scholarly journals Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1618
Author(s):  
Ryan Sprissler ◽  
Bryce Perkins ◽  
Laurel Johnstone ◽  
Hani M. Babiker ◽  
Pavani Chalasani ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Tumor Suppressor Genes ◽  
Tumor Type ◽  
Rare Cancer ◽  
Suppressor Genes ◽  
Germline Variants ◽  
Rare Tumors ◽  
Whole Exome

Whole exome sequencing (WES) of matched tumor-normal pairs in rare tumors has the potential to identify genome-wide mutations and copy number alterations (CNAs). We evaluated 27 rare cancer patients with tumor-normal matching by WES and tumor-only next generation sequencing (NGS) as a comparator. Our goal was to: 1) identify known and novel variants and CNAs in rare cancers with comparison to common cancers; 2) examine differences between germline and somatic variants and how that functionally impacts rare tumors; 3) detect and characterize alleles in biologically relevant genes-pathways that may be of clinical importance but not represented in classical cancer genes. We identified 3343 germline single nucleotide variants (SNVs) and small indel variants—1670 in oncogenes and 1673 in tumor suppressor genes—generating an average of 124 germline variants/case. The number of somatic SNVs and small indels detected in all cases was 523:306 in oncogenes and 217 in tumor suppressor genes. Of the germline variants, six were identified to be pathogenic or likely pathogenic. In the 27 analyzed rare cancer cases, CNAs are variable depending on tumor type, germline pathogenic variants are more common. Cell fate pathway mutations (e.g., Hippo, Notch, Wnt) dominate pathogenesis and double hit (mutation + CNV) represent ~18% cases.

Rare tumor with matched germline whole exome sequencing to identify somatic and inherited variants of clinical significance.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1523-1523
Author(s):  
Bryce Perkins ◽  
Ryan Sprissler ◽  
Hani M. Babiker ◽  
Pavani Chalasani ◽  
Laurel Johnstone ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Significance ◽  
The Body ◽  
Rare Tumor ◽  
Germline Variants ◽  
Rare Tumors ◽  
Whole Exome ◽  
Line Of Therapy

1523 Background: Rare cancer incidence is defined as <6/100,000 cases. These cases are challenging due to delays in diagnosis, late stage at diagnosis, lack of standard of care and poor outcomes. We present molecular profiling of 28 rare tumor cases analyzed by whole exome sequencing (WES) seen in the Early Phase Therapeutics Program. Methods: We performed WES on 15 rare tumors with matched germline DNA, as well as tumor only on 2 additional cases. We sequenced a panel of 500 candidate cancer genes in 6 tumor/normal and 6 tumor only cases. Copy number alterations (CNAs) were assessed for the tumor-normal WES cases with SNVs and small indels for all cases. Caris (AZ) (tumor only) and liquid biopsy (Gaurdant360, CA) were also conducted in these patients for comparison. Results: Rare tumors affected 18 different tissues of the body with 1 case affecting tissue typical of common cancers. The rare tumor group contained 25% pathogenic or likely pathogenic germline variants compared to 7.1% for common tumors. This increased rate of inherited pathogenic variants met statistical significance: Fisher exact test (p = 0.0118). A total of 69 sequence variants and 8 CNAs were identified, 37 were actionable. For all but 3 patients, there was at least one variant associated with an actionable outcome given off-label use or clinical trial participation. There was excellent concordance with results from commercial sequencing; however, our tumor/germline sequencing identified additional germline variants of clinical significance, all were loss-of-function variants in tumor suppressors. Tumor vs. normal analysis showed that the majority of the commercially reported VUS were in fact germline VUS. In one case, a reported pathogenic variant we found to be an inherited pathogenic germline variant. 15 patients received at least 1 line of therapy indicated by genomic sequencing. For these patients the PFS ratio when compared to the most recent line of therapy prior to targeted therapy was 2.02, with 10/15 (67%) patients having a PFS ratio of >1.0, and 6/15 (40%) of patients having PFS ratio >1.3. Conclusions: We demonstrate the importance of tumor-normal analysis, especially in the context of rare tumors. Rare tumor patients may disproportionately benefit from tumor vs. normal WES at diagnosis to improve PFS within targeted therapy trials, guided by genomics.

scholarly journals Centenarian Exomes as a Tool for Evaluating the Clinical Relevance of Germline Tumor Suppressor Mutations

2020 ◽  
Vol 19 ◽  
pp. 153303382091108
Author(s):  
Lubomir Balabanski ◽  
Dimitar Serbezov ◽  
Dragomira Nikolova ◽  
Olga Antonova ◽  
Desislava Nesheva ◽  
...  
Keyword(s):  
Risk Factors ◽  
Tumor Suppressor ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Relevance ◽  
Tumor Suppressor Genes ◽  
Sequencing Data ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

Objectives: The aim of the present study was to evaluate the clinical relevance of mutations in tumor suppressor genes using whole-exome sequencing data from centenarians and young healthy individuals. Methods: Two pools, one of centenarians and one of young individuals, were constructed and whole-exome sequencing was performed. We examined the whole-exome sequencing data of Bulgarian individuals for carriership of tumor suppressor gene variants. Results: Of all variants annotated in both pools, 5080 (0.06%) are variants in tumor suppressor genes but only 46 show significant difference in allele frequencies between the two studied groups. Four variants (0.004%) are pathogenic/risk factors according to single nucleotide polymorphism database: rs1566734 in PTPRJ, rs861539 in XRCC3, rs203462 in AKAP10, and rs486907 in RNASEL. Discussion: Based on their high minor allele frequencies and presence in the centenarian group, we could reclassify them from pathogenic/risk factors to benign. Our study shows that centenarian exomes can be used for re-evaluating the clinically uncertain variants.

scholarly journals Whole-Exome Sequencing of Rare Site Endometriosis-Associated Cancer

Diseases ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 14
Author(s):  
Sonomi Kurose ◽  
Kentaro Nakayama ◽  
Sultana Razia ◽  
Masako Ishikawa ◽  
Tomoka Ishibashi ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Tumor Suppressor Genes ◽  
Undifferentiated Carcinoma ◽  
Small Subset ◽  
Breast Cancers ◽  
Whole Exome ◽  
Rare Site ◽  
Actionable Variants

Malignant transformation of extraovarian endometriosis is rare, with the carcinogenesis mechanism unclear. To clarify the actionable variants of rare-site endometriosis-associated cancer (RSEAC), we performed whole-exome sequencing for the tumor, in two patients. The intestine was affected in both cases, although the histology was that of clear cell carcinoma and undifferentiated carcinoma, respectively. Therefore, the cases were referred to as endometriosis-associated intestinal tumors (EIATs). Actionable variants (all frameshift mutations) were identified in tumor suppressor genes ARID1A, PTEN, and p53; however, no oncogenic variants were identified. Both cases were microsatellite stable. The patient with undifferentiated carcinoma exhibited hypermutator and homologous recombination deficiency phenotypes. The dominant mutation signatures were signature 30 (small subset of breast cancers) and 19 (pilocytic astrocytoma) in patient 1, and signature 5 (small subset of breast cancers) and 3 (breast, ovarian, and pancreatic cancers) in patient 2. Immunohistochemistry revealed positive CD8 and PD-1 expression in both patients; patient 1 also showed positive PDL-1 expression. Our results suggest that RSEAC is associated with variants of tumor suppressor genes as epigenetic alterations. Mutation signature-based whole-exome sequencing could be useful to select an adjuvant chemotherapy regimen. High CD8 and PD-1 expression in RSEAC suggests that immune checkpoint inhibitors are useful for treatment.

scholarly journals Sequential filtering for clinically relevant variants as a method for clinical interpretation of whole exome sequencing findings in glioma

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ege Ülgen ◽  
Özge Can ◽  
Kaya Bilguvar ◽  
Cemaliye Akyerli Boylu ◽  
Şirin Kılıçturgay Yüksel ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Analysis ◽  
Clinical Interpretation ◽  
Germline Variants ◽  
Whole Exome ◽  
Gene Level ◽  
Analysis Workflow ◽  
Tumor Mutational Burden ◽  
Diffuse Gliomas

Abstract Background In the clinical setting, workflows for analyzing individual genomics data should be both comprehensive and convenient for clinical interpretation. In an effort for comprehensiveness and practicality, we attempted to create a clinical individual whole exome sequencing (WES) analysis workflow, allowing identification of genomic alterations and presentation of neurooncologically-relevant findings. Methods The analysis workflow detects germline and somatic variants and presents: (1) germline variants, (2) somatic short variants, (3) tumor mutational burden (TMB), (4) microsatellite instability (MSI), (5) somatic copy number alterations (SCNA), (6) SCNA burden, (7) loss of heterozygosity, (8) genes with double-hit, (9) mutational signatures, and (10) pathway enrichment analyses. Using the workflow, 58 WES analyses from matched blood and tumor samples of 52 patients were analyzed: 47 primary and 11 recurrent diffuse gliomas. Results The median mean read depths were 199.88 for tumor and 110.955 for normal samples. For germline variants, a median of 22 (14–33) variants per patient was reported. There was a median of 6 (0–590) reported somatic short variants per tumor. A median of 19 (0–94) broad SCNAs and a median of 6 (0–12) gene-level SCNAs were reported per tumor. The gene with the most frequent somatic short variants was TP53 (41.38%). The most frequent chromosome-/arm-level SCNA events were chr7 amplification, chr22q loss, and chr10 loss. TMB in primary gliomas were significantly lower than in recurrent tumors (p = 0.002). MSI incidence was low (6.9%). Conclusions We demonstrate that WES can be practically and efficiently utilized for clinical analysis of individual brain tumors. The results display that NOTATES produces clinically relevant results in a concise but exhaustive manner.

scholarly journals Correction: Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified

2019 ◽  
Vol 33 (2) ◽  
pp. 319-319
Author(s):  
Maria Antonella Laginestra ◽  
Luciano Cascione ◽  
Giovanna Motta ◽  
Fabio Fuligni ◽  
Claudio Agostinelli ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Exome Sequencing ◽  
Tumor Suppressor Gene ◽  
Whole Exome Sequencing ◽  
Cell Lymphoma ◽  
Suppressor Gene ◽  
Peripheral T Cell Lymphoma ◽  
Not Otherwise Specified ◽  
Whole Exome

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified

2019 ◽  
Vol 33 (2) ◽  
pp. 179-187 ◽  
Author(s):  
Maria Antonella Laginestra ◽  
Luciano Cascione ◽  
Giovanna Motta ◽  
Fabio Fuligni ◽  
Claudio Agostinelli ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Exome Sequencing ◽  
Tumor Suppressor Gene ◽  
Whole Exome Sequencing ◽  
Cell Lymphoma ◽  
Suppressor Gene ◽  
Peripheral T Cell Lymphoma ◽  
Not Otherwise Specified ◽  
Whole Exome

scholarly journals Integrated Somatic and Germline Whole-Exome Sequencing Analysis in Women with Lung Cancer after a Previous Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 441 ◽  
Author(s):  
Simona Coco ◽  
Silvia Bonfiglio ◽  
Davide Cittaro ◽  
Irene Vanni ◽  
Marco Mora ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Smoking Habit ◽  
Cancer Control ◽  
Sequencing Analysis ◽  
Multiple Cancer ◽  
Germline Variants ◽  
Whole Exome

Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result of harboring rare variants. Sixty patients with LC with previous BC (the study population; SP) and 53 women with either BC or LC and no secondary cancer (control population; CP) were enrolled. Whole exome sequencing was performed in both tumors and unaffected tissues from 28/60 SP patients, and in germline DNA from 32/53 CP. Candidate genes were validated in the remaining individuals from both populations. We found two main mutational signature profiles: S1 (C>T) in all BCs and 16/28 LCs, and S2 (C>A) which is strongly associated with smoking, in 12/28 LCs. The burden test over rare germline variants in S1-LC vs CP identified 248 genes. Validation confirmed GSN as significantly associated with LC in never-smokers. In conclusion, our data suggest two signatures involved in LC onset in women with previous BC. One of these signatures is linked to smoking. Conversely, regardless of smoking habit, in a subgroup of BC survivors genetic susceptibility may contribute to LC risk.

scholarly journals Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei

2019 ◽  
Author(s):  
Mei Sim Lung ◽  
Catherine A. Mitchell ◽  
Maria A. Doyle ◽  
Andrew C. Lynch ◽  
Kylie L. Gorringe ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Splice Site ◽  
Pseudomyxoma Peritonei ◽  
Loss Of Function ◽  
Site Mutation ◽  
Germline Variants ◽  
Missense Variants ◽  
Whole Exome ◽  
Mucinous Tumours

Abstract Background Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours. Materials and Methods Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH. Results Seventeen novel variants in 17 genes were shared by the father and daughter: a nonsense mutation in REEP5 , an essential splice site mutation in THOP1 , and 15 missense variants. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes ( EXOG , RANBP2, RANBP6 and TNFRSF1B ) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic PMP; no LoF or rare missense germline variants were identified. Conclusion Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.

scholarly journals Deletions involving two distinct regions of 6q in B-cell non-Hodgkin lymphoma

Blood ◽  
1992 ◽  
Vol 80 (7) ◽  
pp. 1781-1787 ◽  
Author(s):  
G Gaidano ◽  
RS Hauptschein ◽  
NZ Parsa ◽  
K Offit ◽  
PH Rao ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Tumor Suppressor Genes ◽  
Molecular Evidence ◽  
Low Grade ◽  
Chromosome 6 ◽  
Tumor Type ◽  
Suppressor Genes ◽  
Non Hodgkin Lymphoma

Abstract The recurrent loss of genetic material from a specific chromosomal region in a given tumor type suggests the presence of a tumor- suppressor gene, the loss or inactivation of which may be relevant for tumorigenesis. In this study, we provide molecular evidence for the recurrent association between deletions on the long arm of chromosome 6 and B-cell non-Hodgkin lymphoma (B-NHL). Normal and tumor DNAs from 71 cases of B-NHL were studied for loss of constitutional heterozygosity (LOH) at 19 loci on chromosome 6 using a panel of restriction fragment length polymorphism (RFLP) probes. LOH, indicating deletion of all or part of 6q, was detected in 16 of 71 cases (22.5%), ranging from low- grade to high-grade B-NHL. The isolated loss of 6p or the loss of other chromosomes (8, 17, 22) tested as controls for specificity was not observed in any case. Comparison of the extent of the deletions among different cases allowed the identification of two distinct regions of minimal deletion (RMD) at 6q25 to 6q27 (RMD-1) and at 6q21 to 6q23 (RMD- 2), respectively, suggesting the existence of two tumor-suppressor genes. These data support a role for 6q deletions in B-NHL pathogenesis and provide a basis for identifying the corresponding tumor-suppressor genes.

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