Association Between Homologous Recombination Repair Biomarkers and Survival in Patients With Solid Tumors
Changxia ShaoYixin RenHeng ZhouCai ChenElisha J. DettmanLiam C. LeeRǎzvan CristescuAlexander GozmanFan JinWei Zhou
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Mutations inNeoplastic transformation
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TP53 gene has been found to have the highest correlation with human tumors, and its mutations occurr in about 50% malignant tumors. Its encoded p53 protein is a well-known tumor-suppressor factor in vivo, which is closely related to tumorigenesis. It is found that tumorigenesis has a close relationship with various abnormal biological processes, including cell cycle regulation, apoptosis, DNA damage repair, cell senescence, autophagy, metabolic regulation. This paper reviews the complex network relationship between p53 protein and tumorigenesis from biological processes affecting the tumorigenesis.
Key words:
Neoplams; Tumor suppressor protein p53; Biological processes
Senescence
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Pazzaglia, S., Mancuso, M., Rebessi, S., Di Majo, V., Tanori, M., Biozzi, G., Covelli, V. and Saran, A. The Genetic Control of Chemically and Radiation-Induced Skin Tumorigenesis: A Study with Carcinogenesis-Susceptible and Carcinogenesis-Resistant Mice. Radiat. Res. 158, 78–83 (2002).Outbred carcinogenesis-resistant (Car-R) and carcinogenesis-susceptible (Car-S) mouse lines were generated by phenotypic selection for resistance or susceptibility to two-stage skin carcinogenesis. These two Car mouse lines differ by >100-fold in susceptibility. In the present study, we tested the hypothesis that a subset of genetic loci responsible for susceptibility or resistance to chemical skin tumorigenesis may also be involved in radiation-induced skin tumorigenesis. Skin tumorigenesis was tested in groups of Car-S/R mice after X-ray initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. We found that ionizing radiation can initiate skin tumors in Car-S mice but not in Car-R mice. In Car-S mice, the most effective radiation doses (6 and 10 Gy given in four fractions) gave a threefold increase in tumor multiplicity and a twofold increase in tumor incidence compared to a TPA-only control group. We performed a molecular analysis of Hras gene mutations in skin tumors of Car-S mice induced by X-ray initiation/TPA promotion or by TPA promotion alone. The most notable difference emerging from the comparison of these mutation patterns is the high incidence (∼50%) of papillomas lacking Hras gene mutations in X-ray-initiated/TPA-promoted papillomas compared to 13% in papillomas induced by TPA alone, suggesting that lack of Hras gene mutations is a consistent feature of radiation-induced papillomas.
HRAS
Tumor promotion
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Homologous recombination (HR) is a fundamental evolutionarily conserved process that plays prime role(s) in genome stability maintenance through DNA repair and through the protection and resumption of arrested replication forks. Many HR genes are deregulated in cancer cells. Notably, the breast cancer genes BRCA1 and BRCA2, two important HR players, are the most frequently mutated genes in familial breast and ovarian cancer. Transgenic mice constitute powerful tools to unravel the intricate mechanisms controlling tumorigenesis in vivo. However, the genes central to HR are essential in mammals, and their knockout leads to early embryonic lethality in mice. Elaborated strategies have been developed to overcome this difficulty, enabling one to analyze the consequences of HR disruption in vivo. In this review, we first briefly present the molecular mechanisms of HR in mammalian cells to introduce each factor in the HR process. Then, we present the different mouse models of HR invalidation and the consequences of HR inactivation on tumorigenesis. Finally, we discuss the use of mouse models for the development of targeted cancer therapies as well as perspectives on the future potential for understanding the mechanisms of HR inactivation-driven tumorigenesis in vivo.
Knockout mouse
Gene targeting
Gene knockout
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Psychogenic disease
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Background Although most people with relapsing onset multiple sclerosis (R-MS) eventually transition to secondary progressive multiple sclerosis (SPMS), little is known about disability progression in SPMS. Methods All R-MS patients in the Cardiff MS registry were included. Cox proportional hazards regression was used to examine a) hazard of converting to SPMS and b) hazard of attaining EDSS 6.0 and 8.0 in SPMS. Results 1611 R-MS patients were included. Older age at MS onset (hazard ratio [HR] 1.02, 95%CI 1.01–1.03), male sex (HR 1.71, 95%CI 1.41–2.08), and residual disability after onset (HR 1.38, 95%CI 1.11–1.71) were asso- ciated with increased hazard of SPMS. Male sex (EDSS 6.0 HR 1.41 [1.04–1.90], EDSS 8.0 HR 1.75 [1.14–2.69]) and higher EDSS at SPMS onset (EDSS 6.0 HR 1.31 [1.17–1.46]; EDSS 8.0 HR 1.38 [1.19–1.61]) were associated with increased hazard of reaching disability milestones, while older age at SPMS was associated with a lower hazard of progression (EDSS 6.0 HR 0.94 [0.92–0.96]; EDSS 8.0: HR 0.92 [0.90–0.95]). Conclusions Different factors are associated with hazard of SPMS compared to hazard of disability progres- sion after SPMS onset. These data may be used to plan services, and provide a baseline for comparison for future interventional studies and has relevance for new treatments for SPMS RobertsonNP@cardiff.ac.uk
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Oncogenesis is the result of accumulation of specific gene mutations. Two classes of specific cancer mutations are distinguished: namely those affecting anti-oncogenes and those in which oncogenes are involved. Anti-oncogenes are thought to regulate normal growth by encoding proteins that inhibit the expression of the oncogenes. This is in line with the observation that tumor cells are often homozygous for a defect in an anti-oncogene, as this will allow the expression of an oncogene. In this paper we attempt to calculate the number of anti-oncogenes involved in the genesis of a malignant tumour cell. These calculations were initially performed using a simplified model for oncogenesis and later applied to more complicated situations. These calculations indicate that usually four mutations in anti-oncogenes are required for oncogenesis in adults. This is in contradiction to the well-known 2-hit model of oncogenesis of Knudson which predicts about 10(9) times more de novo arising tumour cells than are observed in reality. Oncogenesis is only observed in proliferating cells. Cell proliferation and growth kinetics in various organs differ greatly. Therefore the time of oncogenesis and tumour manifestation also varies in the different organs. In organs that develop in early life (e.g. retina and neurons of the brain) mitotic activity ceases soon after birth. Consequently neural and retinal tumours emerge only early in life. In contrast, the main development of the female breast occurs after puberty, and the earliest breast tumours will become apparent in young adults. The four recessive mutations in anti-oncogenes required for oncogenesis imply that probably recessive mutations are involved in two loci. It is clear that an inherited mutation in an anti-oncogene at a particular locus causes different tumour types depending on the various organs in which the tumours arise. Comparison of (a) results of calculations about the number of malignant neuroendocrine tumour cells that arise in a pancreatic islet of a patient with inherited MEN1-syndrome with (b) the pathological anatomy of such a patient, suggests that a cell with two or three oncogenic mutations has a growth advantage over normal cells. This leads to cell proliferation in a premalignant lesion until the set of four oncogenic mutations is complete. The clinically premalignant lesions have a maximal mean diameter of about 0.4 cm when the first true malignant tumour cell develops, and the pathologist will probably note malignancy when the lesion has the size of 1-2 cm.(ABSTRACT TRUNCATED AT 400 WORDS)
Proto-Oncogenes
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The hazard ratio and median survival time are the routine indicators in survival analysis. We briefly introduced the relationship between hazard ratio and median survival time and the role of proportional hazard assumption. We compared 110 pairs of hazard ratio and median survival time ratio in 58 articles and demonstrated the reasons for the difference by examples. The results showed that the hazard ratio estimated by the Cox regression model is unreasonable and not equivalent to median survival time ratio when the proportional hazard assumption is not met. Therefore, before performing the Cox regression model, the proportional hazard assumption should be tested first. If proportional hazard assumption is met, Cox regression model can be used; if proportional hazard assumption is not met, restricted mean survival times is suggested.风险比（hazard ratio，HR）和中位生存时间是生存分析时的常规分析和报告指标。本文简要介绍了HR和中位生存时间的关系以及比例风险假定在这两者之间的作用，分析了检索出的58篇文献中的110对风险比和中位生存时间比的差异，并通过实例阐明了产生这种差异的原因。结果表明，在不满足比例风险假定时，Cox回归模型计算得到的风险比是不合理的，且与中位生存时间之比不等价。因此，在使用Cox回归模型前，应先进行比例风险假定的检验，只有符合比例风险假定时才能使用该模型；当不符合比例风险假定时，建议使用限制性平均生存时间。.
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