Molecular characterization of squamous cell carcinoma of the anal canal (SCCA).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 538-538 ◽  
Author(s):  
Benjamin Adam Weinberg ◽  
Heinz-Josef Lenz ◽  
David Arguello ◽  
Wafik S. El-Deiry ◽  
Joanne Xiu ◽  
...  
Keyword(s):  
Low Frequency ◽  
Hpv Infection ◽  
Response To Therapy ◽  
Molecular Characteristics ◽  
Missense Mutations ◽  
Chi Square ◽  
Gene Testing ◽  
Tumor Mutational Burden ◽  
N 93

538 Background: Nivolumab has shown promising results in SCCA patients. The majority of SCCA cases have been linked to prior human papillomavirus (HPV) infection. However, HPV negative tumors are frequently TP53 mutated and often resistant to therapy. Molecular characteristics of SCCA are largely undefined. Here we explored the underlying biology of SCCA and the differences between TP53-wild type ( TP53-WT) and TP53-mutated ( TP53-MT) tumors. Methods: SCCA specimens underwent multiplatform testing with protein expression (IHC), gene amplification (ISH), and sequencing (NGS). Tumor mutational burden (TMB) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparative analyses. Results: In total, 253 tumors were studied. The most frequently mutated genes included PIK3CA (24%), BRCA2 (14%), FBXW7 (12.4%), TP53 (9.7%), and PTEN (8.9%). In a subset of 23 tumors subjected to Illumina NextSeq (592 gene) testing, the most common mutations were NOTCH2 (30%), NOTCH1 (27.3%), POLE (21.7%) , TSC2 (17.4%), PTEN (14.3%), BRAF (13.6%), BRCA2 (13.0%), PIK3CA (13.0%), and FBXW7 (9.5%). Tumors frequently expressed MRP1 (97.6%), EGFR (92.7%), TOP2A (88.5%), TOPO1 (69.5%), MGMT (67.8%), and RRM1 (59.9%). Expression of PD-1 was seen in 55.8% (24/43) of tumors, and PD-L1 in 15.4% (9/34). HER2 was amplified in 2% (3/147) of samples, which has not been previously described in SCCA. When compared with TP53-WT (n = 93) tumors, T P53-MT (n = 10) had higher rates of BRAF (22% vs. 1%, p < 0.001) and RB1 mutations (44% vs. 0%, p < 0.001), whereas TP53-WT had higher expression of TOPO1 (76% vs. 40%, p = 0.01) and TUBB3 (19% vs. 50%, p = 0.02). There were no differences between the two groups in the frequency of PD-1 or PD-L1 expression. Mean TMB was 8.6 mutations/megabase and, using a TMB cut-off > 17 mutations/megabase to define high vs. low TMB, 6.7% of tumors were TMB-High. High TMB did not correlate with PD-1 (p = 0.50) or PD-L1 status (p = 0.52). Conclusions: Molecular profiling differences between TP53-MT and TP53-WT SCCA indicate different carcinogenic pathways and biology, which may influence response to therapy. Low frequency mutations in several druggable genes may provide therapeutic opportunities for patients with SCCA.

Molecular characterization of intestinal (IS) and diffuse subtypes (DS) of gastric adenocarcinomas.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 60-60
Author(s):  
Mohamed E. Salem ◽  
Joanne Xiu ◽  
Alberto Puccini ◽  
Philip Agop Philip ◽  
Richard M. Goldberg ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Low Frequency ◽  
Response To Therapy ◽  
Missense Mutations ◽  
Chi Square ◽  
Nextgen Sequencing ◽  
Gastric Adenocarcinomas ◽  
Frequent Mutations ◽  
Miseq Platform ◽  
Tumor Expression

60 Background: Gastric adenocarcinomas are histologically categorized into IS and DS. TCGA categorization suggests that IS is more common in tumors arising via the chromosomal instability pathway and DS is more common in genomically stable tumors. However, molecular differences between these subtypes are not well understood. Methods: Gastric adenocarcinomas were examined using NextGen sequencing (MiSeq platform on 47 genes or NextSeq on 592 genes), protein expression, and gene amplification techniques. For tumors sequenced with NextSeq, tumor mutational load (TML) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated on known MSI loci in target regions. Chi-square and t-tests were used for comparative analyses. Results: In total, 268 gastric adenocarcinomas with annotated histology (DS [n = 144]; IS [n = 124]) were analyzed. Patients with DS were younger than those with IS (mean age: 27y [DS] vs. 65y [IS], p < 0.0001). The majority of patients with DS were female (56% [DS] vs. 35% [IS], p = 0.0004). Most frequently mutated genes in DS were TP53 (44%), ARID1A (37%) , CDH1 (14%), BAP1 (8%), and PIK3CA (5%); whereas the most frequent mutations in IS were ARID1A (57%), TP53 (51%), CDKN2A (13%), MUTYH (13%), and PIK3CA (12%). IS had a higher rate of APC mutations (10% vs. 2%, p = 0.04), whereas DS had a higher rate of CDH1 (14% vs. 2%, p = 0.01). There was no difference in PD-L1 tumor expression (DS: 4%; IS: 8%). IS, when compared to DS, exhibited higher overexpression of TOP2A (90% vs 50%, p < 0.0001), TS (58% vs 28%, p < 0.0001), RRM1 (47% vs 22%, p = 0.0006), and Her2/neu (14% vs 1%, p < 0.0001), and greater Her2 amplification (19% vs 2%, p < 0.0001). Microsatellite instability was not detected in DS, and there was a trend toward a higher frequency of MSI-high in IS (6% [IS] vs. 0% [DS], p = 0.06), as well as a higher mean TML (10.3 vs. 6.6 mutation/megabase, p = 0.01). Conclusions: Significant molecular differences between IS and DS gastric adenocarcinomas were observed, a finding that indicates different carcinogenic pathways and biology, as well as potential differences in response to therapy. Low frequency mutations in several druggable genes may provide therapeutic options.

scholarly journals Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers

2021 ◽  
Vol 9 (12) ◽  
pp. e003414
Author(s):  
Jung Ho Kim ◽  
Mi-Kyoung Seo ◽  
Ji Ae Lee ◽  
Seung-Yeon Yoo ◽  
Hyeon Jeong Oh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microsatellite Instability ◽  
Molecular Subtype ◽  
Colorectal Cancers ◽  
Molecular Characteristics ◽  
Immune Parameters ◽  
Whole Exome ◽  
Tumor Mutational Burden ◽  
Consensus Molecular Subtype

BackgroundColorectal cancers (CRCs) with microsatellite instability-high (MSI-H) are hypermutated tumors and are generally regarded as immunogenic. However, their heterogeneous immune responses and underlying molecular characteristics remain largely unexplained.MethodsWe conducted a retrospective analysis of 73 primary MSI-H CRC tissues to characterize heterogeneous immune subgroups. Based on combined tumor-infiltrating lymphocyte (TIL) immunoscore and tertiary lymphoid structure (TLS) activity, MSI-H CRCs were classified into immune-high, immune-intermediate, and immune-low subgroups. Of these, the immune-high and immune-low subgroups were further analyzed using whole-exome and transcriptome sequencing.ResultsWe found considerable variations in immune parameters between MSI-H CRCs, and immune subgrouping of MSI-H CRCs was performed accordingly. The TIL densities and TLS activities of immune-low MSI-H CRCs were comparable to those of an immune-low or immune-intermediate subgroup of microsatellite-stable CRCs. There were remarkable differences between immune-high and immune-low MSI-H CRCs, including their pathological features (medullary vs mucinous), genomic alterations (tyrosine kinase fusions vs KRAS mutations), and activated signaling pathways (immune-related vs Wnt and Notch signaling), whereas no significant differences were found in tumor mutational burden (TMB) and neoantigen load. The immune-low MSI-H CRCs were subdivided by the consensus molecular subtype (CMS1 vs CMS3) with different gene expression signatures (mesenchymal/stem-like vs epithelial/goblet-like), suggesting distinct immune evasion mechanisms. Angiogenesis and CD200 were identified as potential therapeutic targets in immune-low CMS1 and CMS3 MSI-H CRCs, respectively.ConclusionsMSI-H CRCs are immunologically heterogeneous, regardless of TMB. The unusual immune-low MSI-H CRCs are characterized by mucinous histology, KRAS mutations, and Wnt/Notch activation, and can be further divided into distinct gene expression subtypes, including CMS4-like CMS1 and CMS3. Our data provide novel insights into precise immunotherapeutic strategies for subtypes of MSI-H tumors.

Tumor mutational burden (TMB) profile of K-RAS/TP-53 co-mutation in metastatic non-small cell lung cancer (m-NSCLC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2626-2626
Author(s):  
Abdul Rafeh Naqash ◽  
Paul R. Walker ◽  
Mahvish Muzaffar ◽  
Rebecca Feldman ◽  
Maida Hafiz ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Immune Checkpoint Blockade ◽  
Missense Mutations ◽  
Nsclc Tissue ◽  
Chi Square ◽  
Tissue Samples ◽  
Therapeutic Implications ◽  
Tumor Mutational Burden ◽  
Metastatic Sites ◽  
Next Generation Sequencing Ngs

2626 Background: Early data suggests that co-occurring genetic events define biological heterogeneity in K-RAS mutant NSCLC, with K-RAS/ TP-53 (KP) co-mutated subset having potential therapeutic vulnerabilities to immune checkpoint blockade (ICB). To explore the immunological basis for these findings, we evaluated the immune biomarker profile (TMB/PD-L1) in KP mutant m-NSCLC using a large next-generation sequencing (NGS) dataset. Methods: Caris life sciences NGS dataset consisting of 1317 m-NSCLC tissue samples from 2016-18 was queried. PD-L1pos was defined as ≥ 1% staining using 22c3 Dako assay. TMB was measured by counting all somatic non-synonymous missense mutations using targeted NGS (592 genes). TMB-high (H) was defined as ≥ 10 mutations/Megabase (mut/Mb). P-values were calculated using Chi-square and Mann-Whitney test. Results: K-RAS mutations were identified in 28.7% (378/1317). Within this K-RAS mutant group, KP subset constituted 49.4% (187/378), remaining were K-RAS mutated/ TP-53 wild type (K-Pwt). 72.2 % (135/187) of KP had PD-L1pos with 51.9% (97/187) having PD-L1 ≥ 50%. KP had higher median TMB vs. K-Pwt (14.5 vs. 9.0 mut/Mb, p<0.001) and higher % of TMB-H vs. K-Pwt (79.9 vs. 45.1%, p<0.001; Table). Even in the PD-L1neg group, KP had higher % of TMB-H vs. K-Pwt (86.5 vs. 41.5%, p<0.001). K-RAS or TP-53 exon-subtypes had no difference in median TMB or % of TMB-H. Across metastatic sites, brain tissue had the highest % of KP subset (38.3%, 68/187) followed by bone (28.9%, 54/187). Within KP subset, brain tissue had higher median TMB vs. bone (16 vs. 11 mut/Mb, p<0.01) as well as greater % of TMB-H vs. bone (86.5 vs. 68.5%, p=0.01). Conclusions: This is the largest dataset to date highlighting the unique immune profile of KP mutant m-NSCLC. Our results show that KP subset has a significantly higher TMB than K-Pwt, especially in the PD-L1neg subgroup. Metastatic site-specific variations in TMB were also observed for the KP subset. These findings could have therapeutic implications in guiding patient selection for ICB and merit prospective investigation.[Table: see text]

Molecular characterization of appendiceal goblet cell carcinoid.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 231-231
Author(s):  
Hiroyuki Arai ◽  
Yasmine Baca ◽  
Curtis Johnston ◽  
Richard M. Goldberg ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Goblet Cell ◽  
Mutation Rates ◽  
Molecular Characteristics ◽  
Goblet Cell Carcinoid ◽  
Chi Square ◽  
Pathologic Features ◽  
Significant Difference ◽  
Tumor Mutational Burden ◽  
Chi Square Test

231 Background: Goblet cell carcinoid (GCC) is a distinct subtype of appendiceal neoplasm that exhibits unique clinical and pathologic features. There are a few reports focusing on the molecular differences between GCC and other appendiceal tumors such as adenocarcinoma and neuroendocrine tumor (NET). Methods: A total of 495 appendiceal tumor samples (53 GCCs, 428 adenocarcinomas and 14 NETs) were tested with Next-Generation Sequencing (NGS) on a 592-gene panel and immunohistochemistry (IHC). Microsatellite instability (MSI) / mismatch repair (MMR) status was tested with a combination of NGS, IHC and fragment analysis. Tumor mutational burden (TMB) was evaluated by NGS, and PD-L1 were tested by IHC (SP142). Molecular characteristics of GCCs are compared with those of adenocarcinomas and NETs, using Chi-square test. Results: The top five genes with most frequent mutation rate in GCCs were TP53 (24.0%), ARID1A (15.4%), SMAD4 (9.4%), KRAS (7.5%) and CHEK2 (4.0%). Compared to adenocarcinomas, GCCs showed significantly lower mutation rates in KRAS (7.5% vs 60.4%), GNAS (3.8% vs 34.4%), APC (1.9% vs 11.7%), while significantly higher mutation rates in CDH1 (3.8% vs 0.7%), CHEK2 (4.0% vs 0.3%), CDC73 (2.0% vs 0.0%), ERCC2 (2.0% vs 0.0%) and FGFR2 (1.9% vs 0.0%). Compared to NETs, GCCs showed significantly lower mutation rate in KRAS (7.5% vs 28.6%), APC (1.9% vs 28.6%), BRCA2 (0.0% vs 7.1%) and FANCA (0.0% vs 7.1%), with all p < 0.05. In GCCs, MSI-H/dMMR, TML-high (> 17mut/Mb) and PD-L1 expression were seen in 0.0%, 0.0% and 2.0%, respectively. No significant difference was observed in these immune-related markers’ frequency, compared to adenocarcinomas and NETs. Conclusions: GCCs had considerably distinct mutational profile compared to appendiceal adenocarcinomas and NETs. Understanding these molecular characteristics may be critical for a development of effective treatment strategy in GCC.

scholarly journals NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii126-ii126
Author(s):  
Amber Ruiz ◽  
Jerome Graber
Keyword(s):  
Treatment Response ◽  
Mismatch Repair ◽  
Case Series ◽  
Germline Mutations ◽  
Molecular Characteristics ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Increased Risk ◽  
Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

scholarly journals Multi-Gene Testing Overview with a Clinical Perspective in Metastatic Triple-Negative Breast Cancer

2021 ◽  
Vol 22 (13) ◽  
pp. 7154
Author(s):  
Martina Dameri ◽  
Lorenzo Ferrando ◽  
Gabriella Cirmena ◽  
Claudio Vernieri ◽  
Giancarlo Pruneri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Gene Testing ◽  
Repair Deficiency ◽  
Targeted Treatments ◽  
Recombination Repair ◽  
Tumor Mutational Burden ◽  
Next Generation Sequencing Ngs

Next-generation sequencing (NGS) is the technology of choice for the routine screening of tumor samples in clinical practice. In this setting, the targeted sequencing of a restricted number of clinically relevant genes represents the most practical option when looking for genetic variants associated with cancer, as well as for the choice of targeted treatments. In this review, we analyze available NGS platforms and clinical applications of multi-gene testing in breast cancer, with a focus on metastatic triple-negative breast cancer (mTNBC). We make an overview of the clinical utility of multi-gene testing in mTNBC, and then, as immunotherapy is emerging as a possible targeted therapy for mTNBC, we also briefly report on the results of the latest clinical trials involving immune checkpoint inhibitors (ICIs) and TNBC, where NGS could play a role for the potential predictive utility of homologous recombination repair deficiency (HRD) and tumor mutational burden (TMB).

scholarly journals The characteristics and risk factors of human papillomavirus infection: an outpatient population-based study in Changsha, Hunan

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bingsi Gao ◽  
Yu-Ligh Liou ◽  
Yang Yu ◽  
Lingxiao Zou ◽  
Waixing Li ◽  
...  
Keyword(s):  
Risk Factors ◽  
Protective Factor ◽  
Hpv Infection ◽  
Population Based ◽  
Cross Sectional Study ◽  
Categorical Variables ◽  
Chi Square ◽  
Cross Sectional ◽  
Hpv Dna ◽  
Test Kit

AbstractThis cross-sectional study investigated the characteristics of cervical HPV infection in Changsha area and explored the influence of Candida vaginitis on this infection. From 11 August 2017 to 11 September 2018, 12,628 outpatient participants ranged from 19 to 84 years old were enrolled and analyzed. HPV DNA was amplified and tested by HPV GenoArray Test Kit. The vaginal ecology was detected by microscopic and biochemistry examinations. The diagnosis of Candida vaginitis was based on microscopic examination (spores, and/or hypha) and biochemical testing (galactosidase) for vaginal discharge by experts. Statistical analyses were performed using SAS 9.4. Continuous and categorical variables were analyzed by t-tests and by Chi-square tests, respectively. HPV infection risk factors were analyzed using multivariate logistic regression. Of the total number of participants, 1753 were infected with HPV (13.88%). Females aged ≥ 40 to < 50 years constituted the largest population of HPV-infected females (31.26%). The top 5 HPV subtypes affecting this population of 1753 infected females were the following: HPV-52 (28.01%), HPV-58 (14.83%), CP8304 (11.47%), HPV-53 (10.84%), and HPV-39 (9.64%). Age (OR 1.01; 95% CI 1–1.01; P < 0.05) and alcohol consumption (OR 1.30; 95% CI 1.09–1.56; P < 0.01) were found to be risk factors for HPV infection. However, the presence of Candida in the vaginal flora was found to be a protective factor against HPV infection (OR 0.62; 95% CI 0.48–0.8; P < 0.001). Comparing with our previous study of 2016, we conclude that the subtype distribution of HPV infection is relatively constant in Changsha. Our data suggest a negative correlation between vaginal Candida and HPV, however, more radical HPV management is required in this area for perimenopausal women and those who regularly consume alcohol.

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