scholarly journals dN/dS dynamics quantify tumour immunogenicity and predict response to immunotherapy

2020 ◽  
Author(s):  
Luis Zapata ◽  
Giulio Caravagna ◽  
Marc J Williams ◽  
Eszter Lakatos ◽  
Khalid AbdulJabbar ◽  
...  
Keyword(s):  
Clinical Response ◽  
Patient Outcomes ◽  
Immune Evasion ◽  
Cancer Evolution ◽  
Immune Selection ◽  
Primary Tumors ◽  
Synonymous Mutations ◽  
Evolutionary Genomic ◽  
Tumor Immunogenicity ◽  
Pre Treatment

AbstractImmunoediting is a major force during cancer evolution that selects for clones with low immunogenicity (adaptation), or clones with mechanisms of immune evasion (escape). However, quantifying immunogenicity in the cancer genome and how the tumour-immune coevolutionary dynamics impact patient outcomes remain unexplored. Here we show that the ratio of nonsynonymous to synonymous mutations (dN/dS) in the immunopeptidome quantifies tumor immunogenicity and differentiates between adaptation and escape. We analysed 8,543 primary tumors from TCGA and validated immune dN/dS as a measure of selection associated with immune infiltration in immune-adapted tumours. In a cohort of 308 metastatic patients that received immunotherapy, pre-treatment lesions in non-responders showed increased immune selection (dN/dS<1), whereas responders did not and instead harboured a higher proportion of genetic escape mechanisms. Ultimately, these findings highlight the potential of evolutionary genomic measures to predict clinical response to immunotherapy.

scholarly journals Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2048
Author(s):  
Antónia Afonso Póvoa ◽  
Elisabete Teixeira ◽  
Maria Rosa Bella-Cueto ◽  
Rui Batista ◽  
Ana Pestana ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Patient Outcomes ◽  
Genetic Alterations ◽  
Papillary Thyroid ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Persistent Disease ◽  
Increased Risk ◽  
Structural Disease

Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002–2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTpmut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAFwt/TERTpmut (HR = 6.8, p = 0.003), BRAFmut/TERTpmut (HR = 3.2, p = 0.056) and BRAFmut/TERTpwt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAFwt/TERTpmut (HR = 24.2, p < 0.001) and BRAFmut/TERTpmut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTpmut regardless of BRAF status (BRAFmut/TERTpmut, log-rank p < 0.001; BRAFwt/TERTpmut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAFmut/TERTpwt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTpmut tumors were predisposed to recurrent structural disease and DSM.

Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3345-3351 ◽  
Author(s):  
Cristina Rodríguez-Antona ◽  
Susanna Leskelä ◽  
Magdalena Zajac ◽  
Marta Cuadros ◽  
Javier Alvés ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Response ◽  
Cell Lines ◽  
Current Therapy ◽  
Fish Analysis ◽  
Primary Tumors ◽  
Chemotherapy Drugs ◽  
T Cell Lymphomas ◽  
Response To Chemotherapy ◽  
Peripheral T Cell Lymphomas

Abstract Peripheral T-cell lymphomas (PTCLs) are aggressive tumors in which the current therapy based on multiagent chemotherapy is not successful. Since cytochrome P450 3A subfamily (CYP3A) enzymes are involved in the inactivation of chemotherapy drugs, we hypothesized that CYP3A and P-glycoprotein (MDR1) expression in these lymphomas could result in a poor clinical response. We measured tumoral CYP3A and MDR1 mRNA content in 44 T-cell lymphomas, finding a large variation in CYP3A expression. Multiplex polymerase chain reaction (PCR) analysis and fluorescence in situ hybridization (FISH) analysis showed genomic gains affecting CYP3A and MDR1 genes in T-cell lines and primary tumors, suggesting that this could be the mechanism underlying the tumoral expression variation. To test whether the tumoral expression of CYP3A and/or MDR1 could influence PTCL treatment outcome, their expression levels were compared with the clinical response and survival of the patients, finding that a high tumoral expression of CYP3A4 was significantly associated with a lower complete remission rate. This was further investigated with cell lines stably expressing CYP3A4 that exhibited an increased resistance to doxorubicin and etoposide. In conclusion, a high CYP3A4 tumoral expression could be useful to predict poor response to the standard PTCL chemotherapy; in these cases alternative chemotherapy combinations or doses should be explored.

scholarly journals Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

2018 ◽  
Vol 116 (2) ◽  
pp. 619-624 ◽  
Author(s):  
Charles Li ◽  
Elena Bonazzoli ◽  
Stefania Bellone ◽  
Jungmin Choi ◽  
Weilai Dong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Metastatic Tumors ◽  
Driver Genes ◽  
Primary Tumors ◽  
Mutational Landscape ◽  
Recurrent Tumors ◽  
Bet Inhibitors

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary–metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

scholarly journals Imaging Features and Patterns of Metastasis in Non-Small Cell Lung Cancer with RET Rearrangements

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 693 ◽  
Author(s):  
Subba R. Digumarthy ◽  
Dexter P. Mendoza ◽  
Jessica J. Lin ◽  
Marguerite Rooney ◽  
Andrew Do ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Imaging Features ◽  
Small Cell Lung ◽  
Primary Tumors ◽  
Imaging Characteristics ◽  
Metastatic Patterns ◽  
Pre Treatment

Rearranged during transfection proto-oncogene (RET) fusions represent a potentially targetable oncogenic driver in non-small cell lung cancer (NSCLC). Imaging features and metastatic patterns of advanced RET fusion-positive (RET+) NSCLC are not well established. Our goal was to compare the imaging features and patterns of metastases in RET+, ALK+ and ROS1+ NSCLC. Patients with RET+, ALK+, or ROS1+ NSCLC seen at our institution between January 2014 and December 2018 with available pre-treatment imaging were identified. The clinicopathologic features, imaging characteristics, and the distribution of metastases were reviewed and compared. We identified 215 patients with NSCLC harboring RET, ALK, or ROS1 gene fusion (RET = 32; ALK = 116; ROS1 = 67). Patients with RET+ NSCLC were older at presentation compared to ALK+ and ROS1+ patients (median age: RET = 64 years; ALK = 51 years, p < 0.001; ROS = 54 years, p = 0.042) and had a higher frequency of neuroendocrine histology (RET = 12%; ALK = 2%, p = 0.025; ROS1 = 0%, p = 0.010). Primary tumors in RET+ patients were more likely to be peripheral (RET = 69%; ALK = 47%, p = 0.029; ROS1 = 36%, p = 0.003), whereas lobar location, size, and density were comparable across the three groups. RET+ NSCLC was associated with a higher frequency of brain metastases at diagnosis compared to ROS1+ NSCLC (RET = 32%, ROS1 = 10%; p = 0.039. Metastatic patterns were otherwise similar across the three molecular subgroups, with high incidences of lymphangitic carcinomatosis, pleural metastases, and sclerotic bone metastases. RET+ NSCLC shares several distinct radiologic features and metastatic spread with ALK+ and ROS1+ NSCLC. These features may suggest the presence of RET fusions and help identify patients who may benefit from further molecular genotyping.

scholarly journals αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion

2019 ◽  
Vol 116 (40) ◽  
pp. 20141-20150 ◽  
Author(s):  
Andrea Vannini ◽  
Valerio Leoni ◽  
Catia Barboni ◽  
Mara Sanapo ◽  
Anna Zaghini ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Αvβ3 Integrin ◽  
Primary Tumors ◽  
Effective Strategies ◽  
Immune Mediated ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Β3 Integrin ◽  
Immunotherapy Target ◽  
Immunosuppressive Microenvironment

Tumors utilize a number of effective strategies, including the programmed death 1/PD ligand 1 (PD-1/PD-L1) axis, to evade immune-mediated control of their growth. PD-L1 expression is mainly induced by IFN receptor signaling or constitutively induced. Integrins are an abundantly expressed class of proteins which play multiple deleterious roles in cancer and exert proangiogenic and prosurvival activities. We asked whether αvβ3-integrin positively regulates PD-L1 expression and the anticancer immune response. We report that αvβ3-integrin regulated constitutive and IFN-induced PD-L1 expression in human and murine cancerous and noncancerous cells. αvβ3-integrin targeted STAT1 through its signaling C tail. The implantation of β3-integrin–depleted tumor cells led to a dramatic decrease in the growth of primary tumors, which exhibited reduced PD-L1 expression and became immunologically hot, with increased IFNγ content and CD8+ cell infiltration. In addition, the implantation of β3-integrin–depleted tumors elicited an abscopal immunotherapeutic effect measured as protection from the challenge tumor and durable splenocyte and serum reactivity to B16 cell antigens. These modifications to the immunosuppressive microenvironment primed cells for checkpoint (CP) blockade. When combined with anti–PD-1, β3-integrin depletion led to durable therapy and elicited an abscopal immunotherapeutic effect. We conclude that in addition to its previously known roles, αvβ3-integrin serves as a critical component of the cancer immune evasion strategy and can be an effective immunotherapy target.

The Hla System and the Clinical Response to Treatment with Chlorpromazine

1976 ◽  
Vol 129 (5) ◽  
pp. 486-489 ◽  
Author(s):  
E. Smeraldi ◽  
L. Bellodi ◽  
E. Sacchetti ◽  
C. L. Cazzullo
Keyword(s):  
Clinical Response ◽  
Negative Correlation ◽  
Significant Positive Correlation ◽  
Significant Negative Correlation ◽  
Response To Treatment ◽  
Positive Correlation ◽  
Hla System ◽  
Schizophrenic Patients ◽  
Clinical Responses ◽  
Pre Treatment

SummaryA group of 33 schizophrenic patients were typed for HLA-SD antigens and their qualitative clinical responses to chlorpromazine therapy determined. A highly significant positive correlation was found between response to chlorpromazine and HLA-A1 positive, while HLA-A2 positive subjects showed a significant negative correlation to chlorpromazine treatment.In a second group of 17 patients the clinical responses to chlorpromazine were evaluated quantitatively, by WPRS, in HLA-A1 positive and HLA-A1 negative patients. There were no pre-treatment differences in the scores. After treatment the scores of positive patients were significantly lower, indicating that they responded to a greater degree.Since the frequency of HLA-A1 in hebephrenic patients is higher than that in other schizophrenics this may explain our earlier finding that hebephrenics, as a group, respond better to chlorpromazine than do other schizophrenics.

Phase II study of an epirubicin and docetaxel (ET) combination as pre and post-operative systemic therapy in patients with early stage breast cancer (EBC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10660-10660
Author(s):  
R. Nishimura ◽  
Y. Rai ◽  
S. Mitsuyama ◽  
S. Toyoshima ◽  
H. Iwasaki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Response ◽  
Early Stage ◽  
Pathologic Complete Response ◽  
Metastatic Breast ◽  
Complete Response ◽  
Breast Conserving Surgery ◽  
Treatment Schedule ◽  
Primary Tumors ◽  
In Situ Carcinoma

10660 Background: The goal of chemotherapy (CT) for EBC is to achieve a high pathologic complete response (CR) leading to an increase in the rate of breast conserving surgery (BCS). ET is one of the most active CT regimens for metastatic breast cancer. The primary endpoint of this study was to evaluate clinical response Methods: Eligible patients (pts) were newly diagnosed with EBC and had large primary tumors (stage II-III, > 3 cm). Forty-seven pts were enrolled and received epirubicin 60 mg/m2 followed by docetaxel 60 mg/m2 every 3 weeks for 4 cycles before surgery. Within 4 weeks after surgery, 4 additional cycles of ET were given to the pts who responded to ET. Results: Forty-five pts were evaluable for safety and clinical response. The median age was 47 (range, 29–75). The tumor size was T2 in 44% of the pts, T3 in 36%, and T4 in 20%. ER and PgR were both positive in 40% of pts, while both negative in 31%. HER2 was positive in 33% of pts. Four cycles of ET at full dose were given to 96% of pts prior to surgery. The clinical response was 73% including 7% CR (95% CI 58–85%); the BCS rate was 36%. Central pathologic review was performed in 37 pts showing disappearance of all tumor cells (grade 1) in 1 patient (3%) and 2 pts (5%) achieved a grade 2 response (in situ carcinoma in the operated breast) by Chevallier’s criteria. Grade 3–4 toxicities included neutropenia (71%), leukocytopenia (69%), febrile neutropenia (18%) and anorexia (9%). Twenty-four of 33 pts who responded to ET received additional ET after surgery. Conclusions: ET showed a high clinical response in previously untreated EBC with acceptable toxicity. In order to improve pathological CRs further, the doses and treatment schedule of this regimen needs to be improved. Currently, we are following the pts to assess differences in survival between pts with or without additional adjuvant ET. No significant financial relationships to disclose.

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