scholarly journals Tumor BRCA testing can reveal a high tumor mutational burden related to POLE pathogenic variants

2021 ◽  
pp. 100855
Author(s):  
M.-C. Villy ◽  
J. Masliah-Planchon ◽  
S. Melaabi ◽  
O. Trabelsi Grati ◽  
E. Girard ◽  
...  
Keyword(s):  
Brca Testing ◽  
Pathogenic Variants ◽  
Mutational Burden ◽  
Tumor Mutational Burden

CMS subtypes characterized by high TMB shows immunosuppressive microenvironment that implies resistance to immunotherapy.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 610-610
Author(s):  
Christopher Szeto ◽  
Chad Garner ◽  
Kevin Kazmierczak ◽  
Charles Joseph Vaske ◽  
Stephen Charles Benz ◽  
...  
Keyword(s):  
Wnt Pathway ◽  
Molecular Subtypes ◽  
Pathogenic Variants ◽  
Mutational Burden ◽  
Mutational Status ◽  
Pathway Activation ◽  
Tumor Mutational Burden ◽  
Significant Enrichment ◽  
Immunosuppressive Microenvironment ◽  
Lower Expression

610 Background: Tumor mutational burden (TMB) is emerging as an important biomarker for immune checkpoint therapy (ICT) response. Yet even in the context of high TMB, ICT are likely ineffective in an immuno-suppressed microenvironment. Here we demonstrate that a well-characterized subtype of CRC, CMS2, associated with Wnt pathway activation, is immunosuppressive despite high TMB. Methods: Tumor/normal-paired DNAseq (WGS or WES) and deep RNAseq (∼200x106reads per tumor) was performed on 464 GI tumors from a commercial database. Samples were classified as high TMB if they had > 200 non-synonymous exonic mutations as previously established (Rizvi et al, 2015). Each sample was assigned to one of the colorectal Consensus Molecular subtypes (CMS) based on RNA classification. A curated panel of 109 genes that discriminate between 22 immune subsets was identified. For each of these immune signatures, a database containing 1880 unselected tumors was used to define a distribution of expression. The study samples were then scored for their deviances within such distributions. Significant enrichment was analyzed between immune subsets, CMS types, TMB status, and somatic mutational status. Results: Compared to other subtypes, CMS1 & CMS2 were significantly high-TMB (adj. p < 3.8E-4 & p < 4.7E-3 respectively). Perplexingly, CMS2 had significantly lower expression of 11 well-established checkpoint and TME markers including LAG3 and PDL1 (adj. p 1.5E-2 & 2.9E-9 respectively), while CMS1 (MSI-enriched) expresses selected TME markers more than other subtypes (PDL1 adj. p < 4.0E-6 & LAG3 adj. p < 1.0E-6). As expected, CMS2 tumors were significantly enriched for likely pathogenic variants in the Wnt-associated gene APC (adj. p < 1.3E-8). Immune-deconvolution indicated substantial exclusion of Tem cells from CMS2 tumors, in line with Wnt/b-catenin blockade of TcmàTem maturation for immunoreactivity. Conclusions: The most common subtype of CRC, CMS2 (~37%), is highly immunosuppressive despite high TMB. ICT is only effective in an immunologically active microenvironment. TMB alone as a biomarker likely is insufficient to indicate the effectiveness of immunotherapy.

The landscape of POLE variants in colorectal and endometrial tumors: Correlation with microsatellite instability (MSI) and tumor mutation burden (TMB).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13538-e13538
Author(s):  
Sanjeevani Arora ◽  
Joanne Xiu ◽  
Davendra Sohal ◽  
Emil Lou ◽  
Richard M. Goldberg ◽  
...  
Keyword(s):  
Life Sciences ◽  
Mutation Rates ◽  
Chi Square ◽  
Tumor Mutation Burden ◽  
Pathogenic Variants ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Polymerase Epsilon ◽  
Very High

e13538 Background: Polymerase epsilon (POLE) is a major replicative DNA polymerase. Somatic POLE pathogenic variants (PV) are prevalent in endometrial cancer (EC) and in germline predispose to colorectal cancer (CRC), EC, and possibly other cancers (CA). PVs in the exonuclease domain (ExoD) [amino acid (AA) 268-471] lead to CAs with exceptionally high TMB. PV and uncertain variants (VUS) outside ExoD are sometimes concurrent with an ExoD PV and/or MSI. We hypothesized that the presence of non-ExoD variants may further increase POLE-associated mutation rate and tumor mutational burden. Methods: We retrospectively examined 1870 CRC and 4481 EC genomic profiles conducted by Caris Life Sciences (6/2016-6/2019). All patients had a 592-targeted gene somatic panel. Profiles with a POLE variant (PV or VUS) were analyzed. Median TMB (TMB, in mutations/megabase) was dichotomized to low/intermed ( < 17) vs high (>17). Tumors were grouped by: single ExoD PV, ExoD PV plus another variant (PV or VUS), or no ExoD PV. Known CRC/EC ExoD PV drivers were identified (Campbell et al, Cell 2017): D275G, P286R, S297F/Y, F367C/L/V, V411L, L424F, P436R/S/Y, M444K/L, A456P, S459F/Y, S461L/P, A465V. Kruskal-Wallis and chi-square tests were used. Results: Overall 4.5% CRC (80/1870) and 6.5% EC (303/4481) samples had POLE variants (Table). High TMB was seen in 56.3% CRC and 53.3% EC. In both CRC/ECs, TMB was higher in tumors with an ExoD PV and a 2nd variant compared to those with a solitary ExoD PV or no ExoD PV (both p < 0.001). MSI was more prevalent in CRC and EC with high TMB but no ExoD PV vs those with either high TMB and an ExoD PV, or low/intermed TMB and no ExoD PV (both p < 0.001). In both CRC/ECs, several ExoD PV associated with very high TMB when non-ExoD regions of POLE contained recurrent variant clusters: AA 1906 (TMB 225); AA 1826-7 (TMB 243); AA 1380-2 (TMB 229). Conclusions: In CRC/ECs, POLE ExoD PV and MSI appear to drive TMB in distinct and largely non-overlapping ways. Non-ExoD POLE variants may synergize with ExoD PVs to further increase mutation rates. [Table: see text]

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.

Comprehensive exploration of tumor mutational burden and immune infiltration in diffuse glioma

2021 ◽  
Vol 96 ◽  
pp. 107610
Author(s):  
Kai Kang ◽  
Fucun Xie ◽  
Yijun Wu ◽  
Zhile Wang ◽  
Li Wang ◽  
...  
Keyword(s):  
Diffuse Glioma ◽  
Immune Infiltration ◽  
Mutational Burden ◽  
Tumor Mutational Burden

scholarly journals Tumor mutational burden assessment in non-small-cell lung cancer samples: results from the TMB2 harmonization project comparing three NGS panels

2021 ◽  
Vol 9 (5) ◽  
pp. e001904
Author(s):  
Javier Ramos-Paradas ◽  
Susana Hernández-Prieto ◽  
David Lora ◽  
Elena Sanchez ◽  
Aranzazu Rosado ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Predictive Value ◽  
Predictive Biomarker ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Reproducibility Study ◽  
Tumor Mutational Burden

BackgroundTumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed.MethodsWe evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined.ResultsBoth panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N=55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity >88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively.ConclusionsBoth panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.

scholarly journals Identification and validation of a miRNA-related expression signature for tumor mutational burden in colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lijun Xu ◽  
Qing Zheng
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Validation Cohort ◽  
Expression Profiles ◽  
Functional Enrichment ◽  
Immune Checkpoints ◽  
Positive Correlation ◽  
Expression Signature ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Abstract Background Tumor mutational burden (TMB) is a promising predictor, which could stratify colorectal cancer (CRC) patients based on the response to immune checkpoint inhibitors (ICIs). MicroRNAs (miRNAs) act as the key regulators of anti-cancer immune response. However, the relationship between TMB and miRNA expression profiles is not elucidated in CRC. Methods Differentially expressed miRNAs (DE miRNAs) between the TMBhigh group and the TMBlow group were identified for the CRC cohort of the TCGA database. In the training cohort, a miRNA-related expression signature for predicting TMB level was developed by the least absolute shrinkage and selection operator (LASSO) method and tested with reference to its discrimination, calibration, and decision curve analysis (DCA) in the validation cohort. Functional enrichment analysis of these TMB-related miRNAs was performed. The correlation between this miRNA-related expression signature and three immune checkpoints was analyzed. Results Twenty-one out of 43 DE miRNAs were identified as TMB-related miRNAs, which were used to develop a miRNA-related expression signature. This TMB-related miRNA signature demonstrated great discrimination (AUCtest set = 0.970), satisfactory calibration (P > 0.05), and clinical utility in the validation cohort. Functional enrichment results revealed that these TMB-related miRNAs were mainly involved in biological processes associated with immune response and signaling pathways related with cancer. This miRNA-related expression signature showed a median positive correlation with PD-L1 (R = 0.47, P < 0.05) and CTLA4 (R = 0.39, P < 0.05) and a low positive correlation with PD-1 (R = 0.16, P < 0.05). Conclusion This study presents a miRNA-related expression signature which could stratify CRC patients with different TMB levels.

Sign in / Sign up

Export Citation Format

Share Document