Childhood cancer is a leading cause of death by disease in children ages 5–14, for which there are no preventive strategies. Due to early‐age of diagnosis and short period of exposure to ...environmental factors, increasing evidence suggests childhood cancer could have strong association with germline alterations in predisposition cancer genes but, their frequency and distribution are largely unknown. Several efforts have been made to develop tools to identify children with increased risk of cancer who may benefit from genetic testing but their validation and application on a large scale is necessary. Research on genetic bases of childhood cancer is ongoing, in which several approaches for the identification of genetic variants related to cancer predisposition have been used. In this paper, we discuss the updated efforts, strategies, molecular mechanisms and clinical implications for germline predisposition gene alterations and the characterization of risk variants in childhood cancer.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Background
Childhood cancer is one of the primary causes of disease‐related death in 5‐ to 14‐year‐old children and currently no prevention strategies exist to reduce the incidence of this disease. ...Childhood cancer has a larger hereditary component compared with cancer in adults. Few genetic studies have been conducted on children with cancer. Additionally, Latin American populations are underrepresented in genomic studies compared with other populations. Therefore, the aim of this study is to analyze germline mutations in a group of mixed‐ancestry Mexican pediatric patients with solid and hematological cancers.
Methods
We analyzed genetic variants from 40 Mexican childhood cancer patients and their relatives. DNA from saliva or blood samples was used for whole‐exome sequencing. All variants were identified following GATK best practices.
Results
We found that six patients (15%) were carriers of germline mutations in CDKN2A, CHEK2, DICER1, FANCA, MSH6, MUTYH, NF1, and SBDS cancer predisposition genes, and additional new variants predicted to be deleterious by in silico algorithms. A population genetics analysis detected five components consistent with the demographic models assumed for modern mixed‐ancestry Mexicans.
Conclusions
This report identifies potential genetic risk factors and provides a better understanding of the underlying mechanisms of childhood cancer in this population.
We found that 15% of confirmed mixed‐ancestry Mexican patients were carriers of germline mutations in CDKN2A, CHEK2, DICER1, FANCA, MSH6, MUTYH, NF1, and SBDS. This first report identifies potential genetic risk factors and provides a better understanding of the underlying mechanisms of childhood cancer in this population.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cementum Protein 1 (CEMP1) is a key regulator of cementogenesis. CEMP1 promotes cell attachment, differentiation, deposition rate, composition, and morphology of hydroxyapatite crystals formed by ...human cementoblastic cells. Its expression is restricted to cementoblasts and progenitor cell subpopulations present in the periodontal ligament. CEMP1 transfection into non-osteogenic cells such as adult human gingival fibroblasts results in differentiation of these cells into a "mineralizing" cell phenotype. Other studies have shown evidence that CEMP1 could have a therapeutic potential for the treatment of bone defects and regeneration of other mineralized tissues. To better understand CEMP1's biological effects in vitro we investigated the consequences of its expression in human gingival fibroblasts (HGF) growing in non-mineralizing media by comparing gene expression profiles. We identified several mRNAs whose expression is modified by CEMP1 induction in HGF cells. Enrichment analysis showed that several of these newly expressed genes are involved in oncogenesis. Our results suggest that CEMP1 causes the transformation of HGF and NIH3T3 cells. CEMP1 is overexpressed in cancer cell lines. We also determined that the region spanning the CEMP1 locus is commonly amplified in a variety of cancers, and finally we found significant overexpression of CEMP1 in leukemia, cervix, breast, prostate and lung cancer. Our findings suggest that CEMP1 exerts modulation of a number of cellular genes, cellular development, cellular growth, cell death, and cell cycle, and molecules associated with cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The current lung cancer classification from the Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society has considerably changed the pathologic diagnosis of ...lung invasive adenocarcinoma, identifying disease subtypes with substantial implications for medical practice, such as clinical, radiological, molecular, and prognostic differences. We analyzed the differences in the genetic expression of adenocarcinoma subtypes according to the new classification. Microarray gene expression analysis was performed on a cohort of 29 adenocarcinoma patients treated at the Instituto Nacional de Cancerología of Mexico from 2008 to 2011. All patients had an available biopsy sample and were classified into 4 different subtypes of adenocarcinoma (2015 World Health Organization classification). Lepidic-predominant adenocarcinoma was the only pattern that exhibited a marked gene expression difference compared with other predominant histologic patterns, revealing genes with significant expression (P < .01). Moreover, we identified 13 genes with specific differential expression in the lepidic-predominant adenocarcinoma that could be used as a gene signature. The lepidic-predominant histologic pattern has a differential gene expression profile compared with all predominant histologic patterns. Additionally, we identified a gene expression signature of 13 genes that have a unique behavior in the lepidic histologic pattern; these 13 genes are candidates for follow-up studies for their potential use as biomarkers or therapeutic targets. Results from this study highlight the importance of the new Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification and exemplify the potential clinical implications of correlating histopathology with exclusive molecular beacons.
•Gene expression analysis in samples from the main histologic adenocarcinoma subtypes.•We identified 13 differentially expressed genes in the lepidic-predominant subtype.•The gene signature includes previous, as well as novel, tumor biomarkers.•Study highlights the importance of the new IASLC/ATS/ERS lung cancer classification.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Rhabdomyosarcoma is the most frequent soft tissue sarcoma in the pediatric population. Two main histopathologic variants have been described, embryonal (ERMS) and alveolar (ARMS), which demonstrate ...clinical and genetic differences. In particular, most ARMS but not ERMS tumors are characterized by the presence of recurrent chromosomal translocations, which have been cytogenetically defined as t(2;13)(q35;q14) and t(1;13)(p36;q14). These translocations form PAX3-FKHR and PAX7-FKHR gene fusions, which encode chimeric transcription factors. These chimeric proteins are hypothesized to generate a novel transcriptional program in the target cell, thereby contributing to multiple aspects of ARMS tumorigenesis. This review highlights recent advances in numerous areas of biomedical investigation that are providing new insights into the biology, molecular pathology, and translational science of ARMS: the identification of downstream targets of PAX3-FKHR and collaborating events in the process of tumorigenesis and metastasis; generation of animal models based on the gene fusion and collaborating events; development of new assays for diagnosis, prognosis, and detection of minimal disseminated disease; and exploration of immune recognition of this tumor and the fusion protein. These findings highlight the continued importance of the fusion proteins in understanding the biology of this tumor and developing improved diagnostics for this tumor, and have led to the initiation of efforts to explore therapeutic strategies based on the increasing understanding of the biology of these fusion proteins.
Ovarian fibrosarcomas are extremely rare tumors with little genomic information available to date. In the present report we present the tumoral exome and transcriptome and the germinal exome of an ...ovarian fibrosarcoma from a 9-years old child. We found a paucity of mutations (0.77/Mb) and CNV alterations. Of these, the most relevant were a point mutation in the metal-binding site of the microRNA-processing DICER1 enzyme and a frame-shift alteration in the tumor suppressor gene NF1. We validated a germinal truncating mutation in DICER1, which was consistent with a DICER1 Syndrome diagnosis, providing the first example of an ovarian fibrosarcoma as the presenting neoplasia in this syndrome. Network and enrichment analyses showed that both a mesenchymal signature and a Hedgehog cascade could be driving the progression of this tumor. We were also able to find a global lincRNA deregulation, as the number of lincRNAs transcripts expressed in the tumor was decreased, with a concomitant upregulation of previously described non-coding transcripts associated with cancer, such as MALAT1, MIR181A1HG, CASC1, XIST and FENDRR. DICER1 Syndrome should be considered as a possible diagnosis in children ovarian fibrosarcoma. The role of lncRNAs in neoplasias associated with DICER1 alterations need to be studied in more detail.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Rhabdomyosarcoma (RMS) is a soft tissue sarcoma categorized into two major subtypes: alveolar RMS (ARMS) and embryonal RMS (ERMS). Most ARMS express the PAX3-FOXO1 (P3F) fusion oncoprotein generated ...by the 2;13 chromosomal translocation. In the present study, the downstream target genes of P3F were identified by analyzing two independent sets of gene expression profiles: primary RMS tumors and RD ERMS cells transduced with inducible P3F constructs. We found 34 potential target genes (27 upregulated and 7 downregulated) that were significantly and differentially expressed between P3F-positive and P3F-negative categories, both in primary RMS tumors and in the inducible P3F cell culture system. Gene ontology analysis of microarray data of the inducible P3F cell culture system employed indicated apoptosis, cell death, development, and signal transduction as overrepresented significant functional categories found in both upregulated and downregulated genes. Therefore, among the 34 potential target genes, the expression of cell death-related Gremlin1, cysteine knot superfamily 1, BMP antagonist 1 (GREM1) and death-associated protein kinase 1 (DAPK1) and development-related myogenic differentiation 1 (MYOD1) and hairy/enhancer-of-split related with YRPW motif 1 (HEY1) genes were further investigated. The differential expression of GREM1, DAPK1, MYOD1 and HEY1 was confirmed in independent tumors and inducible cell culture systems. The expression of GREM1, DAPK1 and MYOD1 were significantly upregulated; HEY1 was significantly downregulated in independent P3F-positive ARMS tumors and transcriptionally active P3F cells, compared to those in ERMS tumors and transcriptionally inactive P3F cells. This study identified target genes of P3F and suggested that four downstream targets (GREM1, DAPK1, MYOD1 and HEY1) can contribute to the biological activities of P3F involved in growth suppression or cell death and myogenic differentiation.
Loss-of-function mutations in the WRN helicase gene cause Werner syndrome- a progeroid syndrome with an elevated risk of cancer and other age-associated diseases. Large numbers of single nucleotide ...polymorphisms have been identified in WRN. We report here the organismal, cellular, and molecular phenotypes of variant rs3087425 (c. 2500C > T) that results in an arginine to cysteine substitution at residue 834 (R834C) and up to 90% reduction of WRN helicase activity. This variant is present at a high (5%) frequency in Mexico, where we identified 153 heterozygous and three homozygous individuals among 3,130 genotyped subjects. Family studies of probands identified ten additional TT homozygotes. Biochemical analysis of WRN protein purified from TT lymphoblast cell lines confirmed that the R834C substitution strongly and selectively reduces WRN helicase, but not exonuclease activity. Replication track analyses showed reduced replication fork progression in some homozygous cells following DNA replication stress. Among the thirteen TT homozygotes, we identified a previously unreported and statistically significant gender bias in favor of males (p = 0.0016), but none of the clinical findings associated with Werner syndrome. Our results indicate that WRN helicase activity alone is not rate-limiting for the development of clinical WS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
In Mexico, cancer represents the second leading cause of death in the pediatric population. The identification of susceptibility genes associated with cancer has been one of the main ...challenges of human genomics. Several studies have proposed that genetic variation in immune-related genes could be a determinant of susceptibility in different types of cancer. In the present study we evaluated the possible association between 10 polymorphisms in genes that participate in innate immunity and the risk of pediatric cancer. We analyzed genotyping data from 101 patients from Hospital Infantil de México “Federico Gómez” (HIM) with confirmed diagnosis of pediatric cancer. The genotypes were compared with 274 healthy adults without a medical history of pediatric cancer. For each polymorphism we calculated allelic and genotypic frequencies and Hardy-Weinberg equilibrium (HWE). The association between cancer and pediatric cancer was analyzed using Pearson chi-square and odds ratio (OR); survival analyses were performed by the log rank test and Kaplan-Meier curves. Our results show that risk of pediatric cancer in our sample is significantly associated with the genetic variants IL8-251 (p= 0.04327, OR= 0.701, IC 95% = 0.496-0.990), IL6-174 (p= 0.0037, OR= 2.413, IC 95% = 1.310-4.445), and IL10-592 (p= 0.0062, OR= 0.670, IC 95% = 0.502-0.894). However, we did not find any significant association between selected polymorphisms and overall or disease-free survival.
Citation Format: Gabriela E. Mercado, Gabriela A. Rosales-Bravo, David Velazquez-Fernandez, Marta Zapata-Tarres, Luis E. Juarez-Villegas. Innate immunity polymorphisms and risk of pediatric cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2083.
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