EPCO-31. GERMLINE AND SOMATIC MUTATIONS IN PEDIATRIC GERM CELL TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi8-vi9
Author(s):  
Dong Song ◽  
Yang Zhao ◽  
Quanhua Mu ◽  
Zhuangzhuang Liang ◽  
Jiajia Wang ◽  
...  
Keyword(s):  
Germ Cell ◽  
Somatic Mutations ◽  
De Novo ◽  
Germ Cell Tumors ◽  
Germline Mutations ◽  
Driver Mutations ◽  
Whole Genome Sequencing Data ◽  
P Value ◽  
Sequencing Data ◽  
Disease Etiology

Abstract Pediatric germ cell tumors (pGCTs), a group of germ-cell-originated neoplasms, currently lack sufficient study. Although somatic activation of KIT/AKT and RAS/MAPK pathways have been revealed, no driver mutations have been detected in most of GCT cases. To extensively explore germline and somatic mutations, we analyzed genomic and/or transcriptomic sequencing data of 236 pGCTs, including data from not only public datasets but also newly collected whole-genome-sequencing data of tumor samples together with case-unaffected-parents trios collected in Shanghai Xinhua Hospital. A new computational pipeline was developed and carried out to identify functional germline and somatic variants. Overall, > 30,000 germline and > 100,000 somatic mutations were detected and prioritized. Particularly, we found germline trisomy 21 in three cases, germline XXY in five cases, and one germline XO, demonstrating the enrichment of germline chromosomal abnormality in pGCTs (p-value < 0.0001). We identified 196 loss-of-function-like inherited germline mutations involving CBL (4/212), PTEN (3/212), TEX11 (2/212), and ATM (1/212). In addition, we detected 2,160 de novo germline mutations (DNMs), and showed an average of 69.7 DNMs per proband, which is compatible to the previously reported incidence. Moreover, we discovered recurrent somatic mutations in known driver genes such as KIT (27/110), KRAS (10/110), NRAS (4/110), MTOR (5/110), PTEN (3/110), and CBL (2/110). Interestingly, somatic hotspot RRAS2 mutations were detected in seven of 110 cases. Subsequent clinical association analysis showed that patients who harbored RRAS2 mutations were younger than those harboring KRAS mutations (p-value < 0.05). Somatic copy number changes were frequently observed, including chr12p+ (47/110), chr21q+ (47/110), chrX+ (34/110), chr13q- (27/110), and chr20q+ (26/110). Furthermore, we identified chromoplexy in nine out of 62 cases, and this alteration is significantly enriched in yolk sac tumors with the occurrence 7/11. Collectively, portraying the mutational landscape of pGCTs, we revealed its disease etiology and potential new drug targets.

Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors

2021 ◽  
Author(s):  
Juan Chen ◽  
Yan Li ◽  
Jianlei Wu ◽  
Yakun Liu ◽  
Shan Kang
Keyword(s):  
Germ Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Peripheral Blood ◽  
Copy Number ◽  
Somatic Mutations ◽  
Germ Cell Tumors ◽  
Germline Mutations ◽  
Deletion Region ◽  
Whole Exome

Abstract Background Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing. Methods The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes corresponding to copy number alterations (CNA) deletion and duplication region, functional annotation of was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region. Results In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YST). Moreover, POU5F1 was the most significant mutated gene with mutation frequency > 10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region) was found in 2 YST and nuclear staining in 2 dysgerminomas (DG) tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I-like receptor, Toll-like receptor, NF-kappa B and Jak–STAT. KRT4, RPL14, PCSK6, PABPC3 and SARM1 mutations were detected in both peripheral blood and tumor samples. Conclusions Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.

scholarly journals De novo indels within introns contribute to ASD incidence

2017 ◽  
Author(s):  
Adriana Munoz ◽  
Boris Yamrom ◽  
Yoon-ha Lee ◽  
Peter Andrews ◽  
Steven Marks ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Target Genes ◽  
De Novo ◽  
Whole Genome Sequencing Data ◽  
P Value ◽  
Whole Genome ◽  
Sequencing Data ◽  
Control Sets ◽  
The Difference

AbstractCopy number profiling and whole-exome sequencing has allowed us to make remarkable progress in our understanding of the genetics of autism over the past ten years, but there are major aspects of the genetics that are unresolved. Through whole-genome sequencing, additional types of genetic variants can be observed. These variants are abundant and to know which are functional is challenging. We have analyzed whole-genome sequencing data from 510 of the Simons Simplex Collections quad families and focused our attention on intronic variants. Within the introns of 546 high-quality autism target genes, we identified 63 de novo indels in the affected and only 37 in the unaffected siblings. The difference of 26 events is significantly larger than expected (p-val = 0.01) and using reasonable extrapolation shows that de novo intronic indels can contribute to at least 10% of simplex autism. The significance increases if we restrict to the half of the autism targets that are intolerant to damaging variants in the normal human population, which half we expect to be even more enriched for autism genes. For these 273 targets we observe 43 and 20 events in affected and unaffected siblings, respectively (p-value of 0.005). There was no significant signal in the number of de novo intronic indels in any of the control sets of genes analyzed. We see no signal from de novo substitutions in the introns of target genes.

scholarly journals A de novo frameshift mutation in ZEB2 causes polledness, abnormal skull shape, small body stature and subfertility in Fleckvieh cattle

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lilian J. Gehrke ◽  
Maulik Upadhyay ◽  
Kristin Heidrich ◽  
Elisabeth Kunz ◽  
Daniela Klaus-Halla ◽  
...  
Keyword(s):  
De Novo ◽  
Small Body ◽  
Protein Product ◽  
Whole Genome Sequencing Data ◽  
Chromosome 2 ◽  
Sequencing Data ◽  
Autosomal Dominant Trait ◽  
Intergenic Regions ◽  
Body Stature ◽  
Growth Of Animals

Abstract Polledness in cattle is an autosomal dominant trait. Previous studies have revealed allelic heterogeneity at the polled locus and four different variants were identified, all in intergenic regions. In this study, we report a case of polled bull (FV-Polled1) born to horned parents, indicating a de novo origin of this polled condition. Using 50K genotyping and whole genome sequencing data, we identified on chromosome 2 an 11-bp deletion (AC_000159.1:g.52364063_52364073del; Del11) in the second exon of ZEB2 gene as the causal mutation for this de novo polled condition. We predicted that the deletion would shorten the protein product of ZEB2 by almost 91%. Moreover, we showed that all animals carrying Del11 mutation displayed symptoms similar to Mowat-Wilson syndrome (MWS) in humans, which is also associated with genetic variations in ZEB2. The symptoms in cattle include delayed maturity, small body stature and abnormal shape of skull. This is the first report of a de novo dominant mutation affecting only ZEB2 and associated with a genetic absence of horns. Therefore our results demonstrate undoubtedly that ZEB2 plays an important role in the process of horn ontogenesis as well as in the regulation of overall development and growth of animals.

scholarly journals Germ Cell Tumor Molecular Heterogeneity Revealed Through Analysis of Primary and Metastasis Pairs

2020 ◽  
pp. 1307-1320
Author(s):  
Michael L. Cheng ◽  
Mark T.A. Donoghue ◽  
François Audenet ◽  
Nathan C. Wong ◽  
Eugene J. Pietzak ◽  
...  
Keyword(s):  
Germ Cell ◽  
Somatic Mutations ◽  
Germ Cell Tumors ◽  
Molecular Heterogeneity ◽  
Targeted Next Generation Sequencing ◽  
Variants Of Unknown Significance ◽  
Resistant Disease ◽  
Oncogenic Mutations ◽  
Dna Copy Number Alterations ◽  
Metastatic Sites

PURPOSE Although primary germ cell tumors (GCTs) have been extensively characterized, molecular analysis of metastatic sites has been limited. We performed whole-exome sequencing and targeted next-generation sequencing on paired primary and metastatic GCT samples in a patient cohort enriched for cisplatin-resistant disease. PATIENTS AND METHODS Tissue sequencing was performed on 100 tumor specimens from 50 patients with metastatic GCT, and sequencing of plasma cell-free DNA was performed for a subset of patients. RESULTS The mutational landscape of primary and metastatic pairs from GCT patients was highly discordant (68% of all somatic mutations were discordant). Whereas genome duplication was common and highly concordant between primary and metastatic samples, only 25% of primary-metastasis pairs had ≥ 50% concordance at the level of DNA copy number alterations (CNAs). Evolutionary-based analyses revealed that most mutations arose after CNAs at the respective loci in both primary and metastatic samples, with oncogenic mutations enriched in the set of early-occurring mutations versus variants of unknown significance (VUSs). TP53 pathway alterations were identified in nine cisplatin-resistant patients and had the highest degree of concordance in primary and metastatic specimens, consistent with their association with this treatment-resistant phenotype. CONCLUSION Analysis of paired primary and metastatic GCT specimens revealed significant molecular heterogeneity for both CNAs and somatic mutations. Among loci demonstrating serial genetic evolution, most somatic mutations arose after CNAs, but oncogenic mutations were enriched in the set of early-occurring mutations as compared with VUSs. Alterations in TP53 were clonal when present and shared among primary-metastasis pairs.

scholarly journals Α de novo 3.8-Mb inversion affecting the EDA and XIST genes in a heterozygous female calf with generalized hypohidrotic ectodermal dysplasia

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Clémentine Escouflaire ◽  
Emmanuelle Rebours ◽  
Mathieu Charles ◽  
Sébastien Orellana ◽  
Margarita Cano ◽  
...  
Keyword(s):  
Ectodermal Dysplasia ◽  
De Novo ◽  
Genetic Disorder ◽  
Hair Follicles ◽  
Whole Genome Sequencing Data ◽  
Recessive Mutation ◽  
Sources Of Information ◽  
Affected Animal ◽  
Sequencing Data ◽  
Hypohidrotic Ectodermal Dysplasia

Abstract Background In mammals, hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that is characterized by sparse hair, tooth abnormalities, and defects in cutaneous glands. Only four genes, EDA, EDAR, EDARADD and WNT10A account for more than 90% of HED cases, and EDA, on chromosome X, is involved in 50% of the cases. In this study, we explored an isolated case of a female Holstein calf with symptoms similar to HED. Results Clinical examination confirmed the diagnosis. The affected female showed homogeneous hypotrichosis and oligodontia as previously observed in bovine EDAR homozygous and EDA hemizygous mutants. Under light microscopy, the hair follicles were thinner and located higher in the dermis of the frontal skin in the affected animal than in the control. Moreover, the affected animal showed a five-fold increase in the number of hair follicles and a four-fold decrease in the diameter of the pilary canals. Pedigree analysis revealed that the coefficient of inbreeding of the affected calf (4.58%) was not higher than the average population inbreeding coefficient (4.59%). This animal had ten ancestors in its paternal and maternal lineages. By estimating the number of affected cases that would be expected if any of these common ancestors carried a recessive mutation, we concluded that, if they existed, other cases of HED should have been reported in France, which is not the case. Therefore, we assumed that the causal mutation was dominant and de novo. By analyzing whole-genome sequencing data, we identified a large chromosomal inversion with breakpoints located in the first introns of the EDA and XIST genes. Genotyping by PCR-electrophoresis the case and its parents allowed us to demonstrate the de novo origin of this inversion. Finally, using various sources of information we present a body of evidence that supports the hypothesis that this mutation is responsible for a skewed inactivation of X, and that only the normal X can be inactivated. Conclusions In this article, we report a unique case of X-linked HED affected Holstein female calf with an assumed full inactivation of the normal X-chromosome, thus leading to a severe phenotype similar to that of hemizygous males.

A retrospective analysis of patients with poor-risk germ cell tumor (PRGCT) treated at Indiana University from 2000 to 2010.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4557-4557
Author(s):  
Nabil Adra ◽  
Costantine Albany ◽  
Daniel Sonnenburg ◽  
Yan Tong ◽  
Nasser H. Hanna ◽  
...  
Keyword(s):  
Germ Cell ◽  
Retrospective Analysis ◽  
Tumor Markers ◽  
Germ Cell Tumor ◽  
Germ Cell Tumors ◽  
Continuous Variable ◽  
Cell Tumor ◽  
P Value ◽  
Indiana University ◽  
Poor Risk

4557 Background: PRGCT represents 14% of germ cell tumors, with 2-year PFS of 50%. PRGCT is defined by primary mediastinal non-seminomatous germ cell tumor (PMNSGCT), non-pulmonary visceral metastasis (NPVM), AFP > 10,000 or hCG > 50,000. This analysis attempts to identify subsets of patients with more or less favorable outcomes among the poor risk groups. Methods: Retrospective analysis of all patients with testicular cancer seen at Indiana University (IU) from 2000-2010. 291 patients with PRGCT identified of whom 79 received initial therapy at IU. We analyzed the following variables: primary site testis/retroperitoneal (T/RP) vs. PMNSGCT, pulmonary vs. NPVM, and the amplitude of serum tumor markers. We identified groups of patients according to the level of tumor marker elevation with cutoff points of AFP 20,000 and hCG 200,000. Results: Mean age 29, mean AFP 8,283, mean hCG 185,667. 24% had PMNSGCT, 48% NPVM, 11% AFP>20,000, and 25% hCG>200,000. When hCG was analyzed as a continuous variable, every 10,000 unit increase in hCG caused the hazard of progression to increase by 1% (p value 0.01). Patients with NPVM had significantly worse PFS. NPVM with elevated hCG had worse outcome than NPVM with normal hCG. This did not correlate as well with AFP. PFS was worse with NPVM than elevated pre-chemotherapy tumor markers. Multiple different criteria for poor risk disease carried significantly worse impact on PFS and OS when compared to having a single criterion for poor risk disease. Conclusions: Our data indicate that patients with NPVM or more than one criteria for PRGCT have a worse outcome compared to other PRGCT subgroups. [Table: see text]

Circulating tumor (ct)-DNA alterations in patients with testicular germ cell tumors.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 415-415
Author(s):  
Archana Agarwal ◽  
Amin Nassar ◽  
Rebecca Nagy ◽  
Catherine Curran ◽  
Sarah Abou Alaiwi ◽  
...  
Keyword(s):  
Germ Cell ◽  
Somatic Mutations ◽  
Demographic Data ◽  
Germ Cell Tumors ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell ◽  
The Usa ◽  
Evolution Of Resistance ◽  
Dna Alterations ◽  
Ctdna Analysis

415 Background: Testicular germ cell tumors (GCT) infrequently harbor somatic mutations. ctDNA assessment allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. We report ctDNA profiling of patients (pts) with testicular GCTs. Methods: 40 patients (pts) with advanced testicular GCTs from multiple institutions in the USA that underwent ctDNA analysis using the Guardant (G)-360 platform were eligible and a total of 48 samples were collected. 36 pts had one sample, 3 pts had 2 samples, 1 pt had 6 samples. De-identified demographic data were collected in addition to data for ctDNA alterations. G360 employed a CLIA-certified ctDNA panel that assessed single nucleotide variant and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants reported at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or found in OncoKB were considered pathogenic. Results: Of 40 patients with testicular GCTs, 13pts (33%) were post systemic therapy. The median age was 36 years (range 20-61). 199 ctDNA alterations were detected in 35 patients (87.5%) across 41 genes. Among the 199 alterations, 102 were believed to be pathogenic and detectable in 26 samples from 25 pts (62.5) (%). The most common pathogenic somatic alterations were KRAS (n = 16/102, 16%), TP53 (n = 16/102, 16%), CCND2 (n = 9/102, 9%), CDK6 (n = 9/102, 9%), MET (n = 9/102, 9%), and RAF1 (n = 6/102, 6%). Conclusions: ctDNA alterations were frequently detected in resistant testicular GCTs and appear similar to alterations previously described in tumor tissue analyses of testicular GCTs. Given that ctDNA offers a non-invasive means of profiling tumor DNA, further development of this promising modality is warranted to study the evolution of resistance to cisplatin-based chemotherapy and new potentially actionable alterations.

scholarly journals Leaf form diversification in an heirloom tomato results from alterations in two different HOMEOBOX genes

2020 ◽  
Author(s):  
Hokuto Nakayama ◽  
Steven D. Rowland ◽  
Zizhang Cheng ◽  
Kristina Zumstein ◽  
Julie Kang ◽  
...  
Keyword(s):  
Gene Network ◽  
Natural Variation ◽  
De Novo ◽  
Whole Genome Sequencing Data ◽  
Phenotypic Traits ◽  
Comparative Genome Analysis ◽  
Sequencing Data ◽  
Single Nucleotide ◽  
Leaf Phenotype ◽  
Gene Network Analysis

AbstractDomesticated plants and animals display tremendous diversity in various phenotypic traits and often this diversity is seen within the same species. Tomato (Solanum lycopersicum; Solanaceae) cultivars show wide variation in leaf morphology, but the influence of breeding efforts in sculpting this diversity is not known. Here, we demonstrate that a single nucleotide deletion in the homeobox motif of BIPINNATA, which is a BEL-LIKE HOMEODOMAIN gene, led to a highly complex leaf phenotype in an heirloom tomato, Silvery Fir Tree (SiFT). Additionally, a comparative gene network analysis revealed that reduced expression of the ortholog of WUSCHEL RELATED HOMEOBOX 1 is also important for the narrow leaflet phenotype seen in SiFT. Phylogenetic and comparative genome analysis using whole-genome sequencing data suggests that the bip mutation in SiFT is likely a de novo mutation, instead of standing genetic variation. These results provide new insights into natural variation in phenotypic traits introduced into crops during improvement processes after domestication.

scholarly journals Impact of Somatic Mutations on Clinical Outcomes Following Flamsa-Bu Conditioning and Allogenic Stem Cell Transplantation in Patients with Poor-Risk Myeloid Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2277-2277
Author(s):  
Karl Haslam ◽  
Niamh Appleby ◽  
Christopher Armstrong ◽  
Catherine M. Flynn ◽  
Stephen Langabeer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
De Novo ◽  
Driver Mutations ◽  
Prognostic Impact ◽  
Poor Risk ◽  
De Novo Aml

Abstract Allogeneic stem cell transplantation (allo-SCT) offers a potentially curative option for eligible patients with poor-risk myeloid malignancies. The prognostic impact of specific mutations such as TP53 is unclear in this context1,2. We report the prognostic impact of mutations in a panel of 19 genes (covering entire coding regions of DNMT3A, CEBPA, GATA2, TET2, TP53 and mutation hot spots of ASXL1, BRAF, CBL, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, NPM1, NRAS, PTPN11, RUNX1 and WT1) identified by targeted sequencing in patients undergoing allo-SCT with FLAMSA-Bu conditioning. Twenty-one patients (10 male, 11 female; median age 55 years; range 36-64 years) were included and identified as having poor risk disease on the basis of acute myeloid leukemia (AML) with primary induction failure (n=5), myelodysplasia (MDS) with high or very high risk R-IPSS scores (n=8, 4 of whom had therapy related MDS), therapy related acute myeloid leukemia with MLL rearrangement (n=1), intermediate-2 or high risk prognostic score for chronic myelomonocytic leukemia (CMML) (n=4), blast crisis of chronic myeloid leukemia (n=1), primary myelofibrosis with blasts > 10% on bone marrow trephine (n=1), mixed phenotype acute leukemia (T/myeloid) with complex karyotype (n=1). Overall, complex karyotypes were detected in 8/21 (38.1%) patients. The median Hematopoietic Cell Transplantation-Comorbidity Index score was 4 (range 0-10). All 21 patients underwent allo-SCT with fludarabine, cytarabine, amsacrine, busulphan, and anti-thymocyte globulin (FLAMSA-Bu) conditioning. Twelve (57.1%) received stem cells from fully HLA matched unrelated donors. Neutrophil engraftment occurred at a median of 24 days (range 11-124 days) and platelet engraftment at a median of 26 days (range 10-221 days) post-transplant. Seven (33.3%) patients developed acute graft versus host disease (GVHD). Ten (47.6%) patients received planned donor lymphocyte infusions. Genomic DNA was available from 16/21 patient samples and was sequenced using the Ion-Torrent platform. Somatic driver mutations were identified in 13/16 (81.2%) patients, 10 of whom had two or more driver mutations. TET2 mutations were the most common lesion, detected in 6/16 (37.5%) cases, followed by RUNX1, ASXL1 and DNMT3A in 3/16 (18.8%) patients each. Ten (47.6%) patients remain alive and disease-free after a median of 19.3 months follow-up. Two treatment-related deaths occurred; one from sepsis in the context of steroid-refractory GVHD and a second patient died of toxoplasmosis infection. Nine (42.9%) patients have relapsed post allo-SCT, three of whom remain alive following salvage therapy. The median progression free survival (PFS) is 841 days and the median overall survival (OS) has not yet been reached. Patients with therapy-related myeloid neoplasms trended towards shorter PFS and OS compared with all other diagnosis (396 vs 841 days, p=0.54; 373 days vs undefined, p=0.11, respectively). All four CMML patients have relapsed at a median of 694 days post FLAMSA-Bu allo-SCT. The median PFS for de novo AML and MDS has not been reached. Monosomal karyotype was associated with a non-significant trend towards shortened PFS (148 days vs 751 days, p=0.11). Cases with TET2 mutations trended towards a shorter PFS compared with wild-type TET2 (751 days vs undefined, p=0.6407) but this did not reach statistical significance. No difference was observed in PFS between TP53 mutated vs wild-type TP53 cases (517 days vs 751 days, p=0.99). FLAMSA-Bu allo-SCT remains a viable treatment option for selected patients with de novo AML and MDS, even patients in whom multiple or adverse somatic mutations are detected. Conversely, durable remissions are uncommon for patients with therapy-related myeloid neoplasms or CMML. These patients may benefit from consideration for alternative treatment strategies. References: 1. Christopeit, M., Badbaran, A., Alawi, M., et al. (2016), Correlation of somatic mutations with outcome after FLAMSA-busulfan sequential conditioning and allogeneic stem cell transplantation in patients with myelodysplastic syndromes. Eur J Haematol. doi:10.1111/ejh.12724 2. Bejar, R., Stevenson, K.E., Caughey, B., et al (2014), Somatic Mutations Predict Poor Outcome in Patients With Myelodysplastic Syndrome After Hematopoietic Stem-Cell Transplantation. JCO 32(25) 2691-2698. Table Patient population and transplant characteristics Table. Patient population and transplant characteristics Disclosures No relevant conflicts of interest to declare.

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