Three discrete areas within the chromosomal 8p21.3–23 region are associated with the development of breast carcinoma of Indian patients

Bhattacharya, Nilanjana; Chunder, Neelanjana; Basu, Debasis; Roy, Anup; Mandal, Santosh K.; Majumder, Jahar; Roychowdhury, Susanta; Panda, Chinmay Kumar

doi:10.1016/j.yexmp.2004.01.002

Cited by 11 publications

(9 citation statements)

References 30 publications

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“…This is in agreement with a previously suggested TSG role for this gene, in which its depletion was shown to increase breast cancer cell proliferation (42). Additionally, the reported 10% of LOH events on the detected 8p23.1 locus in this study have also been indicated in an earlier analysis which recruited Indian population-based clinical samples (43).…”

Section: Integration Of Loh Accompanied By Cn Alterationssupporting

confidence: 93%

Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array

et al. 2011

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Abstract. Breast cancer is a heterogeneous disease, marked by extensive chromosomal aberrations. In this study, we aimed to explicate the underlying chromosomal copy number (CN) alterations and loss of heterozygosity (LOH) implicated in a cohort of Malaysian hospital-based primary breast carcinoma samples using a single nucleotide polymorphism (SNP) array platform. The analysis was conducted by hybridizing the extracted DNA of 70 primary breast carcinomas and 37 normal peripheral blood samples to the Affymetrix 250K Sty SNP arrays. Locus-specific CN aberrations and LOH were statistically summarized using the binary segmentation algorithm and hidden Markov model. Selected genes from the SNP array analysis were also validated using quantitative real-time PCR. The merging of CN and LOH data fabricated distinctive integrated alteration profiles, which were comprised of finely demarcated minimal sites of aberrations. The most prevalent gains (≥30%) were detected at the 8q arm: 8q23.1, 8q23.3, 8q24.11, 8q24.13, 8q24.21, 8q24.22, 8q24.23 and 8q24.3, whilst the most ubiquitous losses (≥20%) were noted at the 8p12, 8p21.1, 8p21.2, 8p21.1-p21.2, 8p21.3, 8p22, 8p23.1, 8p23.1-p23.2, 8p23.3, 17p11.2, 17p12, 17p11.2-p12, 17p13.1 and 17p13.2 regions. Copy-neutral LOH was characterized as the most prevailing LOH event, in which the most frequent distributions (≥30%) were revealed at 3p21.31, 5q33.2, 12q24.12, 12q24.12-q24.13 and 14q23.1. These findings offer comprehensive genome-wide views on breast cancer genomic changes, where the most recurrent gain, loss and copy-neutral LOH events were harboured within the 8q24.21, 8p21.1 and 14q23.1 loci, respectively. This will facilitate the uncovering of true driver genes pertinent to breast cancer biology and the development of prospective therapeutics.

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Section: Integration Of Loh Accompanied By Cn Alterationssupporting

confidence: 93%

Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array

et al. 2011

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“…Sporadic BC samples having MSI in other chromosomal arms have been reported to show frequent mutation and methylation of the DNA mismatch repair gene hMLH1 . ( 19,37 ) On the contrary, we have seen infrequent MSI in different chromosomal arms in primary BC. ( 6,7,9,10,38 ) This might be due to differences in etiology, ethnicity and probably methods used in the analysis.…”

Section: Discussionmentioning

confidence: 75%

Frequent alterations of hMLH1 and RBSP3/HYA22 at chromosomal 3p22.3 region in early and late‐onset breast carcinoma: clinical and prognostic significance

et al. 2008

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Young age can be an independent prognostic factor for adverse prognosis in women with breast carcinoma (BC). In younger women, BC exhibited more aggressive pathological features than older women, indicating differences in biology. Frequent alterations in chromosomal (chr.) 3p22.3 in different malignancies indicated the existence of multiple candidate tumor suppressor genes (TSG) in this region, yet its association with BC remains unclear. In an effort to understand the differences in molecular pathogenesis in two age groups of BC, detailed analysis of alterations at chr.3p22.3 region was carried out in 47 early onset (group-A: 40 years) and 59 lateonset (group-A: >40 years) BC samples. Deletion mapping of the four candidate TSG, hMLH1, APRG1, ITGA9 and RBSP3/HYA22, located within 1 Mb of chr.3p22.3 showed high deletion in hMLH1 and RBSP3/HYA22 genes. Frequent methylation was also observed in these genes and significantly associated with their deletion. Quantitative messenger RNA (mRNA) expression and immunohistochemical analysis showed down-regulation of these genes. Alterations (deletion/methylation) of hMLH1 were significantly associated with RBSP3/HYA22 in group-A (P = 0.02). Significant poor survival in group-A patients with alterations in hMLH1 and RBSP3/ HYA22 and the same in group-B patients with hMLH1 alterations indicated their importance as prognostic markers. Differential association of alterations of these genes with higher histological grades, more advanced stages and positive lymph node involvement were also seen. Thus, the present study suggests hMLH1 and RBSP3/HYA22 to be candidate TSG associated with development of both early and late-onset BC undergoing frequent genetic and epigenetic alteration and having significant prognostic implications. (Cancer Sci 2008; 99: 1984-1991 B reast cancer (BC), is the third most prevalent malignancy and primary cause of death in women worldwide.(1) In India, it accounts for 19% of all cancers among women, and is the second most common cancer when both sexes are considered together, whereas about 23% of eastern Indian women suffer from this disease. (2,3) Considering the age at onset of tumor, BC can be classified as early onset (group-A: ≤40 years) and late-onset (group-B: >40 years).(4,5) However, the cut-off value for early onset BC varies among investigators, ranging from 35-50 years. (6,7) Despite this discrepancy, younger women with BC exhibit more aggressive pathological features, including large tumor size of higher grade, presence of positive lymph nodes, absence of steroid receptors and high S-phase fraction, than older women with BC.(6,7) Another report showed that, in an Asian population, BC patients below 40 years have tumors with a poorer prognostic profile. However, this did not translate into poorer overall survival and might be attributable to more aggressive adjuvant treatment of younger patients.(8) All these reports suggested early onset BC to be a biologically separate disease that independently predicts more adverse outcomes. Thus, the mol...

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“…8p23 is also a common integration site for HBV, a well-known major risk factor in liver cancer (5,10). Similarly, LOH on 8p is found in up to 50% of breast carcinomas and is often associated with advanced tumor stage and aggressive histology (11)(12)(13)(14). Although several tumor suppressors have been mapped to this region, including transcriptional factors Nkx3.1 at 8p21 and FEZ1/LZTS1 at 8p22 (15)(16)(17), even the combined rates of loss of these genes could not account for the extensive alterations seen in human tumors (16), indicating that major tumor suppressor gene or genes remain to be identified.…”

Section: Introductionmentioning

confidence: 99%

The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice

Zhou¹,

Huang²,

Shi³

et al. 2011

J. Clin. Invest.

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Telomerase is activated in most human cancers and is critical for cancer cell growth. However, little is known about the significance of telomerase activation in chromosome instability and cancer initiation. The gene encoding the potent endogenous telomerase inhibitor PinX1 (PIN2/TRF1-interacting, telomerase inhibitor 1) is located at human chromosome 8p23, a region frequently exhibiting heterozygosity in many common human cancers, but the function or functions of PinX1 in development and tumorigenesis are unknown. Here we have shown that PinX1 is a haploinsufficient tumor suppressor essential for chromosome stability in mice. We found that PinX1 expression was reduced in most human breast cancer tissues and cell lines. Furthermore, PinX1 heterozygosity and PinX1 knockdown in mouse embryonic fibroblasts activated telomerase and led to concomitant telomerase-dependent chromosomal instability. Moreover, while PinX1-null mice were embryonic lethal, most PinX1 +/-mice spontaneously developed malignant tumors with evidence of chromosome instability. Notably, most PinX1 mutant tumors were carcinomas and shared tissues of origin with human cancer types linked to 8p23. PinX1 knockout also shifted the tumor spectrum of p53 mutant mice from lymphoma toward epithelial carcinomas. Thus, PinX1 is a major haploinsufficient tumor suppressor essential for maintaining telomerase activity and chromosome stability. These findings uncover what we believe to be a novel role for PinX1 and telomerase in chromosome instability and cancer initiation and suggest that telomerase inhibition may be potentially used to treat cancers that overexpress telomerase.

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Three discrete areas within the chromosomal 8p21.3–23 region are associated with the development of breast carcinoma of Indian patients

Cited by 11 publications

References 30 publications

Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array

Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array

Frequent alterations of hMLH1 and RBSP3/HYA22 at chromosomal 3p22.3 region in early and late‐onset breast carcinoma: clinical and prognostic significance

The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice

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