Functional regulatory variants of <i>MCL1</i> contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: Implications for context‐dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor

Jiang, Yan; Wang, Wenjing; Wang, Jiucun; Lu, Ye; Chen, Yanmei; Jin, Li; Lin, Dongxin; He, Fuchu; Wang, Haijian

doi:10.1002/cncr.26502

Cited by 5 publications

(1 citation statement)

References 26 publications

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“…The current GWAS of complex diseases are almost solely focused on two forms of sequence variations, SNP and copy number variations, but are of relative paucity of research interest in VNTR, the third form of sequence variation. In fact, there are more than one million VNTR dispersed in the human genome, some of which occur in obviously functional positions, such as gene promoters or enhancers targeted by transacting factors, and possibly affect gene regulation and thereby potentially contribute to disease etiology, (20) as exemplified in our previous studies (25,26) and the present investigation. It is notable that the functional VNTR variation at the PTTG1IP promoter is highly polymorphic in humans and differences in allelic types and frequencies among populations are apparent.…”

Section: Discussionmentioning

confidence: 63%

Functional variable number of tandem repeats variation in the promoter of proto‐oncogene PTTG1IP is associated with risk of estrogen receptor‐positive breast cancer

Xiang

Gao

et al. 2012

Cancer Science

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Genetic polymorphisms in the signalling pathway of estrogen receptor (ER) could modify the risk of breast cancer. A variable number of tandem repeats (VNTR) polymorphism in the promoter of PTTG1IP, pituitary tumor transforming gene binding factor targeted by estrogen receptor a (ERa) in endocrine neoplasia, has been shown to be functional, but its relevance to cancer etiology was unknown. We investigated its association with breast cancer risk by genotyping in 658 patients and 866 controls and further analysed its differential interaction with ERa. We found nine types of alleles ranging from 2 to 9 and 11 repeats that form 29 distinct genotypes and 11 different biallelic repeat numbers. Subjects who carry the six-repeats allele (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.17-1.79), long alleles ( ! 6 repeats) (OR, 1.55; 95% CI, 1.17-2.05) or a high dose of biallelic repeats (OR, 1.38; 95% CI, 1.07-1.77) were at significantly increased risk of cancer. In stratification analysis, these associations consistently manifested in ER-positive breast cancer: in ER positive, PR-positive subtype, genotypes with the six-repeats allele (OR, 1.42; 95% CI, 1.06-1.90), long alleles (OR, 1.77; 95% CI, 1.17-2.67) or a high dose of biallelic repeats (OR, 1.67; 95% CI, 1.19-2.33) were associated with cancer risk; in ER positive, HER2-negative subtype, they were susceptible factors with the ORs being 1.46 (95% CI, 1.06-2.02), 2.06 (95% CI, 1.28-3.32) and 1.85 (95% CI, 1.26-2.71), respectively. Furthermore, functional analysis revealed that an increase in the number of tandem repeats enhances the binding affinity of ERa. The present study provides the first epidemiological evidence that functional regulatory variants of PTTG1IP were associated with the risk of ER-positive breast cancer, further supporting its relevance as one proto-oncogene in breast cancer.

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Section: Discussionmentioning

confidence: 63%

Functional variable number of tandem repeats variation in the promoter of proto‐oncogene PTTG1IP is associated with risk of estrogen receptor‐positive breast cancer

Xiang

Gao

et al. 2012

Cancer Science

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Revisiting the role of MCL1 in tumorigenesis of solid cancer: gene expression correlates with antiproliferative phenotype in breast cancer cells and its functional regulatory variants are associated with reduced cancer susceptibility

et al. 2014

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Compared to the well-defined anti-apoptotic role of myeloid cell leukemia sequence 1 (MCL1), its antiproliferative function in tumorigenesis is less studied. We had recently reported that regulatory variants of MCL1 contribute to enhanced promoter activity but reduced risk of lung cancer. We hypothesized that MCL1 expression may manifest antiproliferative phenotype and its functional variations may have etiological relevance for breast cancer. We manipulated MCL1 expression in MCF-7 cells and MDA231 with overexpression and knockdown, analyzed the effects on cell viability and cell cycling phase, and characterized the correlation with expression profiles of key regulators of cell cycle. We further genotyped the -190 insertion polymorphism and the neighboring single nucleotide polymorphisms (SNPs) in 745 breast cancer patients and 537 controls and analyzed their association with cancer risk. We confirmed that heightened expression of MCL1 resulted in decreased proliferation ability of breast cancer cells. We further observed that MCL1 overexpression in breast cancer cells resulted in cell cycle progression arresting in S phase and concomitant enhanced expression of p27, which could be rescued by p27 knockdown with co-transfection of small interfering RNA (siRNA). Furthermore, we found a significant reduction in breast cancer risk [odds ratio (OR) = 0.74; 95 % confidence interval (CI) = 0.59-0.93] associated with -190 insertion genotype; the expression-enhancing regulatory haplotype (OR 0.79; 95 % CI 0.66-0.95) and diplotype (OR 0.71; 95 % CI 0.57-0.89) were consistently associated with decreased cancer susceptibility. The study demonstrates that the expression-enhancing regulatory variants of MCL1 are protective modifiers of breast cancer risk, and reduced cell proliferation and arrested cell cycle progression partly mediated by p27 might be the underlying mechanism.

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Autophagopathies: from autophagy gene polymorphisms to precision medicine for human diseases

et al. 2022

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Functional regulatory variants of MCL1 contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: Implications for context‐dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor

Cited by 5 publications

References 26 publications

Functional variable number of tandem repeats variation in the promoter of proto‐oncogene PTTG1IP is associated with risk of estrogen receptor‐positive breast cancer

Functional variable number of tandem repeats variation in the promoter of proto‐oncogene PTTG1IP is associated with risk of estrogen receptor‐positive breast cancer

Revisiting the role of MCL1 in tumorigenesis of solid cancer: gene expression correlates with antiproliferative phenotype in breast cancer cells and its functional regulatory variants are associated with reduced cancer susceptibility

Autophagopathies: from autophagy gene polymorphisms to precision medicine for human diseases

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