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Small cell lung cancer (SCLC) is a devastating and aggressive neuroendocrine carcinoma of the lung. It accounts for ~15% of lung cancer mortality and has had no improvement in standard treatment options for nearly 30 years. However, there is now hope for change with new therapies and modalities of therapy. Immunotherapies and checkpoint inhibitors are entering clinical practice, selected targeted therapies show promise, and "smart bomb"-based drug/radioconjugates have led to good response in early clinical trials. Additionally, new research insights into the genetics and tumor heterogeneity of SCLC alongside the availability of new tools such as patient-derived or circulating tumor cell xenografts offer the potential to shine light on this beshadowed cancer.
BACKGROUND - Acute leukemias of childhood are a heterogeneous group of malignancies characterized by cytogenetic abnormalities, such as translocations and changes in ploidy. These abnormalities may be influenced by altered DNA repair and cell cycle control processes.
METHODS - We examined the association between childhood acute lymphoblastic leukemia (ALL) and 32 genes in DNA repair and cell cycle pathways using a haplotype-based approach, among 377 childhood ALL cases and 448 controls enrolled during 1995-2002.
RESULTS - We found that haplotypes in APEX1, BRCA2, ERCC2, and RAD51 were significantly associated with total ALL, while haplotypes in NBN and XRCC4, and CDKN2A were associated with structural and numerical change subtypes, respectively. In addition, we observed statistically significant interaction between exposure to 3 or more diagnostic X-rays and haplotypes of XRCC4 on risk of structural abnormality-positive childhood ALL.
CONCLUSIONS - These results support a role of altered DNA repair and cell cycle processes in the risk of childhood ALL, and show that this genetic susceptibility can differ by cytogenetic subtype and may be modified by exposure to ionizing radiation. To our knowledge, our study is the first to broadly examine the DNA repair and cell cycle pathways using a haplotype approach in conjunction with X-ray exposures in childhood ALL risk. If confirmed, future studies are needed to identify specific functional SNPs in the regions of interest identified in this analysis.
Although genetic variations in cell-cycle control genes have been previously linked to cancer risk, no study has specifically evaluated the role of these gene variants in endometrial carcinogenesis. Using data from the Shanghai Endometrial Cancer Study, a population-based case-control study with 1,199 cases and 1,212 age-matched controls (1997-2003), the authors carried out a systematic evaluation of the association of cell-cycle control genes with endometrial cancer risk. Sixty-five tagging or potentially functional single nucleotide polymorphisms in the CCNB1, CCND1, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, and CDKN2A genes were genotyped and evaluated. Three single nucleotide polymorphisms in the CDKN1B gene (rs11055027, rs3759216, and rs34330) were related to endometrial cancer risk, although only the association with rs34330 remained statistically significant after adjustment for multiple comparisons. The odds ratios for rs34330 were 1.33 (95% confidence interval (CI): 1.06, 1.66) and 1.51 (95% CI: 1.16, 1.94) for the CT and TT genotypes, respectively, compared with the CC genotype. In vitro luciferase reporter assays showed that the minor allele (A) in rs3759216, which was associated with decreased endometrial cancer risk (odds ratio = 0.73, 95% CI: 0.56, 0.94) without adjustment for multiple comparisons, significantly increased promoter activity. These findings suggest that polymorphisms of the CDKN1B gene may play a role in endometrial carcinogenesis.
BACKGROUND - The checkpoint with forkhead-associated domain and RING-finger domain (CHFR) is a mitotic checkpoint protein with tumor-suppressor functions. In this study, the authors investigated the epigenetic and genetic mechanisms that regulate CHFR expression in esophageal adenocarcinomas (EACs).
METHODS - Quantitative reverse transcriptase polymerase chain reaction analysis demonstrated downregulation of CHFR transcript in 79% of EACs (44 of 56) compared with 41 normal samples (P < .001). Immunohistochemical analysis of CHFR protein expression showed absence or weak immunostaining for CHFR in 75% of EACs (56 of 75) compared with normal tissue samples. The authors next examined the promoter DNA hypermethylation of CHFR by using quantitative bisulfite pyrosequencing technology. They detected significant CHFR promoter DNA hypermethylation in 31% of tumor samples (18 of 58) compared with normal samples (P < .001). Treatment of OE33 cells with 5-Aza-deoxycytidine led to reduction in the promoter DNA methylation levels with restoration of the CHFR mRNA expression, which confirmed promoter DNA methylation as an epigenetic mechanism regulating CHFR expression. However, they identified several EACs where the CHFR mRNA expression was silenced in the absence of notable methylation. Therefore, the authors examined the relative DNA copy number level of CHFR compared with normal samples.
RESULTS - The results confirmed a decrease or absence of the relative CHFR DNA copy number levels in 59% of tumor samples. Nine tumors that showed loss of CHFR mRNA expression, in absence of promoter DNA hypermethylation, demonstrated a significant loss of relative CHFR DNA copy numbers.
CONCLUSIONS - Taken together, their findings demonstrated that both epigenetic and genetic mechanisms were involved in silencing CHFR expression in EACs.
Cancer 2010. (c) 2010 American Cancer Society.
Telomere attrition, DNA damage and constitutive mitogenic signaling can all trigger cellular senescence in normal cells and serve as a defense against tumor progression. Cancer cells may circumvent this cellular defense by acquiring genetic mutations in checkpoint proteins responsible for regulating permanent cell cycle arrest. A small family of tumor suppressor genes encoding the retinoblastoma susceptibility protein family (Rb, p107, p130) exerts a partially redundant control of entry into S phase of DNA replication and cellular proliferation. Here we report that activation of the p53-dependent DNA damage response has been found to accelerate senescence in human prostate cancer cells lacking a functional Rb protein. This novel form of irradiation-induced premature cellular senescence reinforces the notion that other Rb family members may compensate for loss of Rb protein in the DNA damage response pathway. Consistent with this hypothesis, depletion of p107 potently inhibits the irradiation-induced senescence observed in DU145 cells. In contrast, p130 depletion triggers a robust and unexpected form of premature senescence in unirradiated cells. The dominant effect of depleting both p107 and p130, in the absence of Rb, was a complete blockade of irradiation-induced cellular senescence. Onset of the p107-dependent senescence was temporally associated with p53-mediated stabilization of the cyclin-dependent kinase inhibitor p27 and decreases in c-myc and cks1 expression. These results indicate that p107 is required for initiation of accelerated cellular senescence in the absence of Rb and introduces the concept that p130 may be required to prevent the onset of terminal growth arrest in unstimulated prostate cancer cells lacking a functional Rb allele.
DDB1, a component of a Cul4A ubiquitin ligase complex, promotes nucleotide excision repair (NER) and regulates DNA replication. We have investigated the role of human DDB1 in maintaining genome stability. DDB1-depleted cells accumulate DNA double-strand breaks in widely dispersed regions throughout the genome and have activated ATM and ATR cell cycle checkpoints. Depletion of Cul4A yields similar phenotypes, indicating that an E3 ligase function of DDB1 is important for genome maintenance. In contrast, depletion of DDB2, XPA, or XPC does not cause activation of DNA damage checkpoints, indicating that defects in NER are not involved. One substrate of DDB1-Cul4A that is crucial for preventing genome instability is Cdt1. DDB1-depleted cells exhibit increased levels of Cdt1 protein and rereplication, despite containing other Cdt1 regulatory mechanisms. The rereplication, accumulation of DNA damage, and activation of checkpoint responses in DDB1-depleted cells require entry into S phase and are partially, but not completely, suppressed by codepletion of Cdt1. Therefore, DDB1 prevents DNA lesions from accumulating in replicating human cells, in part by regulating Cdt1 degradation.
The BCL-2 family of apoptotic proteins encompasses key regulators proximal to irreversible cell damage. The BH3-only members of this family act as sentinels, interconnecting specific death signals to the core apoptotic pathway. Our previous data demonstrated a role for BH3-only BID in maintaining myeloid homeostasis and suppressing leukemogenesis. In the absence of Bid, mice accumulate chromosomal aberrations and develop a fatal myeloproliferative disorder resembling chronic myelomonocytic leukemia. Here, we describe a role for BID in preserving genomic integrity that places BID at an early point in the path to determine the fate of a cell. We show that BID plays an unexpected role in the intra-S phase checkpoint downstream of DNA damage distinct from its proapoptotic function. We further demonstrate that this role is mediated through BID phosphorylation by the DNA-damage kinase ATM. These results establish a link between proapoptotic Bid and the DNA-damage response.
In the fission yeast Schizosaccharomyces pombe, the septation initiation network (SIN) triggers cytokinesis after mitosis. We investigated the relationship between Dma1p, a spindle checkpoint protein and cytokinesis inhibitor, and the SIN. Deletion of dma1 inactivates the spindle checkpoint and allows precocious SIN activation, while overexpressing Dma1p reduces SIN signaling. Dma1p seems to function by inhibiting the SIN activator, Plo1p kinase, since dma1 overexpression and deletion phenotypes suggest that Dma1p antagonizes Plo1p localization. Furthermore, failure to maintain high cyclin-dependent kinase (CDK) activity during spindle checkpoint activation in dma1 deletion cells requires Plo1p. Dma1p itself localizes to spindle pole bodies through interaction with Sid4p. Our observations suggest that Dma1p functions to prevent mitotic exit and cytokinesis during spindle checkpoint arrest by inhibiting SIN signaling.
Cyclin-dependent kinase inhibitors (cdki's), including p19(Ink4d) and p27(Kip1), mediate exit from the cell cycle. To determine the function of these cdki's in regulating neurogenesis, we examined retina from wild-type, Ink4d-null, and Ink4d/Kip1-double null animals. Ink4d was expressed in progenitors and select neurons in the mature retina. Ink4d-null retina showed an extended period of proliferation, followed by apoptosis. Colabeling for p19(Ink4d) and p27(Kip1) revealed that a subpopulation of cells expressed both inhibitors. Deletion of Ink4d and Kip1 resulted in continued proliferation that was synergistic. This hyperproliferation led to an increase in number of horizontal cells and differentiated neurons reentering the cell cycle. Deletion of Ink4d and Kip1 also exacerbated the retinal dysplasia observed in Kip1-null mice, which was shown to be partly dependent on p53. These data indicate that select retinal cells express both p19(Ink4d) and p27(Kip1) and that they act cooperatively to ensure cell cycle exit.