Identification of rare variants in the hLIMD1 gene in breast cancer

Huggins, Christopher J.; Gill, Mona; Andrulis, Irene L.

doi:10.1016/j.cancergencyto.2007.06.007

Cited by 12 publications

(10 citation statements)

References 37 publications

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“…The fact that LIMD1 is expressed to varying degrees in all normal and tumour tissues examined in this study corroborates the recent report by Huggins et al, 36 where they analysed the genomic DNA from 235 breast cancer for LIMD1 polymorphisms and found only 0.85% to have any changes. These were 4 coding region alterations, including 2 amino acid substitutions at positions 255 and 302 with no known attributed effects on LIMD1 function.…”

Section: Discussionsupporting

confidence: 92%

“…This is in contrast to analysis of lung cancer where loss of LIMD1 expression predominates, supporting the observation that mutations or deletions in LIMD1 in breast cancers at the C3CER1 region may not occur as frequently compared to lung. 18,36 This immunohistochemical analysis of the breast cancer TMAs indicated that the majority of cellular staining was weak to moderate and localised to the cytoplasm (Figs. 2a and 2b).…”

Section: Limd1 Has Distinct Patterns Of Expression and Subcellular Lomentioning

confidence: 95%

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Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

Spendlove¹,

Al‐Attar²,

Watherstone³

et al. 2008

Intl Journal of Cancer

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The tumour suppressor gene (TSG) LIM domain containing protein 1 (LIMD1) has been associated with transformation of epithelial cells of the lung and its expression is downregulated in all lung tumour samples tested compared to normal lung matched controls. In the first study of its kind we used an anti-LIMD1 specific monoclonal antibody to investigate expression/localisation of the LIMD1 protein in a well-characterised tissue microarray of breast cancers and normal adjacent epithelia. Comparison of tumour with adjacent normal and distant normal tissue demonstrated that LIMD1 expression is moderate to high compared to tumour. There was also a significant correlation with histological grade (p 5 0.0001), tumour size (p 5 0.013) and tumour type (p 5 0.004) indicating an association with aggressive disease. Cytoplasmic LIMD1 expression was seen in 99.3% of cases, with 43.1% showing both nuclear and cytoplasmic localisation. Absence/loss of nuclear staining showed a strong correlation with patient survival and was indicative of poor prognosis (p 5 0.033). There was no association with lymph node status and other clinicopathological parameters. Nuclear staining was more pronounced in better prognosis tumours and normal tissue. This study demonstrates that LIMD1 represents a novel prognostic marker for breast cancer. Combined with the fact that LIMD1 expression is downregulated in lung cancers this clearly indicates that LIMD1 may represent a critical TSG, the function of which is deregulated via overall loss of expression and/or relocalisation within the cell during tumour development. The possible functions of LIMD1 localisation within the nucleus and cytoplasm and its relationship to tumour prognosis are discussed. ' 2008 Wiley-Liss, Inc.Key words: LIMD1; Ajuba; breast cancer; E-cadherin; tissue microarray; prognostic indicator Breast cancer is the most common cause of cancer-related death in women in the western world. Alterations in tumour suppressor genes (TSG) and oncogenes are common causes for the higher proliferative rates and pathogenic characteristics associated with tumour development. Cytogenetics and allelotyping have shown that allelic loss from several distinct regions on chromosome 3p, including 3p25, 3p21-22, 3p21.3, 3p12-13 and 3p14, are the earliest and most frequent genomic abnormalities involved in a wide spectrum of major epithelial cancers of lung 1-6 and breast tissues 7-9 as well as many other epithelial derived cancers. [10][11][12][13] Specifically the 3p21.3 gene cluster contains many TSG and oncogenes and is a region of major loss of heterozygosity in lung cancers. [14][15][16] Abnormalities at the 3p21.3 chromosomal region include homozygous deletions, loss of heterozygosity and expressional deficiencies that can be induced through methylation of promoters, altered mRNA transcripts and loss of protein translocation. 17 The chromosome 3 commonly eliminated region (C3CER1) is located within the 3p21.3 gene cluster. The C3CER1 contains several putative TSG and is eliminated in many forms o...

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Section: Discussionsupporting

confidence: 92%

Section: Limd1 Has Distinct Patterns Of Expression and Subcellular Lomentioning

confidence: 95%

Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

Spendlove¹,

Al‐Attar²,

Watherstone³

et al. 2008

Intl Journal of Cancer

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“…Majority of mutations in LIMD1 were present in and around the pRB binding domain of exon1. Unlike us, Huggins et al detected very low frequency (4%, 6/165) of mutation in exon1 of LIMD1 at different positions in breast carcinoma [21]. In our samples, about 42% (14/33) of the mutations produced non-functional truncated LIMD1 proteins due to premature termination or splice-junction mutations (Table 2).…”

Section: Discussioncontrasting

confidence: 62%

LIMD1 is more frequently altered than RB1 in head and neck squamous cell carcinoma: clinical and prognostic implications

Ghosh

Maiti

et al. 2010

Mol Cancer

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IntroductionTo understand the role of two interacting proteins LIMD1 and pRB in development of head and neck squamous cell carcinoma (HNSCC), alterations of these genes were analyzed in 25 dysplastic head and neck lesions, 58 primary HNSCC samples and two HNSCC cell lines.MethodsDeletions of LIMD1 and RB1 were analyzed along with mutation and promoter methylation analysis of LIMD1. The genotyping of LIMD1 linked microsatellite marker, hmlimD1, was done to find out any risk allele. The mRNA expression of LIMD1 and RB1 were analyzed by Q-PCR. Immunohistochemical analysis of RB1 was performed. Alterations of these genes were correlated with different clinicopathological parameters.ResultsHigh frequency [94% (78/83)] of LIMD1 alterations was observed in the samples studied. Compare to frequent deletion and methylation, mutation of LIMD1 was increased during tumor progression (P = 0.007). Six novel mutations in exon1 and one novel intron4/exon5 splice-junction mutation were detected in LIMD1 along with a susceptible hmlimD1 (CA)20 allele. Some of these mutations [42% (14/33)] produced non-functional proteins. RB1 deletion was infrequent (27%). Highly reduced mRNA expression of LIMD1 (25.1 ± 19.04) was seen than RB1 (3.8 ± 8.09), concordant to their molecular alterations. The pRB expression supported this data. Tumors with LIMD1 alterations in tobacco addicted patients without HPV infection showed poor prognosis. Co-alterations of these genes led the worse patients' outcome.ConclusionsOur study suggests LIMD1 inactivation as primary event than inactivation of RB1 in HNSCC development.

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“…Mutation in LIMD1 has not been reported in HNSCC earlier, however, 2 NCBI SNP reported ref SNPs, rs267236 and rs267237 as well as 4 novel coding region alterations has been found in breast carcinoma. 41 The somatic mutation seen in the samples was homozygous in nature (confirmed by sequencing) (Fig. 5a) and the samples showed either deletion or methylation of this gene (Table II).…”

Section: Mutation Analysismentioning

confidence: 99%

Alterations of 3p21.31 tumor suppressor genes in head and neck squamous cell carcinoma: Correlation with progression and prognosis

Ghosh

Maiti

et al. 2008

Intl Journal of Cancer

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The aim of our study was to analyze the alterations of some candidate tumor suppressor genes (TSGs) viz. LIMD1, LTF, CDC25A, SCOTIN, RASSF1A and CACNA2D2 located in the chromosomal region 3p21.31 associated with the development of early dysplastic lesions of head and neck. In analysis of 72 dysplastic lesions and 116 squamous cell carcinoma of head and neck, both deletion and promoter methylation have been seen in these genes except for CDC25A and SCOTIN where no methylation has been detected. The alteration of LIMD1 was highest (50%) in the mild dysplastic lesions and did not change significantly during progression of tumor indicating its association with this stage of the disease. It was evident that alterations of LTF, CDC25A and CACNA2D2 were associated with development of moderate dysplastic lesions, while alterations in RASSF1A and CACNA2D2 were needed for progression. Novel somatic mutations were seen in exon 1 of LIMD1 (7%), intron 3/exon4 splice junction of LTF (2%) and exon 7 of cdc25A (10%). Quantitative RT-PCR analysis revealed mean reduced expression of the genes in the following order: LTF (67.6 6 16.8) > LIMD1 (53.2 6 20.1) > CACNA2D2 (23.7 6 7.1) > RASSF1A (15.1 6 5.6) > CDC25A (5.3 6 2.3) > SCOTIN (0.58 6 0.54). Immunohistochemical analysis of CDC25A showed its localization both in cytoplasm and nucleus in primary lesions and oral cancer cell lines. In absence of HPV infection, LTF and RASSF1A alterations jointly have adverse impact on survival of tobacco addicted patients. Thus, our data suggested that multiple candidate TSGs in the chromosomal 3p21.31 region were differentially associated with the early dysplastic lesions of head and neck. ' 2008 Wiley-Liss, Inc.Key words: dysplastic lesions; expression; head and neck squamous cell carcinoma; mutation; 3p21.31; survival study; tumor suppressor genes; methylation Head and neck squamous cell carcinoma of (HNSCC) is the sixth most common cancer worldwide and it accounts for 30-40% of all cancer types in Indian subcontinent.1 HNSCC is a heterogeneous epithelial malignant disease arising from mucosa of the upper aerodigestive tract (oral cavity, larynx, oropharynx and hypopharynx) with complex molecular abnormalities. Although the major and common environmental carcinogenic risk factors of tobacco, alcohol, betel quid and HPV infection have long been recognized, details of the genetic and epigenetic events leading to the development and spread of HNSCC remain largely unknown. Array-based gene expression profiling focused the transition of normal mucosa to premalignant lesion as the most important event with majority of transcriptional alterations rather than transition from premalignant lesion to invasive carcinoma during the progression of HNSCC.2 In microcell hybrid system, it has been shown that the introduction of chromosome 3 can suppress the tumorigenicity of oral cancer cell lines, suggesting the presence of at least 1 tumor suppressor gene (TSG) in this chromosome associated with the development of HNSCC.3 According to a recent tumor progr...

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Identification of rare variants in the hLIMD1 gene in breast cancer

Cited by 12 publications

References 37 publications

Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

LIMD1 is more frequently altered than RB1 in head and neck squamous cell carcinoma: clinical and prognostic implications

Alterations of 3p21.31 tumor suppressor genes in head and neck squamous cell carcinoma: Correlation with progression and prognosis

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