scholarly journals An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes

2021 ◽  
Author(s):  
Marion Jaffrelot ◽  
Nadim Farés ◽  
Anne Cécile Brunac ◽  
Anne Pascale Laurenty ◽  
Marie Danjoux ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Genetic Syndromes ◽  
Tumor Mutation Burden ◽  
Repair Deficiency ◽  
Mutation Burden ◽  
Genetic Features ◽  
Mmr Deficiency ◽  
Unusual Phenotype ◽  
Mmr Proteins

AbstractImmunohistochemistry (IHC) and/or MSI-PCR (microsatellite instability-polymerase chain reaction) tests are performed routinely to detect mismatch repair deficiency (MMR-D). Classical MMR-D tumors present a loss of MLH1/PMS2 or MSH2/MSH6 with MSI-High. Other profiles of MMR-D tumors have been described but have been rarely studied. In this study, we established a classification of unusual MMR-D tumors and determined their frequency and clinical impact. All MMR-D tumors identified between 2007 and 2017 were selected. Any profile besides the classical MMR-D phenotype was defined as unusual. For patients with unusual MMR-D tumors, IHC, and PCR data were reviewed, the tumor mutation burden (TMB) was evaluated and clinical and genetic features were collected. Of the 4948 cases of MMR testing, 3800 had both the available IHC and MSI-PCR results and 585 of these had MMR-D. After reviewing the IHC and PCR, 21% of the cases initially identified as unusual MMR-D were reclassified, which resulted in a final identification of 89 unusual MMR-D tumors (15%). Unusual MMR-D tumors were more often associated with non-CRC than classical MMR-D tumors. Unusual MMR-D tumors were classified into four sub-groups: i) isolated loss of PMS2 or MSH6, ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI, iii) four MMR proteins retained with MSI and, iv) complex loss of MMR proteins, with clinical characteristics for each sub-group. TMB-high or -intermediate was shown in 96% of the cancers studied (24/25), which confirmed MMR deficiency. Genetic syndromes were identified in 44.9% (40/89) and 21.4% (106/496) of patients with unusual and classical MMR-D tumors, respectively (P < 0.001). Five patients treated with an immune checkpoint inhibitor (ICI) had a prolonged clinical benefit. Our classification of unusual MMR-D phenotype helps to identify MMR deficiency. Unusual MMR-D phenotype occurs in 15% of MMR-D tumors. A high frequency of genetic syndromes was noted in these patients who could benefit from ICI.

scholarly journals Prevalence of mismatch repair deficiency and Lynch syndrome in a cohort of unselected small bowel adenocarcinomas

2020 ◽  
pp. jclinpath-2020-207040
Author(s):  
Manon Suerink ◽  
Gül Kilinç ◽  
Diantha Terlouw ◽  
Hristina Hristova ◽  
Lily Sensuk ◽  
...  
Keyword(s):  
Small Bowel ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Promoter Hypermethylation ◽  
Bowel Cancer ◽  
Family Management ◽  
Small Bowel Cancer ◽  
Repair Deficiency ◽  
Mmr Deficiency ◽  
Mmr Proteins

AimsPrevious estimates of the prevalence of mismatch repair (MMR) deficiency and Lynch syndrome in small bowel cancer have varied widely. The aim of this study was to establish the prevalence of MMR deficiency and Lynch syndrome in a large group of small bowel adenocarcinomas.MethodsTo this end, a total of 400 small bowel adenocarcinomas (332 resections, 68 biopsies) were collected through the Dutch nationwide registry of histopathology and cytopathology (Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief (PALGA)). No preselection criteria, such as family history, were applied, thus avoiding (ascertainment) bias. MMR deficiency status was determined by immunohistochemical staining of MMR proteins, supplemented by MLH1 promoter hypermethylation analysis and next generation sequencing of the MMR genes.ResultsMMR deficiency was observed in 22.3% of resected and 4.4% of biopsied small bowel carcinomas. Prevalence of Lynch syndrome was 6.2% in resections and 0.0% in biopsy samples. Patients with Lynch syndrome-associated small bowel cancer were significantly younger at the time of diagnosis than patients with MMR-proficient and sporadic MMR-deficient cancers (mean age of 54.6 years vs 66.6 years and 68.8 years, respectively, p<0.000).ConclusionsThe prevalence of MMR deficiency and Lynch syndrome in resected small bowel adenocarcinomas is at least comparable to prevalence in colorectal cancers, a finding relevant both for treatment (immunotherapy) and family management. We recommend that all small bowel adenocarcinomas should be screened for MMR deficiency.

scholarly journals Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Karl P Hodel ◽  
Richard de Borja ◽  
Erin E Henninger ◽  
Brittany B Campbell ◽  
Nathan Ungerleider ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Dna Polymerase ◽  
Mutation Accumulation ◽  
Critical Force ◽  
Mismatch Repair Deficiency ◽  
Tumor Mutation Burden ◽  
Repair Deficiency ◽  
Mutation Burden ◽  
Generation Sequencing

Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε.

EPCO-03. GLIOMA ONCOGENESIS IN THE CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD) SYNDROME

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi1-vi2
Author(s):  
Léa Guerrini-Rousseau ◽  
Jane Merlevede ◽  
Philippe Denizeau ◽  
Felipe Andreiuolo ◽  
Pascale Varlet ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Somatic Mutations ◽  
Mismatch Repair Deficiency ◽  
Mutational Signatures ◽  
Tumor Mutation Burden ◽  
Repair Deficiency ◽  
Whole Exome ◽  
Mutation Burden ◽  
Tumor Material ◽  
Constitutional Mismatch Repair Deficiency

Abstract PURPOSE Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40NS SNV/Mb, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.

scholarly journals Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tong Xie ◽  
Qin Feng ◽  
Zhongwu Li ◽  
Ming Lu ◽  
Jian Li ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Dual Therapy ◽  
Circulating Tumor Dna ◽  
Targeted Sequencing ◽  
Dna Mismatch ◽  
Repair Deficiency ◽  
Mutation Burden

Abstract Background Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs). Case presentation We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib. Conclusion Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.

Molecular correlates of PD-L1 expression in patients with non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9018-9018 ◽  
Author(s):  
Hira Rizvi ◽  
Chaitanya Bandlamudi ◽  
Adam Jacob Schoenfeld ◽  
Jennifer L. Sauter ◽  
Kathryn Cecilia Arbour ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Tissue Sample ◽  
Predictive Biomarker ◽  
Tumor Mutation Burden ◽  
Targeted Next Generation Sequencing ◽  
Mutation Burden ◽  
Genetic Features ◽  
A Minor ◽  
The Impact ◽  
Generation Sequencing

9018 Background: PD-L1 expression is the only FDA-approved predictive biomarker for patients with NSCLC treated with immune checkpoint inhibitors. The impact of tumor molecular profiling on tumor PD-L1 expression is not known. We hypothesized that somatic mutations and copy number alterations may be associated with distinct patterns of PD-L1 expression in patients with NSCLC. Methods: We examined patients with NSCLC in whom PD-L1 testing and targeted next-generation sequencing (MSK-IMPACT) were performed on the same tissue sample. PD-L1 expression was determined by IHC using the E1L3N antibody clone and categorized as PD-L1 high (≥ 50%), intermediate (1-49%), or negative ( < 1%) expression. The association of PD-L1 with individual genes, pathways, tumor mutation burden, whole genome duplication (WGD), and aneuploidy (fraction of genome altered (FGA)) were evaluated. P-values < 0.05 and q-values < 0.15 were considered significant for individual genes. Results: 1023 patients with NSCLC had PD-L1 testing and MSK-IMPACT performed on the same tissue sample, 18% (n = 180) had high, 21% (n = 218) had intermediate, and 61% (n = 625) had negative PD-L1 expression. High PD-L1 expression was significantly enriched in metastatic vs primary lesions (p < 0.001). There was a minor correlation between PD-L1 and TMB (spearman rho = 0.195) and PD-L1 and FGA (spearman rho = 0.11). Similar rates of WGD were found among patients with high, intermediate, and negative PD-L1 expression (p = 0.38). Mutations in KRAS and TERT were significantly enriched in PD-L1 high compared to other groups (p = 0.001, q = 0.14; p < 0.001, q = 0.003). By contrast, mutations in EGFR and STK11 were associated with PD-L1 negativity (p < 0.001, q = 0.001; p = 0.001, q = 0.14). Pathway analysis showed DNA repair (p < 0.001), TP53 (p < 0.001), and SWI/SNF (p = 0.04) pathways significantly associated with PD-L1 high compared to PD-L1 negative expression. Conclusions: The genetic features of NSCLC are associated with distinct patterns of PD-L1 expression. This data may provide insight to how the molecular phenotype can interact with the immunologic phenotype of tumors.

NTRK fusion positive colorectal cancer as a unique subset of CRC with high tumor mutation burden and microsatellite instability.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3544-3544
Author(s):  
Hui WANG ◽  
Qiuxiang Ou ◽  
Xue Wu ◽  
Misako Nagasaka ◽  
Sai-Hong Ignatius Ou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Neurotrophin Receptor ◽  
Driver Mutations ◽  
Fusion Partner ◽  
Tumor Mutation Burden ◽  
Targeted Next Generation Sequencing ◽  
Mutation Burden ◽  
Genetic Features ◽  
Colorectal Cancer Patients

3544 Background: Neurotrophin receptor tyrosine kinase ( NTRK) gene fusions are rare but actionable oncogenic drivers that are present in a wide variety of solid tumors. This study aims to identify the frequency and the clinicopathologic and genetic features of NTRK-driven colorectal cancers (CRC). Methods: Colonic and rectal tumor DNA specimen from colorectal cancer patients submitted for molecular profiling at a CLIA-certified genomics laboratory in China that performed NTRK1/2/3 fusion detection by hybridization-based targeted next generation sequencing (NGS) were retrospectively reviewed. Patients’ demographic, clinical characteristics, and treatment history were retrieved from the database for further evaluation. Results: A total of 2,519 unique Chinese colorectal cancer cases were profiled from April 2016 to May 2020, and 17 NTRK+ fusion events were identified (0.7%, 17/2,519) consisting of 14 cases of NTRK1+ and 3 cases of NTRK3+ fusions. Furthermore, thirteen out of 17 NTRK+ CRC tumors (76%) were microsatellite instability-high (MSI-H) tumors, a much higher rate than that of the molecularly unselected CRC population (8%) or NTRK+ non-CRC tumors ( < 1%). NTRK+ CRC patients also had increased tumor mutation burden (median TMB = 65 mut/MB) compared to that of non- NTRK+ CRC (median TMB = 7.7 mut/MB) or NTRK+ non-CRC tumors (median TMB = 4 mut/MB). POLE/POLD1 mutations were also enriched in NTRK+ CRC (8/17, 47%) relative to molecularly unstratified CRC patients (8%) with over half carrying concurrent POLE and POLD1 mutations. TPM3 was the most common fusion partner of NTRK1 (78%, N = 14), followed by LMNA and TRP. Three NTRK3+ CRC were identified (ETV6-NTRK3, RUNX1-NTRK3, CSNK1G1-NTRK3). RNF43 (71%) was the most frequently mutated gene and the aberrations of RNF43 and ARID1 were significantly enriched in MSI-positive NTRK+ tumors as compared to the MSS NTRK+ subgroup. TP53 (53%) and APC (35%) aberrations frequently co-occurred with NTRK fusions, whereas the majority of the NTRK+ cohort were RAS/BRAF wildtype, except in one case that an oncogenic KRAS Q61R variant co-occurred with RUNX1-NTRK3. Conclusions: NTRK+ colorectal cancer is rare. In addition to the absence of canonical driver mutations, NTRK+ tumors demonstrated increased tumor mutation burden, higher frequency of microsatellite instability, and an enrichment of POLE/POLD1 mutations relative to molecularly unselected CRC population.

scholarly journals Effects of a Novel Thiadiazole Derivative with High Anticancer Activity on Cancer Cell Immunogenic Markers: Mismatch Repair System, PD-L1 Expression, and Tumor Mutation Burden

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 885
Author(s):  
Sofia Sagredou ◽  
Panagiotis Dalezis ◽  
Eirini Papadopoulou ◽  
Maria Voura ◽  
Maria V. Deligiorgi ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Mismatch Repair ◽  
Cell Lines ◽  
Cancer Cell ◽  
Predictive Biomarkers ◽  
Cancer Cell Lines ◽  
Repair System ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Ht 29

Microsatellite instability (MSI), tumor mutation burden (TMB), and programmed cell death ligand-1 (PD-L1) are particularly known as immunotherapy predictive biomarkers. MSI and TMB are closely related to DNA mismatch repair (MMR) pathway functionality, while the PD-L1 checkpoint mediates cancer cell evasion from immune surveillance via the PD-L1/PD-1 axis. Among all the novel triazolo[3,4-b]thiadiazole derivatives, the compound KA39 emerged as the most potent anticancer agent. In the present study, potential alterations in MSI, TMB, and/or PD-L1 expression upon cell treatment with KA39 are explored. We tested three MMR-deficient (DLD-1, LS174T, and DU-145) and two MMR-proficient (HT-29 and PC-3) human cancer cell lines. Our findings support KA39-induced PD-L1 overexpression in all cancer cell lines, although the most outstanding increase was observed in MMR-proficient HT-29 cells. MSI analysis showed that KA39 affects the MMR system, impairing its recognition or repair activity, particularly in MMR-deficient DLD-1 and DU-145 cells, enhancing oligonucleotide production. There were no remarkable alterations in the TMB between untreated and treated cells, indicating that KA39 does not belong to mutagenic agents. Taking together the significant in vitro anticancer activity with PD-L1 upregulation and MSI increase, KA39 should be investigated further for its implication in chemo-immunotherapy of cancer.

scholarly journals Mutational signatures of DNA mismatch repair deficiency in C. elegans and human cancers

2017 ◽  
Author(s):  
B Meier ◽  
NV Volkova ◽  
Y Hong ◽  
P Schofield ◽  
PJ Campbell ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Mutational Signatures ◽  
Dna Mismatch ◽  
C Elegans ◽  
Replication Errors ◽  
Human Cancers ◽  
Repair Deficiency ◽  
Mmr Deficiency ◽  
Mutational Processes

ABSTRACTThroughout their lifetime cells are subject to extrinsic and intrinsic mutational processes leaving behind characteristic signatures in the genome. DNA mismatch repair (MMR) deficiency leads to hypermutation and is found in different cancer types. While it is possible to associate mutational signatures extracted from human cancers with possible mutational processes the exact causation is often unknown. Here we use C. elegans genome sequencing of pms-2 and mlh-1 knockouts to reveal the mutational patterns linked to C. elegans MMR deficiency and their dependency on endogenous replication errors and errors caused by deletion of the polymerase ε subunit pole-4. Signature extraction from 215 human colorectal and 289 gastric adenocarcinomas revealed three MMR-associated signatures, one of which closely resembles the C. elegans MMR spectrum and strongly discriminates microsatellite stable and unstable tumors (AUC=98%). A characteristic difference between human and C. elegans MMR deficiency is the lack of elevated levels of NCG>NTG mutations in C. elegans, likely caused by the absence of cytosine (CpG) methylation in worms. The other two human MMR signatures may reflect the interaction between MMR deficiency and other mutagenic processes, but their exact cause remains unknown. In summary, combining information from genetically defined models and cancer samples allows for better aligning mutational signatures to causal mutagenic processes.

scholarly journals OMIC-08. COMPOUND HETEROZYGOSITY OF POLE AND PMS2 LEADS TO CMMRD-LIKE PHENOTYPE- “POLYNCH” SYNDROME

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i38-i39
Author(s):  
Orli Michaeli ◽  
Hagay Ladany ◽  
Yosef E Maruvka ◽  
Ayelet Erez ◽  
Shay Ben Shachar ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
De Novo ◽  
Clinical Manifestations ◽  
Dna Polymerase Epsilon ◽  
Pathogenic Variants ◽  
Repair Deficiency ◽  
Mutation Burden ◽  
Desmoplastic Medulloblastoma

Abstract Mono-allelic germline pathogenic variants (PV) in one of the mismatch repair (MMR) system genes cause Lynch syndrome, associated mainly with colon and endometrial cancer in adults. Germline PVs in DNA polymerase epsilon (POLE) are associated with a dominantly inherited syndrome which confers risk for polyposis and colon cancer. Brain tumors have been described as part of Lynch syndrome and POLE associated syndrome, mostly in adults. Constitutional mismatch repair deficiency (CMMRd) is caused by bi-allelic mutations in the MMR genes, associated with multiple café au lait macules (CAMs) and high incidence of pediatric cancer, including brain tumors. Both MMRD and POLE associated tumors have high tumor mutation burden (TMB), however, microsatellite status is usually unstable in MMR tumors, and stable in POLE. Germline POLE and CMMRd tumors have different mutational signatures, as is signature of MMR tumors with secondary somatic POLE. We describe a 4.5 y/o male who presented with a grossly metastatic SHH-activated, TP53-wildtype desmoplastic medulloblastoma. Physical examination was noted for CAMs. Family history was positive for a heterozygous POLE variant with variable clinical manifestations. Immunohistochemistry of the tumor showed loss of nuclear expression of the MMR gene PMS2, specifically in tumor cells. Analysis showed exceptionally high TMB (up to 276 Mut/Mb) and both the MMR and the POLE signatures. Germline analysis detected the familial POLE variant as well as a de novo heterozygous PMS2 PV. The phenotype of the patient together with the tumor’s features, led us to classify this case as a CMMRd-like. The patient had a partial response to intensive chemotherapy and is currently on immunotherapy without radiation. Collectively, our data suggest that heterozygous simultaneous germline mutations in MMR and polymerase genes can lead to novel “POLYNCH syndrome” that manifests with an ultra-hypermutant aggressive tumor and requires appropriate treatment and surveillance.

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