Prognostic significance of loss of heterozygosity at loci on chromosome 17p13.3-ter in sporadic breast cancer is evidence for a putative tumour suppressor gene

Liscia, Daniel S.; Morizio, R; Venesio, Tiziana; Palenzona, C; Donadio, Michela; Callahan, Robert

doi:10.1038/sj.bjc.6690427

Cited by 20 publications

(19 citation statements)

References 18 publications

(24 reference statements)

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“…In the present study we have also shown that HIC-1 expression (seven cancers) was associated with YNZ22 LOH (P = 0.015, two-tailed Fisher's exact test) a result which concurs with that previously reported (Fujii et al, 1998). Given the link between YNZ22 LOH and poor prognosis in breast cancer Liscia et al, 1999) one might expect HIC-1 expression would correlate with poor prognosis. These differing associations suggest that HIC-1 may be distinct from a second gene involved in breast cancer marked by YNZ22.…”

Section: Discussionsupporting

confidence: 92%

“…More detailed studies of allelic imbalance in breast cancer, using markers spanning 17p13.3 has further refined the deletion map (Stack et al, 1995). Furthermore, LOH at YNZ22 can occur in the absence of p53 mutation, deletion or over-expression (Cornelis et al, 1994;Thompson et al, 1998) suggesting both regions may be of clinical importance in sporadic breast cancer Liscia et al, 1999). In addition, supportive evidence for the involvement of a tumour suppressor gene, distinct from p53 on chromosome 17p, is strengthened by the functional suppression of malignancy observed following the transfection of chromosome 17 (but not with chromosome 13) into breast cancer cell lines by micro cellmediated chromosome transfer and analysis of the resulting deletions (Casey et al, 1993;Theile et al, 1995).…”

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confidence: 99%

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Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer

et al. 2001

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Summary A new cancer gene, HIC-1 (Hypermethylated in Cancer) telomeric to p53 on chromosome 17p may be of clinical importance in sporadic breast cancer. Regional DNA hypermethylation of 17p13.3 resulting in suppression of gene expression has been shown to precede 17p structural changes in human carcinogenesis. In addition, loss of heterozygosity studies have suggested clinically significant involvement of a gene on 17p13.3 associated with poor prognosis in breast cancer. Using RT-PCR analysis, we demonstrate that the MCF7 (wild type p53) cell line expressed HIC-1 transcripts but the MDAMB231 (mutant p53) cell line did not, suggesting loss of HIC-1 expression and p53 malfunction may be synergistic events in sporadic breast cancer. HIC-1 expression was examined using RT-PCR on RNA extracted from 50 primary untreated, human breast cancers and was detected in only 7/50 (14%) cancers. All seven patients with HIC-1 expression were alive without disease recurrence after 8 years follow-up and 5/7 had detectable p53 wild type mRNA expression. This suggests that retained HIC-1 expression may offer a survival advantage. However the seven cancers had 17p13.3 loss of heterozygosity (LOH; four patients), a feature previously associated with poor prognosis, or were homozygous (three patients) suggesting there may be two genes at 17p13.3 involved in breast carcinogenesis. Using a demethylating drug 5-aza-2′-deoxycytidine (DeoxyC), HIC-1 expression was restored in the MDAMB231 cells, also suggesting restoration of HIC-1 function by reversing HIC-1 hypermethylation may offer a therapeutic avenue in breast cancer.

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer

et al. 2001

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“…The presence of VNTR1 LOH without TP53 mutations could suggest that the tumor is still in an early stage. On the other hand, some tumors may display a TP53 mutation without LOH at 17p13 as observed in breast cancer (28,39,40), hepatocellular carcinoma (28), oral squamous cell carcinoma (30), and gastric cancer (38). In our series, the study of mRNA in four of seven mutated tumors without VNTR1 LOH showed that, in three of four, only the mutated allele is present.…”

Section: Discussionmentioning

confidence: 82%

Somatic TP53 Mutations Are Relatively Rare among Adrenocortical Cancers with the Frequent 17p13 Loss of Heterozygosity

Libé

Groussin

Tissier

et al. 2007

Clinical Cancer Research

110

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Purpose: Allelic losses [loss of heterozygosity (LOH)] at the 17p13 locus are frequent (85%) in adrenocortical cancers.The tumor suppressor geneTP53 is located at 17p13.The aim of the study was to determine the frequency of TP53 somatic inactivating mutations in adrenocortical tumors with 17p13 LOH and their clinico-biological correlations. Experimental Design: TP53 somatic mutations, intragenic LOH (VNTR1 marker), and p53 overexpression were studied in 36 adrenocortical tumors with 17p13 LOH determined by Southern blot. Results: TP53 mutations were detected in 33% of the tumors, and VNTR1 LOH was present in 44% of the cases and did not always correlate with the presence of a TP53 mutation. Only the TP53-mutant tumors exhibit a strong nuclear immunoreactivity. TP53-mutant tumors were significantly larger than wild-type TP53 tumors (median tumor weight: 640 versus 185 g; P = 0.02), were associated with a more advanced stage of tumor progression (MacFarlane stage IV; P = 0.01), and had a shorter disease-free survival (P = 0.03). Conclusions:The finding that only a minority of adrenocortical tumors with 17p13 LOH had either a VNTR1 LOH or a TP53 mutation indicates that TP53 might not be the only or major tumor suppressor gene at 17p13 involved in adrenocortical cancer progression. We suggest that a genetic instability of the 17p13 region, occurring early in adrenocortical cancer development, involves various genes located in this region. TP53 might be only one of them, and its alteration by the occurrence of inactivating mutation is associated with the development of more aggressive tumors.

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“…In several studies, this deletion region was not accompanied by loss of heterozygosity (LOH) at the linked p53 locus located at 17p13.1, suggesting the presence of an additional tumor suppressor gene(s) located in 17p13.3 (Saxena et al 1992;Phillips et al 1993Phillips et al , 1996aCornelis et al 1994;Merlo et al 1994;Schultz et al 1996;Chattopadhyay et al 1997;Liscia et al 1999;Hoff et al 2001). Interestingly, allelic loss at D17S28 and D17S5 also occurs in many other types of cancer, including breast, lung, and brain malignancies (Saxena et al 1992;Merlo et al 1994;Konishi et al 1998;Phelan et al 1998;Liscia et al 1999;Hoff et al 2001).…”

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confidence: 99%

Ovca1 regulates cell proliferation, embryonic development, and tumorigenesis

Chen¹,

Behringer²

2004

Genes Dev.

102

112

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Loss of OVCA1/DPH2L1 correlates with ovarian and breast cancer. To study its in vivo role, we generated Ovca1 mutant alleles in mice. Ovca1 heterozygotes spontaneously develop cancer. Ovca1 mutant mice die during embryonic development and at birth with developmental delay and defects in multiple organ systems. Cell proliferation defects were observed in Ovca1 mutant mouse embryonic fibroblasts (MEFs). p53 deficiency can rescue these Ovca1 mutant MEF proliferation defects and partially rescue Ovca1 mutant embryonic phenotypes. Furthermore, Ovca1; p53 double heterozygotes developed tumors quicker than p53 heterozygotes and with an increased carcinoma incidence. Multiple tumor burden in Ovca1 heterozygotes that were also p53 deficient was significantly higher than in p53 homozygous mutants. These in vivo findings demonstrate that Ovca1 is a tumor suppressor that can modify p53-induced tumorigenesis and suggest that it acts as a positive regulator for cell cycle progression. The close linkage of OVCA1 and p53 on human Chromosome 17 suggests that coordinated loss may be an important mechanism for the evolution of ovarian, breast, and other tumor phenotypes.[Keywords: Tumor suppressor; ovarian cancer; DPH2L1; Ovca2; HIC1; Miller-Dieker syndrome] Supplemental material is available at http://www.genesdev.org.

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Prognostic significance of loss of heterozygosity at loci on chromosome 17p13.3-ter in sporadic breast cancer is evidence for a putative tumour suppressor gene

Cited by 20 publications

References 18 publications

Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer

Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer

Somatic TP53 Mutations Are Relatively Rare among Adrenocortical Cancers with the Frequent 17p13 Loss of Heterozygosity

Ovca1 regulates cell proliferation, embryonic development, and tumorigenesis

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