Loss of heterozygosity at loci from chromosome arm 22Q in human sporadic breast carcinomas

Allione, Florence; Eisinger, François; Parc, Patricia; Noguchi, Tetsuro; Sobol, Hagay; Birnbaum, Daniel

doi:10.1002/(sici)1097-0215(19980119)75:2<181::aid-ijc3>3.0.co;2-q

Cited by 41 publications

(30 citation statements)

References 25 publications

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“…High frequencies of LOH (Ͼ50%) on chromosome arm 22q have been reported in ovarian, breast and colorectal cancers. 3,17,34 We initially identified a putative tumour suppressor locus to chromosome 22q13 6 and subsequently refined this to the 2.1 megabase interval between microsatellite markers D22S299 and CYP2D. 18 Candidate TSGs that we analysed for somatic mutations and excluded as being the target of 22q13.3 LOH include NF2, NAGA, SREPB2 and CYP2D6.…”

Section: Resultsmentioning

confidence: 99%

“…A high frequency of loss of heterozygosity (LOH) on chromosome arm 22q has been reported in a variety of malignancies including colorectal cancers, 1 breast cancers, [2][3][4] ovarian cancers, 5,6 hepatocellular cancers, 7 oral cancers, 8 meningiomas, 9 schwannomas, 10 and pheochromocytomas. 11 The NF2 tumour suppressor gene (TSG) located on 22q12 is somatically inactivated in the majority of tumours of neural crest origin suggesting that it is the main target of allelic loss in these types of tumours.…”

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confidence: 99%

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Mutation analysis of EP300 in colon, breast and ovarian carcinomas

Bryan

Jokubaitis

Chamberlain

et al. 2002

Intl Journal of Cancer

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The putative tumour suppressor gene EP300 is located on chromosome 22q13 which is a region showing frequent loss of heterozygosity (LOH) in colon, breast and ovarian cancers. We analysed 203 human breast, colon and ovarian primary tumours and cell lines for somatic mutations in EP300. LOH across the EP300 locus was detected in 38% of colon, 36% of breast, and 49% of ovarian primary tumours but no somatic mutations in EP300 were identified in any primary tumour. Analysis of 17 colon, 11 breast, and 11 ovarian cancer cell lines identified truncating mutations in 4 colon cancer cell lines (HCT116, HT29, LIM2405 and LIM2412). We confirmed the presence of a previously reported frameshift mutation in HCT116 at codon 1699 and identified a second frameshift mutation at codon 1468. Bi-allelic inactivation of EP300 was also detected in LIM2405 that harbours an insC mutation at codon 927 as well an insA mutation at codon 1468. An insA mutation at codon 1468 was identified in HT29 and a CGA>TGA mutation at codon 86 was identified in LIM2412. Both these lines were heterozygous across the EP300 locus and western blot analysis confirmed the presence of an apparently wild-type protein. Our study has established that genetic inactivation of EP300 is rare in primary colorectal, breast and ovarian cancers. In contrast, mutations are common among colorectal cancer cell lines with 4/17 harbouring homozygous or heterozygous mutations. The rarity of EP300 mutations among these tumour types that show a high frequency of LOH across 22q13 may indicate that another gene is the target of the loss. It is possible that bi-allelic inactivation of EP300 is not necessary and that haploinsufficiency is sufficient to promote tumorigenesis. Alternatively, silencing of EP300 may be achieved by epigenetic mechanisms such as promoter methylation.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Mutation analysis of EP300 in colon, breast and ovarian carcinomas

Bryan

Jokubaitis

Chamberlain

et al. 2002

Intl Journal of Cancer

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“…12,14 The other MCRD/P2 region was confined to a 3 Mb physical distance at 22q13.31 that partially overlaps with an area of deletion previously detected by Oskam et al 13 The cytogenetic band at 22q13.1-3 appears to be a focal 'hot spot' for LOH in many types of human cancer, including breast, colon, ovarian, and head and neck cancers. 11,[36][37][38][39] Lida et al 10 were, in fact, able to map a 2 cM region of allelic loss in breast cancer to the same cytogenetic band. Similarly, Allione et al 11 reported six regions along chromosome 22q, ranging from 3 to 6 cM in size, two of which overlap those intervals identified in this study, and, in oral squamous cell carcinoma, allelic deletion seems to be restricted to D22S274, 39 a marker included within the region of deletion identified in our study.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its link with glioma, 22q LOH correlates with the metastatic ability of pancreatic endocrine tumors. 9 Further, allelic loss on 22q was rarely observed in ductal carcinomas, in situ, of the breast, but was observed in up to 66% of invasive ductal and 75% of lobular carcinomas, 10,11 and occurs more frequently in the advanced stage of various other cancers, suggesting an association between 22q LOH and tumor progression.…”

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confidence: 99%

Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas

Nakamura

Ishida

Shimada

et al. 2005

Laboratory Investigation

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Frequent allelic losses on the long arm of chromosome 22 (22q) in gliomas indicate the presence of tumor suppressor gene (TSG) at this location. However, the target gene(s) residing in this chromosome are still unknown and their putative roles in the development of astrocytic tumors, especially in secondary glioblastoma, have not yet been defined. To compile a precise physical map for the region of common deletions in astrocytic tumors, we performed a high-density loss of heterozygosity (LOH) analysis using 31 polymorphic microsatellite markers spanning 22q in a series of grade II diffuse astrocytomas, anaplastic astrocytomas, primary glioblastomas, and secondary glioblastomas that had evolved from lower grade astrocytomas. LOH was found at one or more loci in 33% (12/36) of grade II diffuse astrocytomas, in 40% (4/10) of anaplastic astrocytomas, in 41% (26/64) of primary glioblastomas, and in 82% (23/28) of secondary glioblastomas. Characterization of the 22q deletions in primary glioblastomas identified two sites of minimally deleted regions at 22q12.3-13.2 and 22q13.31. Interestingly, 22 of 23 secondary glioblastomas affected shared a deletion in the same small (957 kb) region of 22q12.3, a region in which the human tissue inhibitor of metalloproteinases-3 (TIMP-3) is located. Investigation of the promoter methylation and expression of this gene indicated that frequent hypermethylation correlated with loss of TIMP-3 expression in secondary glioblastoma. This epigenetic change was significantly correlated to poor survival in eight patients with grade II diffuse astrocytoma. Our results suggest that a 957 kb locus, located at 22q12.3, may contain the putative TSG, TIMP-3, that appears to be relevant to progression to secondary glioblastoma and subsequently to the prognosis of grade II diffuse astrocytoma. In addition, the possibility of other putative TSGs on 22q12.3-13.2 and 22q13.31 that may also be involved in the development of primary glioblastomas cannot be ruled out.

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“…The 22q12.2-q12.3 region encompasses the neurofibromatosis type 2 (NF2) gene, a candidate TSG at this region (Rouleau et al, 1993). Because NF2 gene mutations are rarely seen in epithelial tumours with high frequency of allele losses at the NF2 gene locus (Takahashi et al, 1993;Englefield et al, 1994;Allione et al, 1998;Miyakawa et al, 1998), an additional TSG involved in tumourigenesis could be located at this region. In several neoplasms it has been established that multiple sequential genetic changes are associated with the development of invasive tumours.…”

Section: Genetics and Genomicsmentioning

confidence: 99%

High resolution chromosome 3p, 8p, 9q and 22q allelotyping analysis in the pathogenesis of gallbladder carcinoma

et al. 2002

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Our recent genome-wide allelotyping analysis of gallbladder carcinoma identified 3p, 8p, 9q and 22q as chromosomal regions with frequent loss of heterozygosity. The present study was undertaken to more precisely identify the presence and location of regions of frequent allele loss involving those chromosomes in gallbladder carcinoma. Microdissected tissue from 24 gallbladder carcinoma were analysed for PCR-based loss of heterozygosity using 81 microsatellite markers spanning chromosome 3p (n=26), 8p (n=14), 9q (n=29) and 22q (n=12) regions. We also studied the role of those allele losses in gallbladder carcinoma pathogenesis by examining 45 microdissected normal and dysplastic gallbladder epithelia accompanying gallbladder carcinoma, using 17 microsatellite markers. Overall frequencies of loss of heterozygosity at 3p (100%), 8p (100%), 9q (88%), and 22q (92%) sites were very high in gallbladder carcinoma, and we identified 13 distinct regions undergoing frequent loss of heterozygosity in tumours. Allele losses were frequently detected in normal and dysplastic gallbladder epithelia. There was a progressive increase of the overall loss of heterozygosity frequency with increasing severity of histopathological changes. Allele losses were not random and followed a sequence. This study refines several distinct chromosome 3p, 8p, 9q and 22q regions undergoing frequent allele loss in gallbladder carcinoma that will aid in the positional identification of tumour suppressor genes involved in gallbladder carcinoma pathogenesis. British Journal of Cancer (2002) Gallbladder carcinoma (GBC) is a relatively uncommon neoplasm which demonstrates considerable geographic and gender variation in incidence (Albores-Saavedra and Henson, 2000). For unknown reasons, it is one of the most frequent neoplasms in Chile, where it is the leading cause of cancer deaths in females (Lazcano-Ponce et al, 2001). It has been well established that invasive GBC is preceded by preneoplastic lesions, including dysplastic changes of the gallbladder epithelium (Albores-Saavedra and Henson, 2000). There is a very limited information about the molecular changes involved in the pathogenesis of GBC (Wistuba and Albores-Saavedra, 1999).It is now well recognised that tumourigenesis is a multistep process resulting from the accumulation of sequential genetic alterations (Fearon and Vogelstein, 1990). In addition to oncogene activation, inactivation of tumour suppressor genes (TSGs) has been shown to play an important role in tumourigenesis (Fearon and Vogelstein, 1990). Allelic loss, manifested as loss of heterozygosity (LOH) at polymorphic loci, is recognised as a hallmark of tumour suppressor genes, whose other allele is inactivated by point mutations or by some other mechanism (Knudson, 1985). Thus, the finding of chromosomal regions with frequent incidence of LOH in a neoplasm suggests that those regions may harbour one or more TSGs.Our recent genome-wide allelotyping analysis on GBC indicated that allelic losses at multiple sites of the genome are freque...

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Loss of heterozygosity at loci from chromosome arm 22Q in human sporadic breast carcinomas

Cited by 41 publications

References 25 publications

Mutation analysis of EP300 in colon, breast and ovarian carcinomas

Mutation analysis of EP300 in colon, breast and ovarian carcinomas

Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas

High resolution chromosome 3p, 8p, 9q and 22q allelotyping analysis in the pathogenesis of gallbladder carcinoma

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