RECENT FINDINGS: p53 plays a major physiological role in embryonic development, by controlling cell proliferation, differentiation and responses to cellular stress. Tumor suppressor function of p53 is commonly lost in adult cancers through genetic alterations. However, both somatic and germline p53 mutations are rare in childhood blastomas, suggesting that in these cancers, p53 may be inactivated through other mechanisms than mutation. In this review, we summarize current knowledge about p53 pathway inactivation in childhood blastomas (specifically neuroblastoma, retinoblastoma and Wilms' tumor) through various upstream mechanisms. Laboratory evidence and clinical trials of targeted therapies specific to exploiting p53 upstream regulators are discussed.
SUMMARY: Despite the low rate of inherent TP53 mutations, p53 pathway inactivation is a common denominator in childhood blastomas. Exploiting p53 and its regulators is likely to translate into more effective targeted therapies with minimal late effects for children. (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/COON/A23).
METHODS: We used semi-quantitative reverse-transcriptase PCR (RT-PCR) and Western blot to investigate the expression of full length p53 (TAp53), Delta40p53, Delta133p53 or p53beta in diagnostic marrow from a clinical cohort of 50 BCP-ALL patients without TP53 mutation (29 males and 21 females, age range 2-14 years) and in the bone marrow cells of 4 healthy donors (used as controls).
RESULTS: Irrespective of isoforms, levels of p53 mRNA were low in controls but were increased by 2 to 20-fold in primary or relapse BCP-ALL. TAp53 was increased in primary BCP-ALL, Delta40p53 was elevated in relapse BCP-ALL, whereas Delta133p53 and p53beta were increased in both. Next, mRNA levels were used as a basis to infer the ratio between protein isoform levels. This inference suggested that, in primary BCP-ALL, p53 was predominantly in active oligomeric conformations dominated by TAp53. In contrast, p53 mostly existed in inactive quaternary conformations containing ≥2 Delta40 or Delta133p53 in relapse BCP-ALL. Western blot analysis of blasts from BCP-ALL showed a complex pattern of N-terminally truncated p53 isoforms, whereas TAp53beta was detected as a major isoform. The hypothesis that p53 is in an active form in primary B-ALL was consistent with elevated level of p53 target genes CDKN1A and MDM2 in primary cases, whereas in relapse BCP-ALL, only CDKN1A was increased as compared to controls.
CONCLUSION: Expression of p53 isoforms is deregulated in BCP-ALL in the absence of TP53 mutation, with increased expression of alternative isoforms in relapse BCP-ALL. Variations in isoform expression may contribute to functional deregulation of the p53 pathway in BCP-ALL, specifically contributing to its down-regulation in relapse forms.
METHODS: A prospective randomized study involving 55 patients in the epidural group and 68 in the control pethidine--inhalational entonox group.
RESULTS: There were significantly more obstetric interventions (instrumental deliveries) in the epidural group (p < 0.01). The total duration of labour and the duration of the second stage was prolonged in the epidural group (p < 0.01). There were more malpositions at the second stage of labour in the epidural group (p < 0.02). There were no differences in fetal outcome (Apgar scores and Special Care Nursery admissions). Patients in the epidural group were consistently happier with their method of pain relief (p < 0.01). Two patients required blood patches while another 2 patients had persistent backache post epidural analgesia.
CONCLUSION: Epidural analgesia in primigravidae in spontaneous labour at term led to an increased instrumental delivery rate, prolonged duration of labour, greater rate of malpositions in the second stage, increased oxytocin requirements but with no difference in fetal outcomes but with happier mothers as compared to the control group.
METHODS: 50 asymptomatic (subjects have remained leukemia-free since treatment cessation) CLS and 50 healthy controls were recruited in this cross-sectional study. Of 50 CLS, 44 had acute lymphoblastic leukemia and 6 had acute myeloid leukemia. G-banded karyotyping was performed on unstimulated peripheral blood leukocytes of all subjects.
RESULTS: CLS had significantly higher occurrence of karyotypic abnormalities compared to controls. Five CLS harbored six nonclonal abnormalities (mostly aneuploidy) while none were found in controls.
CONCLUSION: Subpopulations with nonclonal chromosomal aberrations were present in peripheral blood leukocytes of our cohort of childhood leukemia long-term survivors.
MATERIALS AND METHODS: Cardiovascular risk factors (CRFs) were estimated using the 30-year Framingham Risk Score in 73 childhood leukemia survivors (median age: 25; median years from diagnosis: 19) and 78 healthy controls (median age: 23). Radial arterial stiffness was measured using pulse wave analyzer, while endothelial activation markers were measured by soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). Retinal fundus images were analyzed for central retinal artery/vein equivalents (CRAE/CRVE) and arteriolar-venular ratio (AVR).
RESULTS: cALL survivors had higher CRF (P<0.0001), arterial stiffness (P=0.001), and sVCAM-1 (P=0.007) compared with controls. Survivors also had significantly higher CRVE (P=0.021) while AVR was significantly lower (P=0.026) in survivors compared with controls, compatible with endothelial dysfunction. In cALL survivors with intermediate risk for CVD, CRAE, and AVR are significantly lower, while sVCAM-1 and sICAM-1 are significantly higher when compared with survivors with low CVD risk after adjusting with covariates (age, sex, and smoking status).
CONCLUSIONS: cALL survivors have an increased risk of CVD compared with age-matched peers. The survivors demonstrated microvasculopathy, as measured by retinal vascular analysis, in addition to physical and biochemical evidence of endothelial dysfunction. These changes predate other measures of CVD. Retinal vessel analysis may be utilized as a robust screening tool for identifying survivors at increased risk for developing CVD.
METHODS: Plasma inflammatory cytokines were measured using a cytometric bead array in 87 asymptomatic young adult survivors of childhood ALL (median age, 25 years; age range, 18-35 years) who attended annual follow-up clinic and compared with healthy, age-matched and sex-matched controls. Leukocyte telomere length (LTL) was measured using Southern blot analysis.
RESULTS: Survivors had significant elevation of plasma interleukin-2 (IL-2), IL-10, IL-17a, and high-sensitivity C-reactive protein levels (all P 0.8 mg/dL) was related to increased odds of having metabolic syndrome (odds ratio, 7.256; 95% confidence interval, 1.501-35.074). Survivors also had significantly shorter LTL compared with controls (median, 9866 vs 10,392 base pairs; P = .021). Compared with published data, LTL in survivors was similar to that in healthy individuals aged 20 years older. Survivors who received cranial irradiation had shorter LTL compared with those who had not (P = .013).
CONCLUSIONS: Asymptomatic young adult survivors of childhood ALL demonstrate a biologic profile of chronic inflammation and telomere attrition, consistent with an early onset of cellular processes that drive accelerated aging. These processes may explain the premature development of age-related chronic conditions in childhood cancer survivors. Understanding their molecular basis may facilitate targeted interventions to disrupt the accelerated aging process and its long-term impact on overall health. Cancer 2017;123:4207-4214. © 2017 American Cancer Society.