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BIOMARKER:

POLD1 mutation

i
Other names: DNA Polymerase Delta 1 Catalytic Subunit, Polymerase (DNA) Delta 1 Catalytic Subunit, DNA Polymerase Delta Catalytic Subunit, DNA Polymerase Subunit Delta P125, Polymerase (DNA Directed) Delta 1 Catalytic Subunit (125kD), Polymerase (DNA Directed) Delta 1 Catalytic Subunit 125kDa, CDC2 Homolog (S. Cerevisiae), CDC2 Homolog
Entrez ID:
Related biomarkers:
4ms
Case report: Ovarian steroid cell tumor with CA72-4 elevated. (PubMed, Gynecol Endocrinol)
Following tumor resection, serum CA72-4 levels returned to the average reference interval. Whole-exome sequencing (WES) was utilized to identify ten mutations in MKI67, TICAM1, CHD3, ARID5B, ERBB4, POLD1, FZR1, MTCP1, TBX3, and CLTC genes.
Journal
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ERBB4 (erb-b2 receptor tyrosine kinase 4) • POLD1 (DNA Polymerase Delta 1) • CLTC (Clathrin Heavy Chain) • ARID5B (AT-Rich Interaction Domain 5B)
|
POLD1 mutation
4ms
Glioma oncogenesis in the Constitutional mismatch repair deficiency (CMMRD) syndrome. (PubMed, Neurooncol Adv)
CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors.
Journal • Mismatch repair • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • NF1 (Neurofibromin 1) • POLD1 (DNA Polymerase Delta 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • DICER1 (Dicer 1 Ribonuclease III) • EPHB2 (EPH Receptor B2) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit)
|
PD-L1 expression • POLD1 mutation • SETD2 mutation • POLE mutation + POLD1 mutation
6ms
Comprehensive genomic profiling in RAS/BRAF wild type colorectal cancers (ECP 2024)
All cases harbored variants in key oncogenes or oncosuppressors and druggable alterations in more than one third of them. Five out of nine patients had a high TMB unrelated to microsatellite instability. TMB may serve as biomarker for immunotherapy-based strategies in mismatch repair proficient/microsatellite stable mCRC.
Tumor mutational burden • BRCA Biomarker • IO biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MET (MET proto-oncogene, receptor tyrosine kinase) • BRCA1 (Breast cancer 1, early onset) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • RAS (Rat Sarcoma Virus) • POLD1 (DNA Polymerase Delta 1) • CHEK1 (Checkpoint kinase 1)
|
TMB-H • HER-2 amplification • MET amplification • BRAF wild-type • POLD1 mutation
|
FoundationOne® CDx
7ms
A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer. (PubMed, Oncologist)
Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers (ie, TMB, MMR, and MSI-H) and molecular co-alterations. Those with short variant mutations represented 18% of the POLE/POLD1 cohort and 0.4% of the total cohort examined. This group of patients had a median TMB of 159 mut/Mb (range 34-488), representing the ultra-hypermutated phenotype. This group of patients is important to identify given the potential for exceptional response to immune checkpoint inhibitors.
Journal • Tumor mutational burden • MSi-H Biomarker • BRCA Biomarker • IO biomarker
|
ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • RET (Ret Proto-Oncogene) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
TMB-H • MSI-H/dMMR • ATM mutation • POLE mutation • ALK mutation • RET mutation • POLD1 mutation • POLE mutation + POLD1 mutation
|
Tempus xT Assay
8ms
Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells. (PubMed, Eur J Hum Genet)
We solved this contradiction through the observation that tumorigenesis involves somatic inactivation of the wildtype POLD1 allele. These results imply that exonuclease deficiency of polymerase delta has a recessive effect on mutation rate.
Journal • Tumor mutational burden
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TMB (Tumor Mutational Burden) • POLD1 (DNA Polymerase Delta 1)
|
POLD1 mutation
9ms
Pembrolizumab in Ultramutated and Hypermutated Endometrial Cancer (clinicaltrials.gov)
P2, N=25, Active, not recruiting, Yale University | Trial completion date: Jun 2024 --> Oct 2025 | Trial primary completion date: Jun 2024 --> Oct 2025
Trial completion date • Trial primary completion date • IO biomarker
|
MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
|
Keytruda (pembrolizumab)
9ms
Pembrolizumab in Ultramutated and Hypermutated Endometrial Cancer (clinicaltrials.gov)
P2, N=25, Active, not recruiting, Yale University | Trial completion date: Dec 2028 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024
Trial completion date • Trial primary completion date • IO biomarker
|
MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
|
Keytruda (pembrolizumab)
10ms
GC 2nd Line Durvalumab(MEDI4736)/Tremelimumab Plus Paclitaxel Study (clinicaltrials.gov)
P1/2, N=58, Completed, Asan Medical Center | Active, not recruiting --> Completed
Trial completion
|
PD-L1 (Programmed death ligand 1) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • POLD1 (DNA Polymerase Delta 1) • MSH3 (MutS Homolog 3) • PMS1 (PMS1 protein homolog 1) • POLD2 (DNA Polymerase Delta 2)
|
MSI-H/dMMR • MSH2 mutation • MLH1 mutation • PD-L1 amplification • POLD1 mutation • MSH3 mutation • PMS2 mutation • MLH3 mutation • PMS1 mutation • POLD2 mutation
|
Imfinzi (durvalumab) • paclitaxel • Imjudo (tremelimumab-actl)
10ms
Nivolumab Ipilimumab in Patients With hyperMutated Cancers Detected in Blood (NIMBLe) (clinicaltrials.gov)
P2, N=4, Terminated, Canadian Cancer Trials Group | Active, not recruiting --> Terminated; cfDNA screening data found that the prevalence of POLE/POLD1 mutations was lower than expected. It was determined that there are no feasible options to amend this study in a fashion that would not be duplicative of other currently accruing trials.
Trial termination
|
POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
|
Opdivo (nivolumab) • Yervoy (ipilimumab)
1year
POLD1 DEDD Motif Mutation Confers Hypermutation in Endometrial Cancer and Durable Response to Pembrolizumab. (PubMed, Cancers (Basel))
Charge-discordant AA substitution in the DEDD motif of POLD1 is detrimental to DNA proofreading and should be reclassified as likely pathogenic and possibly predictive of ICI sensitivity.
Journal • PD(L)-1 Biomarker • IO biomarker
|
POLD1 (DNA Polymerase Delta 1) • DEDD (Death Effector Domain Containing)
|
POLD1 mutation
|
Keytruda (pembrolizumab)
1year
Genomic Characteristics and Its Therapeutic Implications in Breast Cancer Patients with Detectable Molecular Residual Disease. (PubMed, Cancer Res Treat)
The Cell cycle pathway, defective DNA mismatch repair, and AID-mediated SHM were found to be the possible causes of detectable MRD. We also found the vast majority of patients with detectable MRD have the opportunity to access targeted therapy.
Journal
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FLT1 (Fms-related tyrosine kinase 1) • POLD1 (DNA Polymerase Delta 1) • GNAS (GNAS Complex Locus) • MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1) • WWP2 (WW Domain Containing E3 Ubiquitin Protein Ligase 2)
|
ATM mutation • POLD1 mutation • MAP3K1 mutation
1year
Molecular and clinical characteristics of POLE/POLD1 alterations among patients with colorectal cancer. (ASCO-GI 2024)
POLE/POLD1 mutations frequently co-exist with MSI-H disease in CRC. Patients with MSS-CRC harboring POLE/POLD1 mutations represent a smaller subgroup of CRC (~1%). The incidence of POLE/POLD1 somatic mutations was more common among patients with colon cancer than those with rectal cancer.
Clinical • MSi-H Biomarker
|
MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • POLD1 (DNA Polymerase Delta 1)
|
MSI-H/dMMR • POLE mutation • MSH6 mutation • MSH2 mutation • MLH1 mutation • POLD1 mutation • PMS2 mutation • POLE mutation + POLD1 mutation
1year
Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families. (PubMed, Acta Neuropathol Commun)
Our data provide evidence that rare POLE/POLD1 germline variants predispose to gliomas that may be susceptible to ICIs. Data compiled here suggest that glioma patients carrying POLE/POLD1 variants may be recognized by cutaneous manifestations, e.g. café-au-lait macules, and benefit from surveillance colonoscopy.
Journal • IO biomarker
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POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
POLD1 mutation • POLE mutation + POLD1 mutation
1year
Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers (clinicaltrials.gov)
P1/2, N=11, Terminated, The Hospital for Sick Children | N=50 --> 11 | Trial completion date: Sep 2022 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2022 --> Nov 2023; Withdrawal of drug supply/funding
Enrollment change • Trial completion date • Trial termination • Trial primary completion date • IO biomarker
|
TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • POLD1 (DNA Polymerase Delta 1) • EPCAM (Epithelial cell adhesion molecule) • MSH3 (MutS Homolog 3) • APOB (Apolipoprotein B)
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MSI-H/dMMR • POLE mutation • MSH2 mutation • POLD1 mutation • PMS2 mutation • EPCAM expression
|
Opdivo (nivolumab)
1year
Comprehensive Genomic Profiling of Early Hormone Receptor Positive Breast Cancer Reveals Diverse Genomic Alterations (AMP 2023)
In a retrospective analysis, we used comprehensive genomic profiling in the well-studied early-stage HR+ BC Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial cohort to characterize genomic alterations that contribute to oncogenesis and may drive recurrence. The genomic landscape of early HR+ BC is diverse and contains many actionable alterations. In addition to activating mutations in well-known BC associated oncogenes, the landscape included high-level CN gain in several RTK genes. The relatively high level of aneuploidy in early-stage HR+ BC was unanticipated and associated with poor risk.
Tumor mutational burden
|
EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR1 (Fibroblast growth factor receptor 1) • CDH1 (Cadherin 1) • POLD1 (DNA Polymerase Delta 1) • MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1) • GATA3 (GATA binding protein 3)
|
TP53 mutation • TMB-H • HR positive • HER-2 negative • PIK3CA mutation • POLD1 mutation
|
Oncomine™ Comprehensive Assay Plus
|
tamoxifen • exemestane
1year
Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1. (PubMed, Genome Med)
Our recommendations, with room for improvement in the coming years as more information become available on carrier families, tumor molecular characteristics and functional assays, are intended to serve the clinical and scientific communities and help improve diagnostic performance, avoiding variant misclassifications.
Journal • Tumor mutational burden
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TMB (Tumor Mutational Burden) • KEAP1 (Kelch Like ECH Associated Protein 1) • POLD1 (DNA Polymerase Delta 1)
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TMB-H • POLD1 mutation
over1year
Diagnostic and therapeutic impact of liquid biopsy in soft tissue sarcomas: A case series (ESMO 2023)
Conclusions LB proved to be an attractive technique to detect significant MA in advanced STS, a group of malignant tumors with a challenging diagnosis and therapeutic approach. This tool can be implemented as an adjunct tool to offer novel therapeutic options to patients as well as fine-tuning of the diagnostic process.
Clinical • Liquid biopsy • Tumor mutational burden • MSi-H Biomarker • IO biomarker • Biopsy
|
TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • NF1 (Neurofibromin 1) • JAK2 (Janus kinase 2) • EWSR1 (EWS RNA Binding Protein 1) • POLD1 (DNA Polymerase Delta 1) • ATF1 (Activating Transcription Factor 1)
|
TMB-H • MSI-H/dMMR • BRAF mutation • NF1 mutation • POLD1 mutation • JAK2 mutation
over1year
The role of immune checkpoint inhibitors for patients with advanced stage microsatellite stable colorectal cancer and high tumor mutation burden: quantity or quality? (PubMed, Expert Opin Biol Ther)
The US Food and Drug Administration (FDA) approved pembrolizumab for patients with unresectable or metastatic solid tumors with tumor mutational burden (TMB) of ≥ 10 mutations/megabase...Predetermined cutoff TMB ≥ 10 mutation per MB does not seem to define a universal cutoff for the benefit of disease-agnostic ICI therapy, particularly for patients with MSS CRC. Patients with POLE/POLD1 mutations with MSS CRC represent a unique biological subgroup of MSS CRC with favorable responses to ICI therapy.
Journal • Checkpoint inhibition • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases
|
TMB (Tumor Mutational Burden) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
TMB-H • POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
|
Keytruda (pembrolizumab)
over1year
Replication DNA polymerases, genome instability and cancer therapies. (PubMed, NAR Cancer)
The aim of this review is to gather and review in some detail recent studies of DNA polymerases ϵ and δ as they pertain to genome instability, cancer and potential therapeutic treatments. The focus here is primarily on recent informative studies on the significance of mutations in genes encoding their catalytic subunits (POLE and POLD1), mutational signatures, mutations in associated genes, model organisms, and the utility of chemotherapy and immune checkpoint inhibition in polymerase mutant tumors.
Journal • IO biomarker
|
POLD1 (DNA Polymerase Delta 1)
|
POLD1 mutation
over1year
Clinicopathological and gene mutation characteristics of uterine carcinosarcoma (PubMed, Zhonghua Yi Xue Za Zhi)
Molecular typing indicated that 3 cases of UCS were of high copy number type/p53 mutation type, and 1 case had POLD1 mutation. Microsatellite stability, low PD-L1 expression and TMB results suggested that UCS patients have no obvious advantage in immunotherapy.
Retrospective data • Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • POLD1 (DNA Polymerase Delta 1) • VIM (Vimentin) • BRD4 (Bromodomain Containing 4) • PAX8 (Paired box 8) • BCL9L (BCL9 Like)
|
PD-L1 expression • TP53 mutation • PD-L1 negative • MSH2 mutation • MLH1 mutation • POLD1 mutation • PMS2 mutation • PGR expression • VIM expression • PD-L1-L
over1year
Pre-operative Targeted Treatments in Molecularly Selected Resectable Colorectal Cancer (UNICORN) (clinicaltrials.gov)
P2, N=98, Recruiting, Gruppo Oncologico del Nord-Ovest | Active, not recruiting --> Recruiting
Enrollment open
|
HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • CD8 (cluster of differentiation 8) • POLD1 (DNA Polymerase Delta 1) • CD4 (CD4 Molecule)
|
HER-2 positive • MSI-H/dMMR • HER-2 amplification • POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
|
Imfinzi (durvalumab) • Vectibix (panitumumab) • Enhertu (fam-trastuzumab deruxtecan-nxki) • balstilimab (AGEN2034) • botensilimab (AGEN1181)
over1year
Integrating POLE/POLD1 mutated for immunotherapy treatment planning of advanced stage non-small cell lung cancer. (PubMed, Thorac Cancer)
Current smokers have a five-fold increased risk of having POLE mutations than never-smokers. POLE/POLD1 mutation status and TMB > 18 can be a composite biomarker for selecting NSCLC patients with survival benefits to ICI treatment.
Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases
|
PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
|
MSK-IMPACT
over1year
Current Progress on Predictive Biomarkers for Response to Immune Checkpoint Inhibitors in Gastric Cancer: How to Maximize the Immunotherapeutic Benefit? (PubMed, Cancers (Basel))
Pharmacotherapy, which for a long time was systemic chemotherapy based on 5-fluorouracil, is the mainstay of management for advanced gastric cancer. Trastuzumab and programmed cell death 1 (PD-1) inhibitors have altered the therapeutic landscape, contributing to noticeably prolonged survivorship in patients with metastatic gastric cancer...Gut microorganisms, genetic mutations like POLE/POLD1 and NOTCH4, tumor lymphoid infiltrating cells (TILs), and other novel biomarkers have the potential to develop into new predictors. Prospective immunotherapy for gastric cancer should be guided by a biomarker-driven precision management paradigm, and multidimensional or dynamic marker testing could be the way to go.
Review • Journal • Checkpoint inhibition • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1) • NOTCH4 (Notch 4)
|
POLD1 mutation
|
Herceptin (trastuzumab) • 5-fluorouracil
over1year
High-grade serous ovarian carcinoma with a sertoliform pattern associated with BRCA mutation: a clinicopathological and molecular analysis. (PubMed, Virchows Arch)
Molecular analysis showed a germline BRCA2 mutation; no mutations were detected in POLE, POLD1, MLH1, MSH2, MSH6, PMS2, APC, CTNNB1, MUTYH, and EPCAM. In conclusion, a sertoliform pattern can be part of the morphological spectrum of BRCA-related HGSC.
Journal • BRCA Biomarker
|
TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • PMS2 (PMS1 protein homolog 2) • WT1 (WT1 Transcription Factor) • BRCA (Breast cancer early onset) • POLD1 (DNA Polymerase Delta 1) • NKX2-1 (NK2 Homeobox 1) • VIM (Vimentin) • MME (Membrane Metalloendopeptidase) • MUTYH (MutY homolog) • CDX2 (Caudal Type Homeobox 2) • GATA3 (GATA binding protein 3) • PAX8 (Paired box 8) • SYP (Synaptophysin)
|
BRCA2 mutation • MSH2 mutation • POLD1 mutation • PMS2 mutation • BRCA mutation • VIM expression
over1year
New P2 trial
|
HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • CD8 (cluster of differentiation 8) • POLD1 (DNA Polymerase Delta 1) • CD4 (CD4 Molecule)
|
HER-2 positive • MSI-H/dMMR • HER-2 amplification • POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
|
Imfinzi (durvalumab) • Vectibix (panitumumab) • Enhertu (fam-trastuzumab deruxtecan-nxki) • balstilimab (AGEN2034) • botensilimab (AGEN1181)
over1year
DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC. (PubMed, Nat Commun)
In turn, MYC increases expression of POLD1, forming a POLD1-MYC positive feedback loop to enhance the pro-carcinogenic effect of POLD1-MYC on BLCA. Overall, our study identifies POLD1 as a promotor of BCLA via a MYC driven mechanism and suggest its potential as biomarker for BLCA.
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • POLD1 (DNA Polymerase Delta 1)
|
MYC expression • POLD1 mutation • MYC positive
over1year
POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma. (PubMed, Int J Mol Sci)
Our current study demonstrated that POLD1 is a potential prognostic biomarker for ccRCC patients. It might create a tumor immunosuppressive microenvironment and inhibit the susceptibility to ferroptosis leading to a poor prognosis.
Journal
|
POLD1 (DNA Polymerase Delta 1)
|
POLD1 mutation
over1year
Immune Checkpoint Inhibitors in pMMR/MSS Colorectal Cancer. (PubMed, J Gastrointest Cancer)
Immune checkpoint inhibitor-based regimens have not yet shown any meaningful positive outcomes for most pMMR/MSS colorectal cancers. A beneficial effect among a minority of these patients has been observed, but concrete biomarkers of response are lacking. Understanding the underlying mechanisms of immune resistance should guide further research for overcoming these obstacles.
Review • Journal • Checkpoint inhibition • MSi-H Biomarker • IO biomarker
|
MSI (Microsatellite instability) • LAG3 (Lymphocyte Activating 3) • POLD1 (DNA Polymerase Delta 1) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2) • BTLA (B And T Lymphocyte Associated)
|
MSI-H/dMMR • POLD1 mutation
almost2years
Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome. (PubMed, Front Mol Biosci)
Overall, future work is required to elucidate if functional consequences could be derived from POLD1 alterations different from missense variants in their proofreading domain. To our knowledge, our study presents the first organoid model for germline POLD1 variants and establishes the basis for its use as a model for disease in SPS, CRC and other malignancies.
Journal
|
MSI (Microsatellite instability) • POLD1 (DNA Polymerase Delta 1)
|
POLD1 mutation
almost2years
Pembrolizumab in Ultramutated and Hypermutated Endometrial Cancer (clinicaltrials.gov)
P2, N=25, Active, not recruiting, Yale University | Trial primary completion date: Dec 2022 --> Dec 2023
Trial primary completion date • IO biomarker
|
MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
POLE mutation • POLD1 mutation
|
Keytruda (pembrolizumab)
almost2years
GC 2nd Line Durvalumab(MEDI4736)/Tremelimumab Plus Paclitaxel Study (clinicaltrials.gov)
P1/2, N=58, Active, not recruiting, Asan Medical Center | Unknown status --> Active, not recruiting | Trial completion date: Jun 2021 --> Jun 2023 | Trial primary completion date: Jun 2021 --> Jun 2023
Enrollment closed • Trial completion date • Trial primary completion date • Metastases
|
PD-L1 (Programmed death ligand 1) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • POLD1 (DNA Polymerase Delta 1) • MSH3 (MutS Homolog 3) • PMS1 (PMS1 protein homolog 1) • POLD2 (DNA Polymerase Delta 2)
|
MSI-H/dMMR • MSH2 mutation • MLH1 mutation • PD-L1 amplification • POLD1 mutation • MSH3 mutation • PMS2 mutation • MLH3 mutation • PMS1 mutation • POLD2 mutation
|
Imfinzi (durvalumab) • paclitaxel • Imjudo (tremelimumab-actl)
almost2years
Whole exome sequencing in Chinese mucinous pulmonary adenocarcinoma uncovers specific genetic variations different from lung adenocarcinoma. (PubMed, Front Oncol)
We not only depicted the genetic and immunologic landscape of Chinese MPA but also reveal its distinction from LUAD in genomic and immune context. Our findings may provide opportunities for therapeutic susceptibility among Chinese MPA patients.
Journal
|
EGFR (Epidermal growth factor receptor) • TP53 (Tumor protein P53) • POLD1 (DNA Polymerase Delta 1)
|
TP53 mutation • POLD1 mutation • NOTCH mutation
2years
Charac­terizing the genomic landscape of POLE/POLD1-mutated colorectal adenocarcinoma. (ASCO-GI 2023)
"Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers and molecular co-alterations. POLE/POLD1 mutations in CRC have been previously described to present with a hypermutated phenotype; however, 78% of tumors exhibited low TMB despite POLE/POLD1 mutations. Thus, these results have identified POLE/POLD1-mutated tumors as a unique genomic subpopulation, and further studies are needed to better characterize POLE/POLD1 mutations in CRC."
KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
TP53 mutation • KRAS mutation • TMB-H • MSI-H/dMMR • POLE mutation • TMB-L • APC mutation • POLD1 mutation
|
Tempus xT Assay
2years
Effect of immunotherapy on the survival outcomes in tumor mutational burden-high (TMB-H) microsatellite stable (MSS) metastatic colorectal cancer (mCRC): A single-institution experience. (ASCO-GI 2023)
Agent specific analysis showed mPFS for patients treated with pembrolizumab was 3.5 months (mean 5.2; range 0.6-15.7), and 3.4 months (mean 12.1; range 0.5-12.1) for patients treated with nivolumab. Five patients received immunotherapy in combination with regorafenib... Although TMB-H demonstrated therapeutic significance in the KEYNOTE 158 study, the utility of 10 mutations/MB as a universal cutoff warrants additional evaluation. Here we report that a TMB-H cutoff value of ≥ 10 for patients with MSS CRC was not associated with clinically meaningful response to immunotherapy, but patients with MSS CRC with POLE/POLD-1 mutations may be more likely to benefit from immunotherapy.
Clinical • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases
|
TMB (Tumor Mutational Burden) • POLD1 (DNA Polymerase Delta 1)
|
TMB-H • POLD1 mutation
|
Keytruda (pembrolizumab) • Opdivo (nivolumab) • Stivarga (regorafenib)
2years
A phase II clinical trial of toripalimab in advanced solid tumors with POLE/POLD1 mutation. (ASCO-GI 2023)
This study showed that patients with POL-EDMs had a good response to ICI therapy, and those with POL-non-EDMs could clinically benefit from anti-PD-1 antibody monotherapy, urging the need for more investigations on immunotherapy combined with chemotherapy in patients with POL-non-EDMs.
Clinical • P2 data • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker • Metastases
|
MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
POLE mutation • POLD1 mutation
|
Loqtorzi (toripalimab-tpzi)
2years
NCI-2018-00115: Pembrolizumab in Treating Participants With Metastatic, Recurrent or Locally Advanced Cancer and Genomic Instability (clinicaltrials.gov)
P2, N=40, Recruiting, Rutgers, The State University of New Jersey | Trial completion date: Oct 2022 --> Oct 2023 | Trial primary completion date: Oct 2022 --> Oct 2023
Trial completion date • Trial primary completion date • Pan tumor • Metastases
|
PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
|
BRCA1 mutation • POLD1 mutation
|
Keytruda (pembrolizumab)
over2years
Testing the Combination of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) in Children, Adolescent, and Young Adult Patients With Relapsed/Refractory Cancers That Have an Increased Number of Genetic Changes, The 3CI Study (clinicaltrials.gov)
P1, N=0, Withdrawn, National Cancer Institute (NCI) | N=26 --> 0 | Trial completion date: Jun 2024 --> Jun 2022 | Active, not recruiting --> Withdrawn | Trial primary completion date: Jun 2024 --> Jun 2022
Enrollment change • Trial completion date • Trial withdrawal • Trial primary completion date • IO biomarker
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TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • POLD1 (DNA Polymerase Delta 1) • MSH3 (MutS Homolog 3)
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MSI-H/dMMR • MSH2 mutation • POLD1 mutation • PMS2 mutation • EPCAM expression • MSH6 expression
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Opdivo (nivolumab) • Yervoy (ipilimumab)
over2years
K-Basket, Avelumab, Biomarker-driven, Advanced Solid Tumor (clinicaltrials.gov)
P2, N=60, Active, not recruiting, Yonsei University | Unknown status --> Active, not recruiting | Trial completion date: Jul 2020 --> Dec 2022 | Trial primary completion date: Dec 2019 --> Aug 2022
Enrollment closed • Trial completion date • Trial primary completion date • IO biomarker • Pan tumor
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PD-L1 (Programmed death ligand 1) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
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PD-L1 expression • MSI-H/dMMR • POLE mutation • POLD1 mutation
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Bavencio (avelumab)
over2years
NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability. (PubMed, Cancer Med)
NTRK-driven colorectal cancer patients demonstrated increased TMB (median = 53 mut/MB, 95% CI: 36.8-68.0 mut/MB), high microsatellite instability, and an enrichment for POLE/POLD1 mutations when compared to molecularly unstratified colorectal cancer population. These data shed light on possible future approach of multimodality treatment regimen including TRK-targeted therapy and immune checkpoint inhibitor therapy in NTRK-positive CRCs.
Journal • Microsatellite instability • MSi-H Biomarker • IO biomarker
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BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1) • NTRK (Neurotrophic receptor tyrosine kinase)
|
TMB-H • MSI-H/dMMR • POLE mutation • POLD1 mutation • NTRK positive • NTRK fusion
over2years
Enrollment closed • IO biomarker
|
TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • POLD1 (DNA Polymerase Delta 1) • MSH3 (MutS Homolog 3)
|
MSI-H/dMMR • MSH2 mutation • POLD1 mutation • PMS2 mutation • EPCAM expression • MSH6 expression
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Opdivo (nivolumab) • Yervoy (ipilimumab)
over2years
Scrutinizing Deleterious Nonsynonymous SNPs and Their Effect on Human POLD1 Gene. (PubMed, Genet Res (Camb))
Among these deleterious nsSNPs, 23 showed a conservation scale of >5, 2 were predicted to be associated with binding site formation, and one acted as a posttranslational modification site. All of them were involved in coil, extracellular structures, or helix formation, and some cause the change in size, charge, and hydrophobicity.
Journal
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POLD1 (DNA Polymerase Delta 1) • SEC23IP (SEC23 Interacting Protein)
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POLD1 mutation
over2years
Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers (clinicaltrials.gov)
P1/2, N=50, Active, not recruiting, The Hospital for Sick Children | Trial completion date: Sep 2021 --> Sep 2022 | Trial primary completion date: Sep 2021 --> Sep 2022
Trial completion date • Trial primary completion date • IO biomarker
|
TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • POLD1 (DNA Polymerase Delta 1) • EPCAM (Epithelial cell adhesion molecule) • MSH3 (MutS Homolog 3) • APOB (Apolipoprotein B)
|
MSI-H/dMMR • POLE mutation • MSH2 mutation • POLD1 mutation • PMS2 mutation • EPCAM expression
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Opdivo (nivolumab)