Accommodating haploinsufficient tumour suppressor genes in Knudson's model

Cook, Wayne D.; McCaw, Benjamin J

doi:10.1038/sj.onc.1203653

Cited by 87 publications

(46 citation statements)

References 41 publications

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“…Thus, other inactivating mechanisms might indeed be involved in loss of SAFB. Recent studies have suggested that haploinsufficiency of some tumour suppressor genes is sufficient for tumorigenesis (Kairouz et al, 1999;Cook and McCaw, 2000) Despite these observations, we can not exclude that another gene in close proximity to SAFB functions as a tumour suppressor gene in human breast cancer. The 19p13 region studied spans approximately 3 megabasepairs of DNA (see Table 1).…”

Section: Discussionmentioning

confidence: 75%

High rates of loss of heterozygosity on chromosome 19p13 in human breast cancer

et al. 2001

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The oestrogen receptor (ER) is a nuclear steroid receptor that upon activation by its ligands (e.g. oestrogen) initiates a cascade of events resulting in increased cellular proliferation in its target tissues (Warner et al, 1999). Since oestrogen is one of the most potent mitogens for breast cancer cells, it is no surprise that ER is the most important target for endocrine therapy of breast cancer (Osborne, 1998). Recently, a number of factors which regulate nuclear hormone receptor activity have been identified. Cofactors capable of increasing receptor action, termed coactivators, include transcriptional intermediary factor 1 (TIF1), nuclear receptor interacting protein (NRIP1), nuclear receptor coactivator 2 (TIF2), steroid receptor coactivator 1 (SRC1), amplified in breast cancer 1 (AIB1), the cyclic AMP (cAMP)-response element binding protein (CREB) binding protein (CBP) (Glass et al, 1997;Shibata et al, 1997) and many more. The family of corepressors (negative regulators) of ER is smaller; the best characterized ones being the nuclear receptor corepressor (N-CoR) (Horlein et al, 1995;Shibata et al, 1997) the silencing mediator of retinoid and thyroid receptors (SMRT) (Chen and Evans, 1995;Sande and Privalsky, 1996) and the repressor of ER activity (REA) (Montano et al, 1999). The overexpression of coactivators or the loss of corepressors could lead to deregulation of oestrogen-dependent pathways related to mammary epithelial cell proliferation, and thus to breast tumorigenesis. And indeed, some of the ER cofactors have recently been characterized as playing major roles in breast tumorigenesis (Horlein et al, 1995;Anzick et al, 1997;Shibata et al, 1997). The ER coactivator AIB1 was cloned during a search on the long arm of chromosome 20 for genes whose expression and copy number are elevated in human breast cancer, and subsequent analysis in 105 breast tumour specimens confirmed its overexpression (Anzick et al, 1997). Interestingly, the breast/ovarian tumour suppressor gene BRCA1 has recently been characterized as an ER corepressor (Fan, 1999) again suggesting that ER coregulators are crucial in breast tumorigenesis. Thus, it might be expected that other ER coactivators and corepressors might play similar important roles in breast cancer development and progression.The nuclear matrix protein SAFB (Renz, 1996;Oesterreich, 1997) has been shown to be an ER corepressor . ER and SAFB interact in in-vitro binding assays (Glutathione-S-Transferase [GST]-pulldown assays) and in cell lines (co-immunoprecipitation experiments). In cell lines, there is binding of SAFB to ER in the presence or absence of oestradiol; however, binding is significantly increased by the antioestrogen tamoxifen. Overexpression of SAFB results in repression of oestrogen-mediated transactivation of gene expression by the ER. Furthermore, as a result of SAFB overexpression, the antagonist activity of tamoxifen on ER can be enhanced, and the agonist activity of tamoxifen can be inhibited.These results led us to investigate whether the ER corep...

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Section: Discussionmentioning

confidence: 75%

High rates of loss of heterozygosity on chromosome 19p13 in human breast cancer

et al. 2001

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“…Further investigation of this observation is now in progress. DISCUSSION Haploinsufficiency is one of the prerequisites for recessive tumor suppressor genes, where serial hits for both alleles are needed for loss of function (23). Inherited cancers show the first hit as a germ-line mutation, and the second hit results in loss of function of the gene, as explained by the hypothesis of Knudson (24).…”

Section: Resultsmentioning

confidence: 94%

A Novel Ankyrin Repeat-containing Gene (Kank) Located at 9p24 Is a Growth Suppressor of Renal Cell Carcinoma

Sarkar¹,

Roy²,

Hatano³

et al. 2002

Journal of Biological Chemistry

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By a combination of genome subtraction and comprehensive analysis of loss of heterozygosity based on mapping hemizygous deletions for a potential tumor-related locus, a minimum overlapping region of deletions at 9p24 the size of 165 kb was identified and found to harbor a new potential tumor suppressor gene for renal cell carcinoma, the Kank gene. Kank (for kidney ankyrin repeat-containing protein) contains four ankyrin repeats at its C terminus. Expression of the gene was suppressed in 6 of 8 or 6 of 10 cancer tissues examined by reverse transcription-PCR or Western blotting, respectively, and in several kidney tumor cell lines due to methylation at CpG sites in the gene. Epigenetic methylation or imprinting seemed to be the first hit, which was followed by a second hit of deletion, resulting in loss of function in many of these deletion cases. Expression of this gene in expression-negative HEK293 cells induced growth retardation at G 0 /G 1 as well as morphological changes.

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“…It has recently been hypothesized that 'haplo-insufficiency' (absence of a single TSG allele), in contrast to Knudson's two-hit model, could provide, on its own, a selective advantage to an emerging tumor cell line and/ or increase the size of the target cell population for mutagenesis (including mutation or loss of the remaining TSG allele). 15 These data suggest that haplo-insufficiency for tumor suppression genes could play a role in ALL pathogenesis. However, in view of the small number of cases and the generally poor prognosis of adult Ph + ALL patients, 16 it is difficult to make hypotheses on the role of specific deleted genes.…”

Section: Discussionmentioning

confidence: 96%

Deletions on der(9) chromosome in adult Ph-positive acute lymphoblastic leukemia occur with a frequency similar to that observed in chronic myeloid leukemia

et al. 2003

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The t(9;22)(q34;q11), generating the Philadelphia chromosome (Ph), is found in more than 90% of patients with chronic myeloid leukemia (CML) and in 15-30% of adults with acute lymphoblastic leukemia (ALL). Different groups have recently described the presence of large genomic deletions adjacent to the translocation breakpoint on the derivative chromosome 9 in 9-16% of CML patients. In the present paper, we report a FISH study of 45 Ph+ adult ALL patients with the aim of investigating the presence of deletions on derivative chromosome 9. In four (9%) of 45 cases, all showing an M-bcr, we detected deletions on der(9). The frequency of deletions we observed is similar to that reported in CML patients. The association of an M-bcr breakpoint and deletions appears significant (P ¼ 0.03). Some authors have suggested a very low incidence of der(9) deletions in ALL. This discrepancy can be explained by taking into account the low percentage of M-bcr ALL patients in the latter study (18%) compared to the present one (44% IntroductionThe BCR-ABL fusion on the Philadelphia (Ph) chromosome is the hallmark of chronic myeloid leukemia (CML), detectable in about 95% of patients. 1 This rearrangement is also present in 15-30% of adults with acute lymphoblastic leukemia (ALL). 2 The Ph chromosome results from a reciprocal translocation between 9q34 and 22q11.2 that transposes the 3 0 segment of the ABL gene from 9q34 to the 5 0 of the BCR gene on 22q11. 3 The breakpoints within the ABL gene at 9q34 can occur in a large region at its 5 0 end, more frequently in the first intron. However, the splicing of the primary hybrid transcript produces an mRNA molecule in which the BCR sequences are always fused to ABL exon a2. In most CML patients and up to 50% of patients with Ph-positive ALL (Ph+ ALL), the BCR breakpoint occurs in a 5.8-kb area spanning exons 12-16 (originally referred to as exons b1-b5), defined as the major breakpoint cluster region (M-bcr). 4,5 Owing to alternative splicing, fusion transcripts with either b2a2 or b3a2 junctions can be formed, giving rise to a 210-kDa chimeric protein (p210). In the remaining adult ALL patients and in rare cases of CML, the BCR break maps in the minor breakpoint cluster region (m-bcr), between the alternative exons e2' and e2. In these cases, a hybrid e1a2 transcript is produced and translated into a 190-kDa chimeric protein (p190). Moreover, a third breakpoint cluster region (m-bcr) was identified downstream of exon 19, giving rise to a 230-kDa fusion protein (p230). Some Ph + ALL and CML patients with p210-type transcripts also show expression of a p190-type fusion product because of alternative splicing of the primary mRNA. 6 Recent papers have pointed out the occurrence of 5 0 ABL and 3 0 BCR deletions next to the translocation breakpoint on the derivative chromosome 9 in a fair percentage of CML patients, ranging from 9 to 16%. 7-10 The deletions are associated with a worse prognosis.We report a detailed study of 45 Ph+ ALL cases performed to assess the incidence of der(9) deletio...

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Accommodating haploinsufficient tumour suppressor genes in Knudson's model

Cited by 87 publications

References 41 publications

High rates of loss of heterozygosity on chromosome 19p13 in human breast cancer

High rates of loss of heterozygosity on chromosome 19p13 in human breast cancer

A Novel Ankyrin Repeat-containing Gene (Kank) Located at 9p24 Is a Growth Suppressor of Renal Cell Carcinoma

Deletions on der(9) chromosome in adult Ph-positive acute lymphoblastic leukemia occur with a frequency similar to that observed in chronic myeloid leukemia

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