 (2%) 5382InsC, and 1/158 (0.6%) 6174delT. In all carriers, the disease was diagnosed after the age of 55, and only one of them had a family history of breast and CaP. In addition, no allelic losses at the BRCA1 locus were demonstrated in 17 patients with a family history of CaP, using seven microsatellite markers. We conclude that the rate of the predominant Jewish BRCA1 and BRCA2 mutations in CaP patients does not significantly differ from that of the general population, and that mutational inactivation of the BRCA1 is rare in familial CaP. Thus, germline BRCA1 and BRCA2 mutations probably contribute little to CaP occurrence, to inherited predisposition, and to early onset disease in Jewish individuals. © 2000 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 99%

The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel

et al. 2000

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“…Nevertheless, the overall contribution of germline BRCAI and BRCA2 mutations to prostate cancer incidence are probably small and could be limited to specific subgroups, such as that studied by Langston et al (1996a). Indeed, a mutation of a tumour-suppressor gene distal to the BRCAJ locus on the long arm of chromosome 17 may make a much greater contribution (Williams et al, 1996). A mutation on chromosome 1 may also play a role (Smith et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer

Lehrer

Fodor²,

Stock³

et al. 1998

Br J Cancer

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Summary Epidemiological studies have demonstrated a clustering of breast and prostate cancers in some families. Moreover, there is an increase in the number of cases of prostate cancer in families with inherited mutations of the breast cancer susceptibility gene BRCA 1. We assessed the role of BRCA1 and BRCA2 in prostate cancer. We tested for the BRCAl 185delAG frameshift mutation, found in 0.9% of Ashkenazi Jews, and the BRCA2 6174delT mutation, found in 1% of Ashkenazi Jews, in Ashkenazi Jewish men with prostate cancer. We studied 60 Ashkenazi men with prostate cancer. A family history was obtained by interview or a self-report questionnaire. Histological confirmation of diagnosis was obtained for all subjects. Ethnic background was confirmed for all subjects by self-report or interview. Mutations of BRCA 1 and BRCA2 were detected by amplification of lymphocyte DNA from peripheral blood according to standard polymerase chain reaction (PCR) and dot blot procedures. Patients' ages ranged from 55 to 80 years (mean ± s.d. 70 ± 5.25). There were six men with a family history of prostate cancer; three of these had a father with prostate cancer. Five of the men had a family history of breast cancer, in a mother, a sister or an aunt. None,of the men had a family history of both breast and prostate cancer. None of the 60 men carried the 1 85delAG BRCA 1 or 61 74delT BRCA2 mutations. Of 268 Ashkenazi Jewish women with sporadic breast cancer, tested in an unrelated study, 16 carried either the 1 85delAG mutation of BRCA 1 or the 61 74delT mutation of BRCA2. There was a significant difference in the incidence of the BRCA 1 and BRCA2 mutations in the breast and prostate cancer cases (P = 0.05, two-tailed Fisher's exact test). The contribution of germline BRCA 1 and BRCA2 mutations to prostate cancer incidence is probably small and could be limited to specific subgroups.

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“…14,15 Although the BRCA1 tumor-suppressor gene has been localized to this region, not all of the prostate tumor-suppressor activity in the region of 17q21 has been fully accounted for by the BRCA1 gene, 16 so that BRCA1 itself appears to play only a minor role in prostate cancer development. 17 The NM23 metastasissuppressor gene also localizes to 17q, 16 but has been excluded as the prostate metastasis-suppressor gene within the vicinity of 17q21. 14,15 Since the human p75 NTR gene maps to the region of 17q21, 12 in the vicinity of a tumor-suppressor gene 13 and a metastasis-suppressor gene, 14,15 its function(s) within the human prostate may be of significance to the development of prostate cancer.…”

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confidence: 99%

Neurotrophin receptor p75^NTR suppresses growth and nerve growth factor‐mediated metastasis of human prostate cancer cells

Krygier

Djakiew

2001

Intl Journal of Cancer

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The loss of tumor-and/or metastasis-suppressor gene function contributes to the transformation of human prostate epithelial cells to a malignant pathology. Such a putative tumor-suppressor and metastasis-suppressor gene(s) has been mapped to the region of 17q21, which coincidentally is in the vicinity of the human gene locus for the neurotrophin receptor p75 NTR . The p75 NTR is expressed in normal human prostate epithelial cells and exhibits an inverse association of p75 NTR expression with the malignant progression of the prostate, consistent with a pathologic role of the p75 NTR as a putative tumor and metastasis suppressor. Utilizing stable transfectants of the TSU-pr1 and PC-3 human prostate tumor cell lines that exhibit a rank order (dose-dependent) increase in p75 NTR protein expression, we investigated the effects of the p75 NTR in combination with its predominant ligand, nerve growth factor (NGF), on tumor cell growth. A rank order (dose-dependent) increase in p75 NTR expression was found to suppress the growth of prostate tumors in severe combined immunodeficient (SCID) mice. Treatment of these tumors with NGF stimulated both proliferation as indicated by PCNA expression and apoptosis as indicated by TUNEL assay, the net result of which was no change in the overall growth of the tumors. However, NGF was found to increase the formation of satellite tumors, both contiguous and noncontiguous with respect to the primary tumor mass, indicating dose-dependent induction of metastasis. Significantly, the formation of satellite tumors was suppressed by the expression of p75 NTR . This suggests that p75 NTR is a tumor suppressor of growth and a metastasis suppressor of NGF-stimulated migration of human prostate tumor cells.

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Evidence for a Tumor Suppressor Gene Distal to BRCA1 in Prostate Cancer

Abstract: The data suggest that the region distal to BRCA1 may contain 1 or more prostate-specific tumor suppressor genes and that BRCA1 itself plays only a minor role in prostate cancer development.

Cited by 10 publications

References 22 publications

The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel

The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel

Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer

Neurotrophin receptor p75^NTR suppresses growth and nerve growth factor‐mediated metastasis of human prostate cancer cells

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Evidence for a Tumor Suppressor Gene Distal to BRCA1 in Prostate Cancer

Abstract: The data suggest that the region distal to BRCA1 may contain 1 or more prostate-specific tumor suppressor genes and that BRCA1 itself plays only a minor role in prostate cancer development.

Cited by 10 publications

References 22 publications

The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel

The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel

Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer

Neurotrophin receptor p75NTR suppresses growth and nerve growth factor‐mediated metastasis of human prostate cancer cells

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Neurotrophin receptor p75^NTR suppresses growth and nerve growth factor‐mediated metastasis of human prostate cancer cells