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.

Gene Expression Distinguishes Burkitt Lymphoma from Other Aggressive Lymphomas and Identifies Patients Who Are Highly Curable with Intensive Chemotherapeutic Regimens.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 415-415 ◽  
Author(s):  
Sandeep S. Dave ◽  
K. Fu ◽  
G. Wright ◽  
Lloyd Lam ◽  
T. C. Greiner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Burkitt Lymphoma ◽  
Target Genes ◽  
Molecular Subtype ◽  
Performance Status ◽  
B Cell Lymphoma ◽  
Aggressive Lymphoma ◽  
Molecular Characteristics ◽  
Fish Analysis ◽  
Stem Cell Rescue

Abstract Background Burkitt lymphoma(BL) is a potentially curable, aggressive lymphoma. The distinction between BL and diffuse large B-cell lymphoma (DLBCL) is important because they differ significantly in clinical management. The distinction can be difficult because DLBCL can resemble BL in morphology, immunophenotype and cytogenetics. We investigated whether gene expression profiling (GEP) could create a molecular definition of BL that can reliably distinguish it from DLBCL. Methods Biopsy samples were collected from 312 patients with a diagnosis of sporadic BL or Burkitt-like lymphoma, or DLBCL. All cases were reviewed by a panel of expert hematopathologists. GEP of all the samples was carried out using a specialized oligonucleotide microarray. We constructed a predictor using 197 genes to distinguish BL from each molecular subtype of DLBCL. Leave-one-out cross-validation was used to evaluate the predictor’s performance. Chemotherapy treatments were grouped into either CHOP-like(CHOP, CNOP) or intensive(BFM, CODOX-M IVAC, regimens requiring stem cell rescue). Results After pathology review, the samples were reclassified as:classic BL(25 cases), atypical BL(19), DLBCL(261), and unclassifiable lymphoma(7). All classic BL and 18/19 cases of atypical BL shared a profile that was strikingly different from that of all the molecular subtypes of DLBCL, including those DLBCL cases that have a c-myc translocation. C-myc and its target genes, and genes related to germinal center differentiation were expressed at high levels in BL. NF-kB and its target genes and MHC class-I genes were expressed at very low levels in BL. Interestingly, 10 cases that were DLBCL by pathology were classified as BL by the predictor. The diagnosis of BL was supported by FISH analysis indicating a c-myc translocation. Among adults identified as having BL by the predictor (with full clinical data in N=15), overall survival was markedly superior for those receiving intensive regimens compared to CHOP-like regimens(Fig 1). The groups were similar with regard to age, stage, performance status and sites of involvement. Conclusion This study demonstrates that the molecular characteristics of BL can be used to accurately distinguish it from DLBCL. Importantly, a subgroup of BL was identified by the predictor that could not be diagnosed as BL by conventional criteria. The ability of the predictor to identify patients who benefit from aggressive therapies suggests that it will be useful in the diagnosis and management of patients with Burkitt lymphoma. Figure Figure

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.

scholarly journals The role of PDGFRA as a therapeutic target in young colorectal cancer patients

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tae Won Kim ◽  
Hye Kyung Hong ◽  
Chung Lee ◽  
Sunmin Kim ◽  
Woo Yong Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Subtype ◽  
Age Groups ◽  
Young Patients ◽  
Growth Factor Receptor ◽  
Predictive Biomarker ◽  
Molecular Characteristics ◽  
Novel Therapeutic Strategies ◽  
Consensus Molecular Subtype

Abstract Background Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear. Methods We conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation. Results Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = − 0.526). Moreover, PDGFRA showed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients. Conclusions Our study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients.

FOXA1 expression in Iraqi women with ER+ breast cancer: A case control study

2020 ◽  
Vol 2 (02) ◽  
Author(s):  
Iman Al-Bedairy ◽  
Mais Shamsa ◽  
Safaa aldeen Salim ◽  
Mohammed Mahdi ◽  
Karam Dawood ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Molecular Subtype ◽  
Estrogen Receptor Α ◽  
Luminal Breast Cancer ◽  
Molecular Characteristics ◽  
Luminal A ◽  
Fresh Tissue ◽  
Iraqi Women ◽  
Foxa1 Expression

Background: Breast cancer is a heterogeneous disease that can be classified into many subtypes according to histopathological and molecular characteristics. Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor (α-ER)-chromatin binding and function. FOXA1 expression is related to luminal breast cancer with a good prognosis. Objectives: The present study is sought to determine the gene expression of FOXA1 in Iraqi women with ER+ breast cancer from fresh tissue. Methods: Forty-eight fresh malignant breast tissues analyzed by immunohistochemistry assay to choose ER+ sample submitted to RT-qPCR to evaluate FOXA1 gene expression. Results: ER-positive was 72.91% of the total samples, luminal A was the most common molecular subtype with 56.25%. Conclusions: Highly significant FOXA1 gene expression in Iraqi women with breast cancer makes it eligible to be a good predictor or a biomarker for breast cancer.

scholarly journals Distal Colorectal Cancers with Microsatellite Instability (MSI) Display Distinct Gene Expression Profiles that Are Different from Proximal MSI Cancers

2006 ◽  
Vol 66 (20) ◽  
pp. 9804-9808 ◽  
Author(s):  
Toshiaki Watanabe ◽  
Takashi Kobunai ◽  
Etsuko Toda ◽  
Yoko Yamamoto ◽  
Takamitsu Kanazawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microsatellite Instability ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Colorectal Cancers ◽  
Distinct Gene

scholarly journals Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Jitske van den Bulk ◽  
Els M. E. Verdegaal ◽  
Dina Ruano ◽  
Marieke E. Ijsselsteijn ◽  
Marten Visser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mismatch Repair ◽  
Molecular Subtype ◽  
Tumor Infiltrating Lymphocytes ◽  
Colorectal Cancers ◽  
Cell Reactivity ◽  
Mutation Burden ◽  
Consensus Molecular Subtype ◽  
Infiltrating Lymphocytes

Abstract Background The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, this observation does not exclude the existence of neoantigen-specific T cells in colorectal cancers with low mutation burden and the exploitation of their anti-cancer potential for immunotherapy. Therefore, we investigated whether autologous neoantigen-specific T cell responses could also be observed in patients diagnosed with mismatch repair-proficient colorectal cancers. Methods Whole-exome and transcriptome sequencing were performed on cancer and normal tissues from seven colorectal cancer patients diagnosed with mismatch repair-proficient tumors to detect putative neoantigens. Corresponding neo-epitopes were synthesized and tested for recognition by in vitro expanded T cells that were isolated from tumor tissues (tumor-infiltrating lymphocytes) and from peripheral mononuclear blood cells stimulated with tumor material. Results Neoantigen-specific T cell reactivity was detected to several neo-epitopes in the tumor-infiltrating lymphocytes of three patients while their respective cancers expressed 15, 21, and 30 non-synonymous variants. Cell sorting of tumor-infiltrating lymphocytes based on the co-expression of CD39 and CD103 pinpointed the presence of neoantigen-specific T cells in the CD39+CD103+ T cell subset. Strikingly, the tumors containing neoantigen-reactive TIL were classified as consensus molecular subtype 4 (CMS4), which is associated with TGF-β pathway activation and worse clinical outcome. Conclusions We have detected neoantigen-targeted reactivity by autologous T cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. These findings warrant the development of specific immunotherapeutic strategies that selectively boost the activity of neoantigen-specific T cells and target the TGF-β pathway to reinforce T cell reactivity in this patient group.

scholarly journals Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance)

2019 ◽  
Vol 37 (22) ◽  
pp. 1876-1885 ◽  
Author(s):  
Heinz-Josef Lenz ◽  
Fang-Shu Ou ◽  
Alan P. Venook ◽  
Howard S. Hochster ◽  
Donna Niedzwiecki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Molecular Subtype ◽  
Progression Free Survival ◽  
Classification Systems ◽  
Phase Iii ◽  
Primary Tumors ◽  
Phase Iii Trial ◽  
Consensus Molecular Subtype ◽  
Predictive And Prognostic Value

PURPOSE To determine the predictive and prognostic value of the consensus molecular subtypes (CMSs) of colorectal cancer (CRC) that represent a merging of gene expression–based features largely in primary tumors from six independent classification systems and provide a framework for capturing the intrinsic heterogeneity of CRC in patients enrolled in CALGB/SWOG 80405. PATIENTS AND METHODS CALGB/SWOG 80405 is a phase III trial that compared the addition of bevacizumab or cetuximab to infusional fluorouracil, leucovorin, and oxaliplatin or fluorouracil, leucovorin, and irinotecan as first-line treatment of advanced CRC. We characterized the CMS classification using a novel NanoString gene expression panel on primary CRCs from 581 patients enrolled in this study to assess the prognostic and predictive value of CMSs in these patients. RESULTS The CMSs are highly prognostic for overall survival (OS; P < .001) and progression-free survival (PFS; P < .001). Furthermore, CMSs were predictive for both OS ( P for interaction < .001) and PFS ( P for interaction = .0032). In the CMS1 cohort, patients treated with bevacizumab had a significantly longer OS than those treated with cetuximab ( P < .001). In the CMS2 cohort, patients treated with cetuximab had a significantly longer OS than patients treated with bevacizumab ( P = .0046). CONCLUSION These findings highlight the possible clinical utility of CMSs and suggests that refinement of the CMS classification may provide a path toward identifying patients with metastatic CRC who are most likely to benefit from specific targeted therapy as part of the initial treatment.

Differential Wnt Pathway Gene Expression and E-Cadherin Truncation in Sporadic Colorectal Cancers with and without Microsatellite Instability

2008 ◽  
Vol 14 (4) ◽  
pp. 995-1001 ◽  
Author(s):  
Paloma Ortega ◽  
Alberto Morán ◽  
Carmen de Juan ◽  
Cristina Frías ◽  
Susana Hernández ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microsatellite Instability ◽  
Wnt Pathway ◽  
Colorectal Cancers ◽  
Pathway Gene ◽  
E Cadherin
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