Cyclin D1,ERCC1 Gene Polymorphism And Susceptibility To Childhood Acute Lymphoblastic Leukemia In A Chinese Population

Acute lymphoblastic leukemia (ALL), a heterogeneous diseasecharacterized by the predominance of lymphoblasts or immature hematopoieticprecursors , is the most frequent malignancy that affects children worldwide.Although the clinical and pathologic aspects of leukemia are well documented,little is known about leukemogenesis , particularly with respect to the roles ofinherited genetic susceptibility and environmental factors .Little attention hasbeen paid to the role of genetic susceptibilityin the etiology of childhood ALL.It is believed that genetic factors and environmental exposures predisposechildren to leukemogenesis.A frequent target in transitional cell carcinogenesis is deregulation of G1into S-phase progression in the cell cycle, whose transition through G1 into Sphase is regulated by cyclins, cyclin-dependent kinase, and their inhibitors.Mitogenic and antiproliferative signals are integrated to dictate the levels ofcyclin D1 in the cell. Cyclin D1 can associate with the CDK4 or CDK6proteins to activate catalytic activity. This action of cyclinD1 is antagonized byp16ink4a, which binds to the CDK-moiety and disrupts the association withcyclin D1. Active CDK/cyclin D1 complexes initiate phosphorylation of theretinoblastoma tumor suppressor, which disrupts ability RB-mediatedtranscriptional repression of E2F and facilitates cell cycle progression. CyclinD1, as a key regulator essential for the process, has been shown to be involvedin various types of human cancer.Cyclin D1 overexpression and CCND1amplification have been demonstrated in a variety of cancers .In 1995, afrequent polymorphism (A/G) was identified in the final codon of exon 4 ofthe CCND1 gene. A common A/G single nucleotide polymorphism (A870G)within entron 4 of the cyclin D1 gene results in two distinct mRNA transcripts(isoforms a and b). The alternately spliced RNA transcripts (isoform b)encodes a protein in which the last 55 amino acids of theCterminus of cyclinD1 are replaced by a shorter sequence encoded by intron 4. Thispolymorphism does not lead to a change in amino acid level, but the variantnucleotide interferes with splicing from exon 4 to exon 5 because of its uniquelocalization within a conserve splice donor region. It has been postulated thatthe A allele enhances alternative gene splicing, leading to formation of analtered protein that does not contain the sequences involved in protein turnover.Therefore DNA damage in cells from subjects with the A allele may bypassthe G1/S checkpoint of the cell cycle control mechanism more easily thandamage in cells not carrying the polymorphism.The Cyclin D1 genotype has been significantly correlated with clinicaloutcome in patients with non–small cell cancer of the lung, squamous cellcarcinoma of the head and neck, squamous cell carcinoma of theoral/pharyngeal cavity, hereditary nonpolyposis colorectal cancer, andepithelial ovarian cancer. Although Costea et al reported that Cyclin D1genepolymorphism is related to event-free survival rate/periodin French Canadianchildren with ALL, the relation between gene polymorphism of Cyclin D1 andthe onset risk of ALL remains unknown.To examine the genotypic frequency of Cyclin D1 polymorphism, weperformed a case-control study in a Chinese population of 183 children withALL and 190 healthy controls by PCR and PCR-RFLP methods .we firstfound that the AA genotype of Cyclin D1 showed a tendency to increase ALLrisk., especially T-ALL among younger than 10 years and at high risk, and hada lower probability of event-free survival compared to carriers of the G variant.The results of the present study suggested that Cyclin D1geneticpolymorphism may be related to the occurrence ,development and prognosis ofALL in a population of Chinese children.Recent opinions consider cancer as a genetic disease. Many importantgenes involving in cancer genesis have been discovered, with their mutationsprecisely identified, and the pathways through which they act characterized.The nucleotide excision repair (NER) pathway deals with UV light-inducedDNA damage. In the inherited disorder, xeroderma pigmentosum, NERdeficiency results in a 1000-fold increased incidence of skin cancer, but also a20-fold increase in internal tumours, indicating that NER is also important inthe repair of endogenous DNA damage. It is known that defective DNA repairis a risk factor for many types of cancer. Genetic polymorphism probably hasan important role in determining cancer susceptibility and is currently thesubject of intensive investigation. Excision repair cross-complementationgroup1 (ERCC1), a highly conserved enzyme, is the major component of NERprocess and is specific to the NER pathway. ERCC1 may be important inrepairing DNA damage, e.g removal of DNA adducts and rejoining ofdouble-stranded DNA breaks caused by X-ray irradiation. A defect in ERCC1results in the most severe DNA repair deficiency. ERCC1 polymorphisms wererecently found to be significantly associated with increasing cancer risk. Thus,the CC genotype in ERCC1 C8092A was significantly associated with theincreased risk of oligoastrocytoma and squamous cell carcinoma of head andneck (SCCHN). In addition to its association with lung cancer, Suk et al. alsoshowed that carrying at least one ERCC1 8092A allele was associated with asignificantly increased risk of grade 3 or 4 gastrointestinal toxicity amongplatinum-treated non-small-cell lung cancer patients. The ERCC1 19007G> Apolymorphism was studied in colorectal cancer but no significant associationwas found. Despites these reports on association of genetic polymorphism ofERCC1 with increased risk in these solid tumors, the relationship betweenthese polymorphisms and susceptibility to childhood ALL has not beenexplored in Chinese children. In this study, we compared the frequency ofpolymorphisms in ERCC1 genes between children ALL and a control group.To examine the genotypic frequency of ERCC1 polymorphism, weperformed a case-control study in a Chinese population of 183 children withALL and 190 healthy controls by PCR and PCR-RFLP methods . For theERCC1 8092C> A polymorphism, individuals carrying the CC genotype had asignificantly higher risk when compared with those carrying at least one Aallele gene (AA /AC). Analysis after stratification for sex showed that malescarrying 8092C C polymorphism were associated with highly significantincreased risk of ALL but not females. There was no association betweenERCC1 19007G >A polymorphism and ALL risk when all patients as a groupwere analyzed. However, the males carrying 19007A allele were associatedwith highly significant increased risk of ALL. For the ERCC1 8092C> Apolymorphism, individuals under10 years old carrying CC genotype hadsignificantly higher risk. However, the19007G >A polymorphism was notassociated with such age-related ALL risk. We first found that the ERCC18092C> A polymorphism may be related to occurrence of childhood ALL in aChinese population.Our find will help us to understand the pathogenesis , andprognosticate the development of ALL.