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Chemotherapy Curability in Leukemia, Lymphoma, Germ Cell Tumors and Gestational Malignancies: A Reflection of the Unique Physiology of Their Cells of Origin.

ABSTRACT: Cytotoxic DNA damaging chemotherapy brings clinical benefits in the treatment of many metastatic malignancies. However routine curative treatment remains restricted to a small number of malignancies including acute leukemia, high grade lymphoma, germ cell tumors, gestational malignancies and some of the rare childhood cancers. The detailed explanation for this dramatic divergence in outcomes remains to be elucidated. However, we have previously argued that there is a strong correlation between presence of the unique genetic events of immunoglobulin gene variable/diversity/joining (VDJ) recombination, somatic hypermutation (SHM), meiosis, nuclear fusion and gastrulation occurring in cells of origin of these malignancies and their high sensitivity to DNA damaging chemotherapy. In this study we have reviewed some of the basic physiological information relating to the specialized activity and sensitivity to DNA damage mediated apoptosis of normal cells undergoing these processes. In each of unique genetic events there are dramatic changes in apoptotic sensitivity. In VDJ recombination and somatic hypermutation over 95% of the cells involved undergo apoptosis, whilst in meiosis and nuclear fusion there are dramatic short term increases in the apoptotic sensitivity to DNA damage. It is apparent that each of the malignancies arising during these processes retains some of the unique phenotype associated with it. The impact of the physiological differences is most clearly seen in the two non-mutational malignancies. Gestational choriocarcinoma which arises shortly after nuclear fusion is routinely curable with chemotherapy whilst CIMP-positive ependymomas which is not linked to any of the unique genetic events is highly resistant. A similar pattern is found in a pair of malignancies driven by a single driver mutation. Infantile acute lymphoblastic leukemia (ALL) arises in a cell undergoing the early stages of VDJ recombination and has a 40% cure rate in contrast pediatric rhabdoid malignancy which is not linked to a unique genetic event responds very poorly to chemotherapy treatment. The physiological changes occurring in cancer cells at the time of the malignant transformation appear to have a major impact on the subsequent sensitivity to chemotherapy and curability. New therapies that impact on these pathways may be of therapeutic value.

SUBMITTER: Savage P

PROVIDER: S-EPMC7295948 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Chemotherapy Curability in Leukemia, Lymphoma, Germ Cell Tumors and Gestational Malignancies: A Reflection of the Unique Physiology of Their Cells of Origin.

Savage Philip P

Frontiers in genetics 20200609

Cytotoxic DNA damaging chemotherapy brings clinical benefits in the treatment of many metastatic malignancies. However routine curative treatment remains restricted to a small number of malignancies including acute leukemia, high grade lymphoma, germ cell tumors, gestational malignancies and some of the rare childhood cancers. The detailed explanation for this dramatic divergence in outcomes remains to be elucidated. However, we have previously argued that there is a strong correlation between p ...[more]

PMID: 32582272

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Project description:The cell of origin of the five subtypes (I-V) of germ cell tumors (GCTs) are assumed to be germ cells from different maturation stages. This is (potentially) reflected in their methylation status as fetal maturing primordial germ cells are globally demethylated during migration from the yolk sac to the gonad. Imprinted regions are erased in the gonad and later become uniparentally imprinted according to fetal sex. Here, 91 GCTs (type I-IV) and four cell lines were profiled (Illumina's HumanMethylation450BeadChip). Data was pre-processed controlling for cross hybridization, SNPs, detection rate, probe-type bias and batch effects. The annotation was extended, covering snRNAs/microRNAs, repeat elements and imprinted regions. A Hidden Markov Model-based genome segmentation was devised to identify differentially methylated genomic regions. Methylation profiles allowed for separation of clusters of non-seminomas (type II), seminomas/dysgerminomas (type II), spermatocytic seminomas (type III) and teratomas/dermoid cysts (type I/IV). The seminomas, dysgerminomas and spermatocytic seminomas were globally hypomethylated, in line with previous reports and their demethylated precursor. Differential methylation and imprinting status between subtypes reflected their presumed cell of origin. Ovarian type I teratomas and dermoid cysts showed (partial) sex specific uniparental maternal imprinting. The spermatocytic seminomas showed uniparental paternal imprinting while testicular teratomas exhibited partial imprinting erasure. Somatic imprinting in type II GCTs might indicate a cell of origin after global demethylation but before imprinting erasure. This is earlier than previously described, but agrees with the totipotent/embryonic stem cell like potential of type II GCTs and their rare extra-gonadal localization. The results support the common origin of the type I teratomas and show strong similarity between ovarian type I teratomas and dermoid cysts. In conclusion, we identified specific and global methylation differences between GCT subtypes, providing insight into their developmental timing and underlying developmental biology. Data and extended annotation are deposited at GEO (GSE58538 and GPL18809).

Dataset Information

Chemotherapy Curability in Leukemia, Lymphoma, Germ Cell Tumors and Gestational Malignancies: A Reflection of the Unique Physiology of Their Cells of Origin.

Publications

Chemotherapy Curability in Leukemia, Lymphoma, Germ Cell Tumors and Gestational Malignancies: A Reflection of the Unique Physiology of Their Cells of Origin.

Similar Datasets

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