45 research outputs found
Abstracts from the 3rd Conference on Aneuploidy and Cancer: Clinical and Experimental Aspects
Somatic Genetic Variation in Children: from Mosaicism to Cancer
This thesis concerns various aspects of somatic mosaicism and genetic intratumor heterogeneity in childhood cancer.In paper I, I show that aneuploidy in itself does not lead to the level of chromosomal instability that is typically seen in malignant cells. This finding strongly argues against the so called autocatalytic theory of carcinogenesis.Paper II illustrates that, in rare cases, low-level somatic mosaicism can be unmasked by hitchhiking on the clonal expansion seen in carcinogenesis. Paper III demonstrates that the level of somatic mosaicism at the copy number level in fetuses is lower than in adult humans and that fetal hepatocytes are no more aneuploid than other cells from the fetus. Furthermore, we also detect an organ specific genomic profile in the fetal thymus, due to physiological T-cell receptor rearrangement.Paper IV highlights that intratumor genetic heterogeneity is a common feature in chemotherapy treated pediatric cancers. In this paper, we also demonstrate that the presence of genetic heterogeneity within single biopsies is associated with lower event free survival and cancer specific overall survival, and that it was a better prognostic predictor than the burden of somatic genetic aberrations.Paper V provides a map of the landscape of intratumor genetic heterogeneity within the primary lesion in Wilms tumor, neuroblastoma and rhabdomyosarcoma. We also discover four different evolutionary trajectories, and show that the presence of some of these evolutionary patterns within the primary tumor predicts inferior survival.In conclusion, the findings presented in this thesis demonstrate that genetic variation is a rare but significant feature in normal cells of young human tissues. In contrast, such variation is extremely common within childhood solid tumors. Our data suggest that increased knowledge of the evolutionary dynamics within a tumor might lead to improved risk stratification and more personalized treatment
Immune checkpoint inhibitors in Wilms' tumor and Neuroblastoma : What now?
Background: Therapeutic activation of tumor-infiltrating lymphocytes using monoclonal antibodies targeting PD1 or PD-L1 (immune checkpoint inhibitorsâICIs) has revolutionized treatment of specific solid tumors in adult cancer patients, and much hope has been placed on a similar effect in relapsed or refractory solid pediatric tumors. Recent clinical trials have disappointingly shown an almost nonexistent response rate, while case reports have demonstrated that some pediatric patients do achieve durable responses when treated with this type of drug. Aim: To elucidate this paradox, we mapped the landscape of expressed neoantigens as well as the levels of immune cell infiltration in the two most common extracranial solid pediatric tumors: Wilms tumor and neuroblastoma using state-of-the-art in silico analysis of a large cohort of patients with these tumors. Methods: By integration of whole exome sequencing and RNA-sequencing, we mapped the landscape of neoantigens in the TARGET cohorts for these diagnoses and correlated these findings with known genetic prognostic markers. Results: Our analysis shows that these tumors typically have much lower levels of expressed neoantigens than commonly seen in adult cancers, but we also identify subgroups with significantly higher levels of neoantigens. For neuroblastomas, the cases with higher levels of neoantigens were confined to the group without MYCN-amplification and for Wilms tumor restricted to the TP53-mutated cases. Furthermore, we demonstrate that neuroblastomas have an unexpectedly high level of CD8+ tumor-infiltrating lymphocytes, even when compared to adult tumor types where ICI is an approved treatment. Conclusion: These results could be important to consider when designing future clinical trials of ICI treatment in pediatric patients with relapsed or refractory solid tumors
Re: Case reports and systematic review suggest that children may experience similar longâterm effects to adults after clinical COVIDâ19
Re: Case reports and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19
Reply to Duesberg: Stability of peritriploid and triploid states in neoplastic and nonneoplastic cells
Neuroblastoma with flat genomic profile : A question of representativity?
Neuroblastoma is one of the most common paediatric malignancies. Detection of somatic genetic alterations in this tumour is instrumental for its risk stratification and treatment. On the other hand, an absence of detected chromosomal imbalances in neuroblastoma biopsies is difficult to interpret because it is unclear whether this situation truly reflects the tumour genome or if it is due to suboptimal sampling. We here present a neuroblastoma in the left adrenal of a newborn. The tumour was subjected to single-nucleotide polymorphism array analysis of five tumour regions with >80% tumour cells in histological mirror sections. This revealed no aberrations compared with a normal reference sample from the patient. Whole exome sequencing identified two single-nucleotide variants present in most tumour regions, corroborating that the tumour resulted from monoclonal expansion. Our data provide proof-of-principle that rare cases of neuroblastoma can have a normal whole genome copy number and allelic profile
Whole chromosome gain does not in itself confer cancer-like chromosomal instability.
Constitutional aneuploidy is typically caused by a single-event meiotic or early mitotic error. In contrast, somatic aneuploidy, found mainly in neoplastic tissue, is attributed to continuous chromosomal instability. More debated as a cause of aneuploidy is aneuploidy itself; that is, whether aneuploidy per se causes chromosomal instability, for example, in patients with inborn aneuploidy. We have addressed this issue by quantifying the level of somatic mosaicism, a proxy marker of chromosomal instability, in patients with constitutional aneuploidy by precise background-filtered dual-color FISH. In contrast to previous studies that used less precise methods, we find that constitutional trisomy, even for large chromosomes that are often trisomic in cancer, does not confer a significantly elevated rate of somatic chromosomal mosaicism in individual cases. Constitutional triploidy was associated with an increased level of somatic mosaicism, but this consisted mostly of reversion from trisomy to disomy and did not correspond to a proportionally elevated level of chromosome mis-segregation in triploids, indicating that the observed mosaicism resulted from a specific accumulation of cells with a hypotriploid chromosome number. In no case did the rate of somatic mosaicism in constitutional aneuploidy exceed that of "chromosomally stable" cancer cells. Our findings show that even though constitutional aneuploidy was in some cases associated with low-level somatic mosaicism, it was insufficient to generate the cancer-like levels expected if aneuploidy single-handedly triggered cancer-like chromosomal instability
Example of the discrete time branching process in Chiron.
<p>Aneuploidy is generated at a specific rate (<i>p</i>) of mitotic mis-segregation, where trisomic (red circles) and monosomic cells (green circles) have certain probabilites (<i>s</i><sub>t</sub> and <i>s</i><sub>m</sub> respectively) of permanent proliferative arrest/death (black horizontal bars) at each mitotic cycle. Two or more aneusomies will result in increased probabilities of arrest/death as exemplified by cells labelled++and +â.</p