Microsatellite instability status differentially associates with intratumoral immune microenvironment in human cancers

Abstract Based on clinical outcomes in colorectal cancer, high microsatellite instability (MSI-H) has recently been approved by the Food and Drug Administration (FDA) as a genetic test to select patients for immunotherapy targeting PD-1 and/or CTLA-4 without limitation to cancer type. However, it is unclear whether the MSI-H would broadly alter the tumor microenvironment to confer the therapeutic response of different cancer types to immunotherapy. To fill in this gap, we performed an in silico analysis of tumor immunity among different MSI statuses in five cancer types. We found that consistent with clinical responses to immunotherapy, MSI-H and non-MSI-H samples from colorectal cancer (COAD-READ) exhibited distinct infiltration levels and immune phenotypes. Surprisingly, the immunological difference between MSI-H and non-MSI-H samples was diminished in stomach adenocarcinoma and esophageal carcinoma (STAD-ESCA) and completely disappeared in uterine corpus endometrial carcinoma (UCEC). Regardless of cancer types, the abundance of tumor-infiltrating immune cells, rather than MSI status, strongly associated with the clinical outcome. Since preexisting antitumor immune response in the tumor (hot cancer) is accepted as a prerequisite to the therapeutic response to anti-PD-1/CTLA-4 immunotherapy, our data demonstrate that the impact of MSI varied on immune contexture will lead to the further evaluation of predictive immunotherapy responsiveness based on the universal biomarker of MSI status.

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Clinicopathological features of Egyptian colorectal cancer patients regarding somatic genetic mutations especially in KRAS gene and microsatellite instability status: a pilot study

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-019-0028-z ◽

2019 ◽

Vol 20 (1) ◽

Author(s):

Neemat M. Kassem ◽

Gamal Emera ◽

Hebatallah A. Kassem ◽

Nashwa Medhat ◽

Basant Nagdy ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Cpg Island ◽

Human Cancer ◽

Statistical Significance ◽

Public Health Problem ◽

World Health ◽

Cpg Island Methylator Phenotype ◽

Number Of Patients ◽

The Impact

Abstract Background Colorectal cancer (CRC) is the third most common cause of cancer-related deaths which contributes to a significant public health problem worldwide with 1.8 million new cases and almost 861,000 deaths in 2018 according to the World Health Organization. It exhibits 7.4% of all diagnosed cancer cases in the region of the Middle East and North Africa. Molecular changes that happen in CRCs are chromosomal instability, microsatellite instability (MSI), and CpG island methylator phenotype. The human RAS family (KRAS, NRAS, and HRAS) is the most frequently mutated oncogenes in human cancer appearing in 45% of colon cancers. Determining MSI status across CRCs offers the opportunity to identify patients who are likely to respond to targeted therapies such as anti-PD-1. Therefore, a method to efficiently determine MSI status for every cancer patient is needed. Results KRAS mutations were detected in 31.6% of CRC patients, namely in older patients (p = 0.003). Codons 12 and 13 constituted 5/6 (83.3%) and 1/6 (16.7%) of all KRAS mutations, respectively. We found three mutations G12D, G12C, and G13D which occur as a result of substitution at c.35G>A, c.34G>T, and c.38G>A and have been detected in 4/6 (66.6%), 1/6 (16.7%), and 1/6 (16.7%) patients, respectively. Eleven (57.9%) patients had microsatellite instability-high (MSI-H) CRC. A higher percentage of MSI-H CRC was detected in female patients (p = 0.048). Eight patients had both MSI-H CRC and wild KRAS mutation with no statistical significance was found between MSI status and KRAS mutation in these studied patients. Conclusion In conclusion, considering that KRAS mutations confer resistance to EGFR inhibitors, patients who have CRC with KRAS mutation could receive more tailored management by defining MSI status. MSI-high patients have enhanced responsiveness to anti-PD-1 therapies. Thus, the question arises as to whether it is worth investigating this association in the routine clinical setting or not. Further studies with a larger number of patients are needed to assess the impact of MSI status on Egyptian CRC care.

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Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

Current Treatment Options in Oncology ◽

10.1007/s11864-021-00870-z ◽

2021 ◽

Vol 22 (8) ◽

Author(s):

Federica Pecci ◽

Luca Cantini ◽

Alessandro Bittoni ◽

Edoardo Lenci ◽

Alessio Lupi ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Cancer Progression ◽

Checkpoint Inhibitors ◽

Tnm Classification ◽

Standard Of Care ◽

First Line Therapy ◽

Combination Strategies ◽

The Impact

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

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Exploration of the MSI landscape in Chinese pan-cancer patient by Next-Generation Sequencing.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14576 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14576-e14576

Author(s):

Xinlu Liu ◽

Jiasheng Xu ◽

Jian Sun ◽

Deng Wei ◽

Xinsheng Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Correlation Analysis ◽

Cancer Patients ◽

Cancer Type ◽

Multiple Tumor ◽

Treatment Plans ◽

Cancer Types ◽

Chinese Cancer Patients ◽

Colorectal Cancer Patients ◽

Pan Cancer

e14576 Background: Clinically, MSI had been used as an important molecular marker for the prognosis of colorectal cancer and other solid tumors and the formulation of adjuvant treatment plans, and it had been used to assist in the screening of Lynch syndrome. However, there were currently few reports on the incidence of MSI-H in Chinese pan-cancer patients. This study described the occurrence of MSI in a large multi-center pan-cancer cohort in China, and explored the correlation between MSI and patients' TMB, age, PD-L1 expression and other indicators. Methods: The study included 8361 patients with 8 cancer types from multiple tumor centers. Use immunohistochemistry to detect the expression of MMR protein (MLH1, MSH2, MSH6 and PMS2) in patients with various cancer types to determine the MSI status and detect the expression of PD-L1 in patients. Through NGS technology, 831 genes of 8361 Chinese cancer patients were sequenced and the tumor mutation load of the patients was calculated. The MSI mutations of patients in 8 cancer types were analyzed and the correlation between MSI mutations of patients and the patient's age, TMB and PD-L1 expression was analyzed. Results: The test results showed that MSI patients accounted for 1.66% of pan-cancers. Among them, MSI-H patients accounted for the highest proportion in intestinal cancer, reaching 7.2%. The correlation analysis between MSI and TMB was performed on patients of various cancer types. The results showed that: in each cancer type, MSI-H patients had TMB greater than 10, and 26.83% of MSI-H patients had TMB greater than 100 in colorectal cancer patients. The result of correlation analysis showed that there was no significant correlation between the patient's age and the risk of MSI mutation ( P> 0.05). In addition to PAAD and LUAD, the expression of PD-L1 in MSI-H patients was higher than that in MSS patients in other cancer types( P< 0.05). The correlation analysis between PD-L1 expression and TMB in patients found that in colorectal cancer, the higher the expression of PD-L1, the higher the patient's TMB ( P< 0.05). Conclusions: In this study, we explored the incidence of MSI-H in pan-cancer patients in China and found that the TMB was greater than 10 in patients with MSI-H. Compared with MSS patients, MSI-H patients have higher PD-L1 expression, and the higher the PD-L1 expression in colorectal cancer, the higher the TMB value of patients.

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Immunotherapy, Inflammation and Colorectal Cancer

Cells ◽

10.3390/cells9030618 ◽

2020 ◽

Vol 9 (3) ◽

pp. 618 ◽

Cited By ~ 15

Author(s):

Charles Robert Lichtenstern ◽

Rachael Katie Ngu ◽

Shabnam Shalapour ◽

Michael Karin

Keyword(s):

Colorectal Cancer ◽

Growth Factor ◽

Microsatellite Instability ◽

Mismatch Repair ◽

The United States ◽

Chemotherapeutic Agents ◽

Adoptive T Cell Therapy ◽

Current Status ◽

Cancer Type ◽

T Cell Therapy

Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR–MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR–MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).

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In Silico Analysis of a Highly Mutated Gene in Cancer Provides Insight into Abnormal mRNA Splicing: Splicing Factor 3B Subunit 1K700E Mutant

Biomolecules ◽

10.3390/biom10050680 ◽

2020 ◽

Vol 10 (5) ◽

pp. 680 ◽

Cited By ~ 2

Author(s):

Asmaa Samy ◽

Baris Suzek ◽

Mehmet Ozdemir ◽

Ozge Sensoy

Keyword(s):

Rna Splicing ◽

In Silico Analysis ◽

Therapy Resistance ◽

Mrna Splicing ◽

Splicing Factor ◽

Cancer Types ◽

Dynamics Simulations ◽

Aberrant Rna ◽

The Impact ◽

Splicing Machinery

Cancer is the second leading cause of death worldwide. The etiology of the disease has remained elusive, but mutations causing aberrant RNA splicing have been considered one of the significant factors in various cancer types. The association of aberrant RNA splicing with drug/therapy resistance further increases the importance of these mutations. In this work, the impact of the splicing factor 3B subunit 1 (SF3B1) K700E mutation, a highly prevalent mutation in various cancer types, is investigated through molecular dynamics simulations. Based on our results, K700E mutation increases flexibility of the mutant SF3B1. Consequently, this mutation leads to i) disruption of interaction of pre-mRNA with SF3B1 and p14, thus preventing proper alignment of mRNA and causing usage of abnormal 3’ splice site, and ii) disruption of communication in critical regions participating in interactions with other proteins in pre-mRNA splicing machinery. We anticipate that this study enhances our understanding of the mechanism of functional abnormalities associated with splicing machinery, thereby, increasing possibility for designing effective therapies to combat cancer at an earlier stage.

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National Cancer Diagnosis Audit: avoidable delays to diagnosis

British Journal of General Practice ◽

10.3399/bjgp19x703073 ◽

2019 ◽

Vol 69 (suppl 1) ◽

pp. bjgp19X703073

Author(s):

Ruth Swann ◽

Georgios Lyratzopoulos ◽

Greg Rubin ◽

Elizabeth Pickworth ◽

Sean McPhail

Keyword(s):

Cancer Diagnosis ◽

Cancer Type ◽

Logistic Regression Models ◽

Patient Demographics ◽

Cancer Types ◽

General Practices ◽

Diagnostic Interval ◽

Reported Data ◽

The Impact

BackgroundA prolonged time taken to diagnose cancer can lead to poorer survival and reduced quality of life. Characterising avoidable delays to a patient’s diagnosis could help to direct quality improvement initiatives aimed at enhancing patient safety and ultimately patient outcomes.AimTo assess the validity of data on avoidable delays collected as part of the English National Cancer Diagnosis Audit (NCDA) and to estimate the predictors of avoidable delays to diagnosis by patient demographics and cancer type.MethodParticipating general practices (n = 439; 5% practices) submitted primary care data on patients (n = 17 042) diagnosed with cancer in 2014 in England. GPs reported delays to the diagnosis that they considered avoidable. Quantile regression was used to understand the impact of an avoidable delay on the diagnostic interval. Logistic regression models were used to investigate the factors associated with avoidable delay.ResultsThe GP recorded an avoidable delay to cancer diagnosis in 24% of cases (n = 3372). The median diagnostic interval was 57 days longer in patients where an avoidable delay was recorded. Results have shown significant associations between avoidable delay and certain cancer types (odds ratio [OR] 1.73 for stomach versus lung cancer) and an increasing number of comorbidities (OR 1.43 for patients with ≥3 versus 0).ConclusionGP-reported data showed a longer diagnostic interval in patients thought to have had an avoidable delay to their diagnosis, indicating construct validity of the data collected. Data from the NCDA is being used to better understand avoidable delays to diagnosis, and identify possible solutions for improving the diagnostic pathway in some cases.

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Cancer Type-Dependent Correlations betweenTP53Mutations and Antitumor Immunity

10.1101/692715 ◽

2019 ◽

Author(s):

Lin Li ◽

Mengyuan Li ◽

Xiaosheng Wang

Keyword(s):

Antitumor Immunity ◽

Colon Adenocarcinoma ◽

Joint Effect ◽

The Cancer Genome Atlas ◽

Cancer Type ◽

Mutation Burden ◽

Cancer Genome Atlas ◽

Negative Role ◽

Stomach Adenocarcinoma ◽

Cancer Types

AbstractMany studies have shown thatTP53mutations play a negative role in antitumor immunity. However, a few studies reported thatTP53mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found thatTP53-mutated cancers had significantly higher levels of antitumor immune signatures thanTP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast,TP53-mutated cancers had significantly lower antitumor immune signature levels thanTP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover,TP53-mutated cancers likely had higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) thanTP53-wildtype cancers. However, the TMB differences were more marked betweenTP53-mutated andTP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more greatly than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations betweenTP53mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused byTP53mutations on tumor immunity. Our data suggest that theTP53mutation status could be a useful biomarker for cancer immunotherapy response depending on cancer types.

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Anti-PD-1/Anti-PD-L1 Drugs and Radiation Therapy: Combinations and Optimization Strategies

Cancers ◽

10.3390/cancers13194893 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4893

Author(s):

Jihane Boustani ◽

Benoît Lecoester ◽

Jérémy Baude ◽

Charlène Latour ◽

Olivier Adotevi ◽

...

Keyword(s):

Radiation Therapy ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Optimal Dose ◽

Target Volume ◽

Clinical Responses ◽

Cancer Types ◽

The Impact

Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials.

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Assessing adherence to the American College of Chest Physicians’ (ACCP) recommendations for thromboprophylaxis in hospitalized cancer patients

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9047 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9047-9047

Author(s):

A. N. Amin ◽

S. A. Stemkowski ◽

J. Lin ◽

G. Yang

Keyword(s):

Colorectal Cancer ◽

At Risk ◽

Cancer Patients ◽

Significant Risk ◽

Minimum Length ◽

Cancer Type ◽

Specific Recommendation ◽

Inclusion Criteria ◽

Vte Prophylaxis ◽

Cancer Types

9047 Background: This study evaluates whether clinicians are providing appropriate VTE prophylaxis to at-risk surgical and non- surgical cancer patients in accordance with ACCP guidelines. Methods: Premier's inpatient administrative data were used to assess VTE prophylaxis rates in fourteen cancer types. Patients age 40 or older, with a minimum length of stay of six days, and no contraindications for anti-coagulation were included in the study. Two rates were determined; the rate of discharges receiving any level of anticoagulation and the rate of patients receiving appropriate prophylaxis by comparing daily use of anti-coagulants and compression devices, dosage, and prophylaxis duration with ACCP recommendations. The 6th guidelines were used due to their release prior to the study period. Rates based on the 7th guidelines were calculated for the same patient cohort to assess how the revised guidelines affect our findings. Trends were assessed by comparing prophylaxis rates by quarter. Results: 72,391 discharges from 225 hospitals between January 2002 and September 2005 met the inclusion criteria. 29% of all at-risk cancer discharges received the recommended prophylaxis regimen. Rates varied by cancer type ranging from 18.7% in prostate to 36.3% in colorectal cancer discharges. 55% did not receive any anti-coagulation prophylaxis, 9.5% received insufficient dosage and 5.8% did not receive prophylaxis for the appropriate duration. The appropriate VTE prophylaxis rate is higher for surgical cancer than for non-surgical cancer discharges (32.3% vs. 27.7%). Trends suggest a slight increase in appropriate prophylaxis rates for all types of cancer discharges. Appropriate prophylaxis rates based on 7th guidelines are lower than rates based on the 6th guidelines due to the more specific recommendation in the 7th guidelines. Conclusions: Cancer patients are known to have significant risk for VTE, yet VTE prophylaxis for at-risk non-surgical cancer patients in hospitals is not optimal. Rates for surgical cancer patients were only slightly higher. Using the 7th recommendations results in lower prophylaxis rates. More effort is required to increase awareness of the ACCP recommendations for thromboprophylaxis in cancer patients. No significant financial relationships to disclose.

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