Driver mutations of intrahepatic cholangiocarcinoma shape clinically relevant genomic clusters with distinct molecular features and therapeutic vulnerabilities

Abstract INTRODUCTION Intramedullary spinal cord tumors (IMSCTs) are a rare, heterogeneous group of neoplasms with limited treatment options and high rates of morbidity and mortality. Next-generation sequencing has revealed opportunities for targeted therapies of the intracranial counterparts of IMSCT, but little is known about the molecular features of IMSCT. METHODS To better understand the genetic basis of these tumors we performed whole exome sequencing on fifty-one IMSCT and matched germline DNA, including 29 ependymomas, 16 astrocytomas, 4 gangliogliomas,1hemangioblastoma, and 1 oligodendroglioma. Whole-genome sequencing was further performed on 12 IMSCT to discover possible structural variants. RESULTS Though recurrent somatic mutations in IMSCTs were rare, we identified NF2 mutations in 15.7% of tumors (ependymoma, N = 7; astrocytoma, N = 1), RP1 mutations in 5.9% of tumors (ependymoma, N = 3), and ESX1 mutations in 5.9% of tumors (ependymoma, N = 3). We further identified copy number amplifications in CTU1 in 25% of myxopapillary ependymomas. Given the paucity of somatic driver mutations, we further performed whole-genome sequencing of 12 tumors (ependymoma, N = 9; astrocytoma, N = 3). Overall, we observed that IMSCTs with intracranial histologic counterparts did not harbor the canonical mutations associated with their intracranial counterparts (eg glioblastoma). CONCLUSION Our findings suggest that the origin of IMSCTs may be distinct from tumors arising within other compartments of the central nervous system and provides a framework to begin more biologically based therapeutic strategies.

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NSCLC driver mutations in the Quebec population: Epidemiologic and clinical evaluation.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e22159 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e22159-e22159

Author(s):

Wissam Saliba ◽

Mustapha Ali Tehfe ◽

Roula Albadine ◽

Danh Tran-Thanh ◽

Denis Soulieres ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Stage ◽

Smoking History ◽

Driver Mutations ◽

Molecular Testing ◽

Tobacco Exposure ◽

Molecular Features ◽

Pcr Rflp ◽

Different Populations ◽

Regional Disease

e22159 Background: Recent advances in lung cancer treatment embrace the recognition of molecular pathways implicated in its pathogenicity, paving the path to personalized therapies. We conducted a retrospective analysis to characterize the molecular features of the population treated for non-squamous non-small cell lung cancer (NS-NSCLC) in the province of Quebec. Methods: 622 patients with NS-NSCLC and adequate tumor blocks, treated at the CHUM between 2006 and 2008, were included. All samples were tested for ALK translocations (by IHC and FISH), EGFR classical exon 19 and 21 mutations by PCR (fragment analysis and qPCR) and for KRAS codon 12 and 13 mutations by mismatch PCR-RFLP. Molecular features were matched to demographic characteristics and clinical outcomes. Results: So far, complete results are available for 153 patients. Considering the amount of tumor tissue available, this population is largely represented by patients with local or loco-regional disease (n= 140, 91.5%). A minority of patients (10.3%) was never or light smokers (< 10 pack-yrs). Only 2 patients (1.3%) were of Asian descent. The following table depicts the outcomes of this cohort of patients segregated according to mutation status and extent of disease. Conclusions: ALK rearrangements were not identified in this unselected NS-NSCLC population characterized by localized disease and strong smoking history. ALK translocation prevalence in different populations is likely to be largely influenced by its tumor stage distribution, tobacco exposure and the use of selection criteria for molecular testing. An expanded cohort of patients will be presented at the meeting. [Table: see text]

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Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features

Modern Pathology ◽

10.1038/modpathol.2013.241 ◽

2014 ◽

Vol 27 (8) ◽

pp. 1163-1173 ◽

Cited By ~ 97

Author(s):

Jau-Yu Liau ◽

Jia-Huei Tsai ◽

Ray-Hwang Yuan ◽

Chih-Ning Chang ◽

Hsin-Jung Lee ◽

...

Keyword(s):

Intrahepatic Cholangiocarcinoma ◽

Molecular Features

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Genetic Subgroups Inform on Pathobiology in Adult and Pediatric Burkitt Lymphoma

10.1101/2021.12.05.21267216 ◽

2021 ◽

Author(s):

Nicole Thomas ◽

Kostiantyn Dreval ◽

Daniela S. Gerhard ◽

Laura K. Hilton ◽

Jeremy S. Abramson ◽

...

Keyword(s):

Burkitt Lymphoma ◽

Somatic Hypermutation ◽

B Cell Lymphoma ◽

Epidemiological Studies ◽

Sub Saharan Africa ◽

Driver Mutations ◽

Barr Virus ◽

Molecular Features ◽

Genetic Features ◽

Epstein Barr

AbstractBurkitt lymphoma (BL) accounts for the majority of pediatric non-Hodgkin lymphomas (NHL) and is relatively rare but significantly more lethal when diagnosed in adults. The global incidence is highest in Sub-Saharan Africa, where Epstein-Barr virus (EBV) positivity is observed in 95% of all tumors. Both pediatric (pBL) and adult (aBL) cases are known to share some driver mutations, for example MYC translocations, which are seen in > 90% of cases. Sequencing efforts have identified many common somatic alterations that cooperate with MYC in lymphomagenesis with approximately 30 significantly mutated genes (SMG) reported thus far. Recent analyses revealed non-coding mutation patterns in pBL that were attributed to aberrant somatic hypermutation (aSHM). We sought to identify genomic and molecular features that may explain clinical disparities within and between aBL and pBL in an effort to delineate BL subtypes that may allow for the stratification of patients with shared pathobiology. Through comprehensive sequencing of BL genomes, we found additional SMGs, including more genetic features that associate with tumor EBV status, and established three new genetic subgroups that span pBL and aBL. Direct comparisons between pBL and aBL revealed only marginal differences and the mutational profiles were consistently better explained by EBV status. Using an unsupervised clustering approach to identify subgroupings within BL and diffuse large B-cell lymphoma (DLBCL), we have defined three genetic subgroups that predominantly comprise BL tumors. Akin to the recently defined DLBCL subgroups, each BL subgroup is characterized by combinations of common driver mutations and non-coding mutations caused by aSHM. Two of these subgroups and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among the aBL and pBL cohorts. These findings highlight not only a shared pathogenesis between aBL and pBL, but also establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiological studies, and diagnostic and therapeutic strategies.

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Whole-Exome Sequencing Reveals New Potential Mutations Genes for Primary Mucosa-Associated Lymphoid Tissue Lymphoma Arising From the Kidney

Frontiers in Oncology ◽

10.3389/fonc.2020.609839 ◽

2021 ◽

Vol 10 ◽

Author(s):

Shuang Wen ◽

Tianqing Liu ◽

Hongshuo Zhang ◽

Xu Zhou ◽

Huidan Jin ◽

...

Keyword(s):

Exome Sequencing ◽

Tumor Cells ◽

Whole Exome Sequencing ◽

Lymphoid Tissue ◽

Clinical Investigation ◽

Driver Mutations ◽

Low Grade ◽

Driver Genes ◽

Molecular Features ◽

Whole Exome

Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT) lymphomas involving the kidney were extremely rare, genetic alteration or molecular features was not yet explored, which may lead to limited choices for postoperative adjuvant or targeted. Whole-exome sequencing based tumor mutation profiling was performed on the tumor sample from a 77-year-old female presenting with discomfort at the waist was pathologically diagnosed as MALT lymphomas in the right kidney. We identified 101 somatic SNVs, and the majority of the identified SNVs were located in CDS and intronic regions. A total of 190 gain counts of CNVs with a total size of 488,744,073 was also investigated. After filtering with the CGC database, seven predisposing genes (ARID4A, COL2A1, FANCL, ABL2, HSP90AB1, FANCA, and DIS3) were found in renal MALT specimen. Furthermore, we compared somatic variation with known driver genes and validated three mutational driver genes including ACSL3, PHOX2B, and ADCY1. Sanger sequencing of germline DNA revealed the presence of a mutant base T of PHOX2B and a mutant base C of ADCY1 in the sequence, which were discovered for the first time in MALT lymphomas involving the kidney. Moreover, immunohistochemical analysis revealed that tumor cells were positive for CD20, CD79a, PAX5, CD21, and CD23, and expression of CD3, CD5, and CD8 were observed in reactive T lymphocytes surrounding tumor cells. These findings illustrated that concurrent aberrant PHOX2B and ADCY1 signaling may be a catastrophic event resulting in disease progression and inhibition of the putative driver mutations may be alternative adjuvant therapy for MALT lymphoma in the kidney which warrants further clinical investigation.

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Clinical Discernment, Bone Marrow, and Molecular Diagnostics Are Equally Important to Solve the Phenotypic Mimicry among Subtypes of Myeloproliferative Neoplasms

Reports ◽

10.3390/reports4030027 ◽

2021 ◽

Vol 4 (3) ◽

pp. 27

Author(s):

Susann Schulze ◽

Nadia Jaekel ◽

Christin Le Hoa Naumann ◽

Anja Haak ◽

Marcus Bauer ◽

...

Keyword(s):

Bone Marrow ◽

Clinical Judgment ◽

Systemic Mastocytosis ◽

Myeloproliferative Neoplasms ◽

Accurate Diagnosis ◽

Molecular Techniques ◽

Driver Mutations ◽

Therapeutic Consequences ◽

Molecular Features ◽

Disease Entities

The 2016 WHO classification integrates clinical, bone marrow (BM)-morphology, and molecular features to define disease entities. This together with the advancements in molecular detection and standardization of BM features enable an accurate diagnosis of myeloproliferative neoplasms (MPN) in the majority of patients. Diagnostic challenges remain due to phenotypic mimicry of MPN, failing specificity of BM-morphology, and the fact that phenotype-driver mutations, such as JAK2V617F, are not exclusive to a particular MPN, and their absence does not preclude any of these. We present a series of cases to illustrate themes to be considered in complex cases of MPN, such as triple-negative (TN)-MPN or MPN-unclassifiable (MPN-U). Eleven patients labelled as TN-MPN or MPN-U were included. Serum tryptase and NGS were part of a systematic/sequential multidisciplinary evaluation. Results were clustered into four categories based on diagnostic entities and/or how these diagnoses were made: (A) With expanding molecular techniques, BCR-ABL1 and karyotyping should not be missed; (B) systemic mastocytosis is underdiagnosed and often missed; (C) benign non-clonal disorders could mimic MPN; and (D) NGS could prove clonality in some “TN”-MPN cases. The prognostic/therapeutic consequences of an accurate diagnosis are immense. In TN-MPN or MPN-U cases, a multidisciplinary re-evaluation integrating molecular results, BM-morphology, and clinical judgment is crucial.

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Clinical significance of next-generation sequencing in Chinese patients with relapsed/refractory Wilm’s tumor.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e22003 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e22003-e22003

Author(s):

Juan Wang ◽

Fei-fei Sun ◽

Wanming Hu ◽

Lian Zhang ◽

Qing WANG ◽

...

Keyword(s):

Next Generation Sequencing ◽

Wilms Tumor ◽

Copy Number Variations ◽

Chinese Patients ◽

Driver Mutations ◽

Cancer Center ◽

Large Sample Size ◽

Next Generation ◽

Molecular Features ◽

Generation Sequencing

e22003 Background: Medical advances have been greatly improved in the survival rate for Wilms’ tumor, but the survival is still dismal for relapsed/refractory (R/R) patients. In the present study, we aimed to investigated the genomic profiling and the incidence of germline cancer susceptibility mutations of Chinese patients with R/R WT. Methods: From Jun 18, 2020 to Dec 22, 2020, the tumor specimens with matched blood samples obtained from R/R pediatric WT in Sun Yat-Sen University Cancer Center were performed next-generation sequencing (NGS) using a 539 cancer-related gene panel in a CAP-certified laboratory (Simcere Diagnostic Co, Ltd). Clinical information including age, gender and tumor histology were collected. Somatic and germline variations including single nucleotide variants (SNV), insertion-deletion variants (Indels), copy number variations (CNVs) and fusion, as well as tumor mutational burden (TMB)/microsatellite instability (MSI) were analyzed. IHC staining for PD-L1 expression was performed by FDA-approved VENTANA PD-L1(SP263) assay. Results: Eight patients with R/R WT were enrolled in this study, including 5 males and 3 females, with a median age of 6 years old (range, 3-14). All of the pathology was identified as favorable histology WT (FHWT). Of the specimens, 8 were from pulmonary and 1from peritoneum. We identified 152 reportable molecular aberrations, with a median of 19 (0-24). CNVs accounted for the majority of the total somatic aberrations, followed by SNVs, the percentage was 77% and 22%, respectively. Genes with either CNVs or SNVs were detected in FGFR1 (n=4), ERBB2(n=3), MYCN(n=4), MET(n=2), CDK4/6(n=2), TP53(n=2), CTNNB1(n=2), MYC(n=2), NF1(n=2), MDM4(n=2), CHEK2(n=1), FBXW7(n=1), EGFR(n=1). Notable cancer driver mutations were also characterized, such as the amplifications of ERBB2/MET/EGFR/FGFR1, and the point variations of CHEK2/FBXW7/NF1. Besides, a novel ASB12 intergenic region- AMER1 fusion was identified. Both of the patients available for PD-L1 evaluation showed negative PD-L1 expression on tumor cells. The median TMB was 1.47 (range, 0-7.8). All patients were microsatellite stabilization (MSS). A 4-year-old patient suffering peritoneal relapse harbored a germline pathogenic mutation in FANCA (c.1777-1G>C, intron 19), this locus has never been reported in WT before. Conclusions: We discovered some driver genes mutations which potentially sensitive to the corresponding targeted drugs in Chinese R/R WT patients. Large sample size was needed to provide a better understanding of molecular features in R/R WT patients to achieve precision medicine.

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Defective mismatch repair associated mutational signatures, a prognostic and predictive biomarker in endometrial cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5528 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5528-5528

Author(s):

Yifan Emily Chang ◽

Naomi N Adjei ◽

Wafa Khadraoui ◽

Gary Altwerger

Keyword(s):

Mismatch Repair ◽

Immune Checkpoint ◽

Predictive Biomarker ◽

Driver Mutations ◽

Mutational Signatures ◽

Expression Levels ◽

Molecular Features ◽

Mmr Deficiency ◽

Checkpoint Genes ◽

Defective Mismatch Repair

5528 Background: Mismatch repair (MMR) deficiency is the distinguishing molecular feature of a significant portion of endometrial cancers (UCEC), and tumors with MMR deficiency have been identified as candidates for immune checkpoint blockade therapy. We studied MMR deficiency in UCEC using defective mismatch repair associated mutational signatures (MMRd-ams). Methods: WES-derived somatic mutation data of 531 UCEC samples from TCGA Pan-Cancer Atlas were analyzed. COSMIC mutational signatures for each sample were calculated using the R package deconstructSigs. MMRd-ams were correlated with clinical and molecular features for 507 TCGA samples (cBioPortal). Samples were divided into High MMRd-ams ( n = 192) and Low MMRd-ams ( n = 315) groups by the average of the representative MMRd-ams (0.2396). Fractions of tumor immune infiltrates were derived from CIBERSORT. Results: A significantly higher percentage of patients (47/192, 24.5%) in the High MMRd group had somatic putative driver mutations in at least 1 of the MMR genes ( MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2 and EPCAM), compared with patients in the Low MMRd group (37/315, 11.8%, p = 0.0003). 15% (54/359) of tumors in the non-MSI subtypes expressed significant MMRd-ams and were categorized in the High MMRd-ams group. Patients in the High MMRd-ams group had longer progression-free survival (PFS) ( p = 0.0457, log-rank). Analysis of the inferred composition of tumor immune infiltrates revealed that the High MMRd-ams group had significantly higher fraction of CD8+ T cells ( p < 0.0001), higher fraction of T follicular helper cells ( p < 0.0001) and lower fraction of M2 macrophages ( p < 0.001). Tumors in the High MMRd-ams group also displayed higher mRNA expression levels of immune checkpoint genes: PDCD1 ( p = 0.0013), and CTLA4 ( p = 0.0016). Conclusions: MMRd-ams may be a prognostic and predictive biomarker with significant clinical impact. High MMRd-ams patients prognostically demonstrated longer PFS. Predictively, high MMRd-ams was associated with increased tumor immune infiltrates and elevated expression levels of CTLA4 and PDCD1 , known immune checkpoint genes exploitable by immune checkpoint therapies. MMRd-ams importantly characterized a subset of patients that were non-MSI but fit the MMR deficient phenotype by mutational signature. Together these findings open an avenue for recognizing and treating a previously unidentifiable group of patients.

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FGFR3-TACC3 fusion in bladder cancer: Enrichment in the young, never-smokers, and Asians.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.465 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 465-465

Author(s):

Amin Nassar ◽

Kevin Lundgren ◽

Mark Pomerantz ◽

Eliezer Mendel Van Allen ◽

Atish Dipankar Choudhury ◽

...

Keyword(s):

Bladder Cancer ◽

Massively Parallel Sequencing ◽

Age Groups ◽

Therapeutic Targets ◽

Driver Mutations ◽

Genomic Alteration ◽

Cancer Genes ◽

Asian Ethnicity ◽

Molecular Features ◽

Never Smokers

465 Background: Bladder cancer patients (pts) are typically elderly with median age ~70 years. We hypothesized that younger pts (≤age 50) with muscle-invasive bladder cancer (MIBC) have distinct molecular features, including potential driver mutations that could serve as therapeutic targets. Methods: We used the MIBC TCGA cohort (n = 412, Cell 2017) analyzed by whole exome sequencing as a discovery cohort, and then confirmed observations using 356 pts with MIBC and high grade (HG) non-MIBC analyzed at Dana Farber Cancer Institute (DFCI) by the Oncopanel assay. Oncopanel assesses 447 somatic cancer genes and 191 regions across 60 genes for rearrangement detection by massively parallel sequencing. We examined associations between age (≤50, 51-65, and > 65) and molecular features, using the χ2 test for discrete data, and the Wilcoxon Rank Sum Test for quantitative data. Nominal p values were obtained, and the FDR correction was employed to obtain q values. Results: The following DNA alterations were significantly enriched in the TCGA in ≤50 vs 51-65 vs > 65 age groups respectively: focal deletion in CREBBP (3/25 [12%] vs 2/137 [1.5%] vs 1/250 [0.4%], p < 0.0001, q = 0.0126); microRNA Cluster III (13/25 [52%] vs 53/137 [38.7%] vs 55/250 [22%], p = 0.0005, q = 0.0252); fusion in FGFR3-TACC3 (3/25 [12%] vs 2/137 [1.5%] vs 5/250 [2%], p = 0.0055, q = 0.1386). Given that FGFR3-TACC3 fusions are potential therapeutic targets, we examined the association between FGFR3-TACC3 fusions and clinical features in a pooled analysis combining the TCGA and DFCI cohorts totaling 768 pts. FGFR3-TACC3 fusions were enriched in: ≤50 age group vs 51-65 vs > 65 (4/33 [12.1%] vs 7/232 [3%] vs 6/503 [1.2%] respectively, p = 0.0001). Fusions were also significantly more common in Asians vs. Blacks vs. Whites (6/47 [12.8%] vs 1/28 [3.6%] vs 10/666 [1.5%] respectively, p < 0.0001) and in never-smokers vs. ever smokers (12/194 [6.2%] vs 5/545 [0.9%] respectively, p < 0.0001). Conclusions: FGFR3-TACC3 fusion, a known potentially actionable genomic alteration in MIBC, is significantly enriched in young pts, never-smokers and those of Asian ethnicity. Clinical testing to detect FGFR3-TACC3 fusion should be prioritized for MIBC and HG-non-MIBC pts meeting these criteria.

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Comprehensive next-generation sequencing to portray distinctive molecular characteristics of hypermutant lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15255 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15255-e15255

Author(s):

Hongbin Zhang ◽

Yuan Wang ◽

Qiaoxia Ji ◽

Hongmei Cai ◽

Xiangcun Liang ◽

...

Keyword(s):

Lung Cancer ◽

Next Generation Sequencing ◽

Genetic Factors ◽

Brca1 Gene ◽

Driver Mutations ◽

Molecular Characteristics ◽

Next Generation ◽

Molecular Features ◽

Genetic Profiles ◽

Generation Sequencing

e15255 Background: Tumor mutation burden (TMB) has been confirmed to predict the sensitivity to immunotherapy across multiple tumor types. Multiple genetic factors have been confirmed to increase the level of TMB, such as mutations in DNA damage repair (DDR) genes, POLE/POLD1, and high microsatellite instability (MSI). However, the extent that these factors contribute to hypermutation in lung cancer has not been fully investigated. Methods: We retrospectively reviewed the genetic profiles of 1000 lung cancer patients (pts) who underwent 1021-panel matched tumor-normal next-generation sequencing using tumor tissue samples and peripheral blood. Their TMB status were analyzed to determine the threshold of hypermutation. The clinicopathological characteristics, genetic profiles and genetic factors related to hypermutation were investigated for the pts in hypermutant cohort. Results: The threshold of hypermutation was determined as 19 muts/MB (top 5% in 1000 pts). As a result, 53 pts were included in the hypermutant cohort. A total of 1725 nonsynonymous somatic variants in 506 genes were identified. The most frequently mutated genes included TP53 (88.7%), LRP1B (71.7%), MLL2 (35.8%), EPHA5 (34.0%), and FAT1 (34.0%). KRAS was mutated in 17% pts, whereas mutations in EGFR, BRAF, ERBB2, MET were identified less commonly. MSI-high was observed in 5 cases. A germline mutation in BRCA1 gene was identified in an adenocarcinoma patient. Compared to genetic profiles of non-small cell lung cancer from TCGA database, mutations in multiple DDR genes were enriched in the hypermutant cohort (Table). No known driver mutation in POLE/POLD1 was identified. Conclusions: MSI-high and mutations in DDR genes may be associated with high level of TMB, whereas POLE/POLD1 driver mutations may not be related to hypermutant lung cancer. Hypermutant lung cancer displays distinctive molecular features that may be used as complementary indicators to screening pts sensitive to immunotherapy. [Table: see text]

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