TP53 Mutation Status Research Articles

Abstract OT2-12-01: Clinical Application of LFSPRO: A Prospective Study

Abstract Background: Individuals with Li-Fraumeni Syndrome (LFS) have increased risk of developing cancers of several types, such as early-onset breast cancer, soft-tissue/bone sarcoma, leukemia, brain tumors, and more, throughout their lifetime. LFS is primarily caused by autosomal dominant germline mutations in the TP53 tumor suppressor gene. It is difficult to identify TP53 mutation carriers because of the overlap in the occurrence of multiple cancer types in LFS with other inherited cancer syndromes. In order to improve the accuracy of risk assessment for these families, the LFSPRO risk model was created to predict the likelihood of a proband having LFS based off detailed patient and family history information, as well as predict cancer-specific risks for patients who have already been identified as having LFS. Specific Aims: The primary aim of this study is to evaluate the concordance of LFSPRO and clinical criteria in predicting TP53 mutation status in patients undergoing germline TP53 testing. Trial Design: After receiving standard genetic counseling, patients identified as concerning for a potential TP53 mutation by a MD Anderson genetic counselor (GC) are run through LFSPRO. LFSPRO TP53 mutation carrier risk, whether the patient meets Chompret and/or Classic criteria, decision to test, and genetic test results are collected. Select GCs are then asked to complete a survey regarding their experience with LFSPRO. Eligibility Criteria: Through standard genetic counseling practice, MD Anderson GCs identify patients with a clinical suspicion for a TP53 germline mutation. All patients identified are run through LFSPRO. Out of these identified patients, select GCs that participated in the initial genetic counseling session are asked to complete a survey over their experience using the LFSPRO. Statistical methods: We will evaluate the concordance in the prediction of TP53 mutation carrier status between LFSPRO and current clinical criteria as compared to the outcome of genetic testing results. We will cross-tabulate the predicted TP53-mutation status (positive vs. negative) with the carrier status in a 2 × 2 table and calculate the sensitivity and specificity of each prediction tool separately (LFSPRO, clinical criteria), with 95% confidence interval. Accrual: Currently, 72 patients have been run through LFSPRO. Select GCs have completed the survey regarding their experience with LFSPRO on 20 of these patients. Data collection began in December 2021 and is currently ongoing. Funding: This research is supported by the Cancer Research and Prevention Institute of Texas. Contact: Jacynda Woodman-Ross, MS, CGC, The University of Texas MD Anderson Cancer Center, jawoodman@mdanderson.org Citation Format: Jacynda Woodman-Ross, Elissa Dodd-Eaton, Jessica Corredor, Sierra O. Green, Nam H. Nguyen, Nathaniel Hernandez, Courtney D. DiNardo, Wenyi Wang, Banu K. Arun. Clinical Application of LFSPRO: A Prospective Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-12-01.

A TP53-associated metabolic gene signature for the prediction of overall survival and therapeutic responses in hepatocellular carcinoma

BackgroundTP53 is one of the most prevalent mutated genes in hepatocellular carcinoma (HCC), while the role of TP53 mutations in HCC metabolic reprogramming remains unclear. MethodsThe differential analysis of gene expression profile between HCC patients with wild-type and mutated TP53 was performed to identify TP53-associated metabolic genes (TMGs). The TMGs were utilized to construct and validate a TP53-associated metabolic gene signature (TMS). Comprehensive bioinformatics analyses were performed to explore clinical application value and biological interpretability of TMS. ResultsWe identified 86 TMGs based on the TP53 mutation status. TMS including CYP26B1, CYP2C9, G6PD, PYGM and TKTL1 was constructed and validated to identify the low-TMSscore group had a better prognosis than the high-TMSscore group. Tryptophan metabolism and fatty acid metabolism were significantly enriched in the low-TMSscore group. Moreover, it was characterized by a higher abundance of gamma delta T cell and natural killer cell than the high-TMSscore group. Compared to the high-TMSscore group, the low-TMSscore group was more likely to respond to immune checkpoint therapy. ConclusionsThe TMS is a potential strategy for prognostic prediction and immune checkpoint therapy guidance for HCC patients. Our study provides new insights into the involvement of TP53 mutations in tumor metabolic reprogramming.

Uses of Vascular Endothelial Growth Factor C as a Lung Adenocarcinoma Prognostic Biomarker.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer and a leading cause of death worldwide. Vascular endothelial growth factor C (VEGF-C) has been identified as a prognosis prediction marker for LUAD. However, VEGF-C protein expression does not appear to significantly relate to LUAD patient survival in several studies. We carried out a bioinformatic analysis to review the effect of VEGF-C mRNA expression on LUAD patient outcomes. GEPIA, UALCAN, TCGAportal, OncoLnc, LCE, GeneMANIA, Metascape, ImmuCellAI, and GSCA online databases were utilized. The expression levels of VEGF-C mRNA between normal tissue and LUAD tissue, overall survival (OS) analysis, function analysis, tumor microenvironment and drug sensitivity were conducted in the current study. We found that the expression level of VEGF-C mRNA was significantly lower in LUAD than normal tissue. Low expression of VEGF-C mRNA was also associated with better OS. VEGF-C expression was correlated with both NF1 and TP53 mutation status. No relationship was observed between VEGF-C and Tr1 or CD4 T-cell infiltrate scores. Additionally, VEGF-C was associated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance. The sensitivity of 5-fluorouracil was positively correlated with VEGF-C, and the sensitivity of TGX221 was negatively correlated with VEGF-C. The activity of BI-2536 and BRD-A94377914 was positively correlated with VEGF-C. Novel LUAD prognostic biomarkers such as VEGF-C mRNA may aid diagnosis and treatment, and may help identify optimal LUAD populations for therapeutic treatments.

DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation.

Although TP53 mutations in acute myeloid leukemia (AML) are associated with poor response to venetoclax, the underlying resistance mechanism remains unclear. Herein, we investigated the functional role of dynamin-related protein 1 (DRP1) in venetoclax sensitivity in AML cells with respect to TP53 mutation status. Effects of DRP1 inhibition on venetoclax-induced cell death were compared in TP53-mutated (THP-1 and Kasumi-1) and TP53 wild-type leukemia cell lines (MOLM-13 and MV4-11), as well as in primary AML cells obtained from patients. Venetoclax induced apoptosis in TP53 wild-type AML cells but had limited effects in TP53-mutated AML cells. DRP1 expression was downregulated in MOLM-13 cells after venetoclax treatment but was unaffected in THP-1 cells. Cotreatment of THP-1 cells with venetoclax and a TP53 activator NSC59984 downregulated DRP1 expression and increased apoptosis. Combination treatment with the DRP1 inhibitor Mdivi-1 and venetoclax significantly increased mitochondria-mediated apoptosis in TP53-mutated AML cells. The combination of Mdivi-1 and venetoclax resulted in noticeable downregulation of MCL-1 and BCL-xL, accompanied by the upregulation of NOXA, PUMA, BAK, and BAX. These findings suggest that DRP1 is functionally associated with venetoclax sensitivity in TP53-mutated AML cells. Targeting DRP1 may represent an effective therapeutic strategy for overcoming venetoclax resistance in TP53-mutated AML.

Orelabrutinib in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma patients: Multi-center, single-arm, open-label, phase 2 study.

Orelabrutinib is a novel, small molecule, selective irreversible Bruton's tyrosine kinase inhibitor. The aim of this study was to evaluate the efficacy and safety in patients with refractory or relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This is single-arm, multi-center, open-label, phase 2 study in 80 eligible Chinese patients, who were treated with monotherapy of orelabrutinib at 150 mg once daily. Overall response rate evaluated by an independent review committee was the primary endpoint, and secondary endpoints include progression-free survival, overall survival, and safety. Independent review committee assessed overall response rate was 92.5% (74/80); complete response 21.3% (17/80), partial response 60.0% (48/80), partial response with lymphocytosis 11.3% (9/80). At a 32.3-month median follow-up, the median progression-free survival had not been achieved, while the 30-month progression-free survival rate and overall survival rates were 70.9% (95% confidence interval [CI], 59.5-79.6) and 81.3% (95% CI, 70.8-88.2), respectively. Orelabrutinib also revealed substantial response in patients with high prognostic risks: overall response rates of patients carrying positive TP53 mutational status or del(17p), del(11q), as well as unmutated immunoglobulin heavy-chain variable region gene were 100%, 94.7%, and 93.9%, respectively. Most adverse events were in low grade, with 86.8% of AEs being Grade 1 or 2. Nearly 67% of patients were still receiving orelabrutinib after almost a 3-year follow-up. In conclusion, Orelabrutinib demonstrated compelling efficacy as well as safety profiles, with a noteworthy number of patients obtaining complete response in refractory or relapsed CLL/SLL.

Utilizing digital pathology and immunohistochemistry of p53 as an adjunct to molecular testing in myeloid disorders

TP53 mutation status guides early therapeutic decisions in the treatment of clonal myeloid disorders and serves as a simple means of monitoring response to treatment. We aim here to develop a standardized protocol for evaluating TP53 mutation status in myeloid disorders using immunohistochemistry assisted by digital image analysis and further compare this approach to manual interpretation alone. To accomplish this, we obtained 118 bone marrow biopsies from patients with hematologic malignancy and molecular testing for mutations associated with acute myeloid leukemia was performed. Clot or core biopsy slides were stained for p53 and digitally scanned. Overall mutation burden was assessed digitally using two different metrics to determine positivity, compared to the results of manual review, and correlated with molecular results. Using this approach, we found that digital analysis of immunohistochemistry stained slides performed worse than manual categorization alone in predicting TP53 mutation status in our cohort (PPV 91%, NPV 100% vs. PPV 100%, NPV 98%). While digital analysis reduced inter- and intraobserver variability when assessing mutation burden, there was poor correlation between the quantity and intensity of p53 staining and molecular analysis (R2 = 0.204). Therefore, digital image analysis of p53 immunohistochemistry accurately predicts TP53 mutation status as confirmed by molecular testing but does not offer a significant advantage over manual categorization alone. However, this approach offers a highly standardized methodology for monitoring disease status or response to treatment once a diagnosis has been made.

Correlation Analysis of the TP53 Mutation With Clinical Characteristics in the Prognosis of Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) with TP53 mutations has a worse prognosis. It was generally more resistant to chemotherapy and radiation. Our aim was to investigate the correlation between the TP53 co-mutated gene and clinical features, and prognostic value in patients with NSCLC. Seventy-three patients with a diagnosis of NSCLC at our hospital were recruited. They were divided into the TP53 mutation status (minor) (TP53 MU) and TP53 wild-type (major) (TP53 WT) groups according to their clinical characteristics after their mutation data and clinical information were collected. Serum markers were compared between groups using Mann-Whitney U test. Other clinical factors were compared between groups using χ2 test and Fisher exact test. The log-rank test was used to compare survival curves. Of the 73 patients with NSCLC, 37 (50.68%) were found to carry TP53 mutation. TP53 MU and TP53 WT groups (n = 36) showed a significant difference in the number of smokers, incidence of squamous cell carcinoma, EGFR mutation, and number of advanced patients (P < .05), while gender, age, lymph node metastasis, and KRAS mutation did not differ significantly between the 2 groups. The survival curves in the TP53/KRAS and the TP53/EGFR co-mutation groups suggest that patients with NSCLC may have a shorter progression-free survival (PFS) if they carry one of the 2 types of co-mutation. TP53 gene mutations are more common in patients with NSCLC and squamous cell carcinoma. New predictive markers for NSCLC prognosis may be TP53/KRAS and TP53/EGFR co-mutations.

TP53 Signature Can Predict Pathological Response From Neoadjuvant Chemotherapy and Is a Prognostic Factor in Patients With Residual Disease.

The TP53 signature that predicts the mutation status of TP53 has been shown to be a prognostic factor and predictor of neoadjuvant chemotherapy (NAC) response. The current study sought to investigate the utility of the TP53 signature for predicting pathological complete response (pCR) and its prognostic significance among patients with residual disease (RD). The study followed a retrospective cohort study design. Patients with T1-3/N0-1 from a cohort of those with HER2-negative breast cancer who received NAC were selected. Ability to predict pCR was evaluated using odds ratio, positive and negative predictive values, sensitivity, and specificity. Prognostic factors in the RD group were explored using the Cox proportional hazards model with distant recurrence-free survival (DRFS). Four independent cohorts were used for validation. A total of 333 eligible patients were classified into the TP53 mutant signature (n = 154) and wild-type signature (n = 179). Among the molecular and pathological factors, the TP53 signature had the highest predictive power for pCR. In 4 independent cohorts (n = 151, 85, 104, and 67, respectively), pCR rate in TP53 mutant signature group was significantly higher than that in the wild-type group. Univariate and multivariate analyses on DRFS in the RD group identified the TP53 signature and nodal status as independent prognostic factors, with the former having a better hazard ratio than the latter. After comparing DRFS between 3 groups (pCR, RD/TP53 wild-type signature, and RD/TP53 mutant signature groups), the RD/TP53 mutant signature group showed significantly worse prognosis compared with others. The RD/TP53 wild-type signature group did not exhibit inferior DRFS compared with the pCR group. Our results showed that the TP53 mutant signature can predict pCR and that combining pathological response and TP53 mutant signature allows for the identification of subgroups with truly poor prognosis.

Clinical features of complex karyotype in newly diagnosed acute myeloid leukemia.

Complex karyotype acute myeloid leukemia (CK-AML) has been classified as an adverse-risk subtype. Although a few reports have further classified CK-AML as typical (including monosomy of chromosomes 5, 7 and 17 or deletion of 5q, 7q and/or 17p) or atypical, the clinical features of these subtypes in Japanese patients remain unclear. We retrospectively analyzed a total of 115 patients with CK-AML, including 77 with typical CK-AML and 38 with atypical CK-AML. Median overall survival (OS) was significantly shorter in patients with typical CK-AML than atypical CK-AML (143days vs. 369days, P = 0.009). Among patients with typical CK-AML, those with monosomy 17 or deletion of 17p had significantly shorter OS than patients without such abnormalities (105days vs. 165days, P = 0.033). TP53 mutations were more predominant in patients with typical CK-AML than in patients with atypical CK-AML (69.7% vs. 32.4%, P < 0.001). Patients with typical CK-AML had a poor prognosis regardless of TP53 mutation status. Among patients with atypical CK-AML, however, prognosis was worse for those with the TP53 mutation than those without the mutation. In conclusion, prognosis is extremely poor for both typical CK-AML and atypical CK-AML with TP53 mutation.

Prognostic value, immune signature and molecular mechanisms of the SUMO family in pancreatic adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) has a high degree of malignancy and a very poor prognosis, and the 5-year overall survival rate of patients is approximately 7%. To improve the prognosis of patients with PAAD, a more comprehensive and in-depth study of the pathogenesis of PAAD and the identification of new diagnostic markers and treatment targets are urgently needed. Increasing evidence supports that the small ubiquitin-like modifier (SUMO) family is closely related to the occurrence and development of a variety of cancers. However, the function of the SUMO family in PAAD is not clear, and related research is very scarce. Methods: R, Cytoscape, cBioPortal, and other software and online databases were used to comprehensively analyze the expression characteristics, prognostic value, and oncogenic mechanism of the SUMO family in PAAD. Results: SUMO family members are highly expressed in PAAD, and high expression of SUMO family members is significantly associated with poor clinicopathological features and poor prognosis in PAAD patients. In addition, SUMO family members are significantly coexpressed with M6A methylation regulators and various oncogenes and play an activating role in various oncogenic pathways, including EMT. Furthermore, it is worth noting that the close association between SUMO family members and TP53 mutation status and the negative regulatory effect of SUMO1/2 on PAAD immunity may represent the potential mechanism by which SUMO family members promote the development of PAAD. Moreover, the coexpression characteristics of SUMO family members and a variety of cancer-promoting immune checkpoint genes, as well as the positive correlation between SUMO4 expression level and the sensitivity of various targeted or chemotherapeutic drugs, including gemcitabine, paclitaxel, and doxorubicin, suggest future clinical directions of this study. Conclusion: The SUMO family is closely related to the occurrence and development of PAAD and can be used as a new biomarker and therapeutic target for patients with PAAD.

TP53 Co-Mutation Status Association with Clinical Outcomes in Patients with EGFR-Mutant Non-Small Cell Lung Cancer.

TP53 co-mutations have shown association with poor prognosis in various solid tumors. For EGFR-mutated advanced non-small cell lung cancer (aNSCLC), conflicting results exist regarding its impact on survival. Clinical outcomes and genomic data were obtained retrospectively from the real-world (rw) de-identified clinicogenomic database. Patients who initiated therapy for EGFR-mutated aNSCLC between January 2014 and December 2020 were identified. Clinical outcomes were evaluated by TP53-mutational status. In 356 eligible EGFR-mutated aNSCLC patients (median age 68 years), 210 (59.0%) had TP53 co-mutation and 146 (41.0%) had TP53 wild-type tumor. Unadjusted analysis showed significantly shorter survival in patients with TP53 co-mutation versus TP53 wild-type (rw progression-free survival [rwPFS]: HR = 1.4, 95% CI 1.1-1.9, p = 0.0196; overall survival [OS]: HR = 1.6, 95% CI 1.1-2.2, p = 0.0088). Multivariable analysis confirmed independent association between TP53 co-mutation and worse rwPFS (HR = 1.4, 95% CI 1.0-0.9, p = 0.0280) and OS (HR = 1.4, 95% CI 1.0-2.0, p = 0.0345). Directionally consistent findings were observed for response rates, and subgroups by EGFR-activating mutation and first-line (1 L) therapy, with more pronounced negative effect in 1 L EGFR-TKI subgroup. TP53 co-mutations negatively affected survival in patients with EGFR-mutated aNSCLC receiving standard 1 L therapy in real-world practice.

Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study

Introduction: CLL/SLL is usually characterized by consecutive relapses and response to therapy ultimately dictates survival. While ibrutinib, a first-generation Bruton tyrosine kinase inhibitor (BTKi), has become standard therapy, it has well-described off-target effects that can limit use. Compared with ibrutinib, zanubrutinib, a next-generation BTKi, provides improved BTK occupancy across disease-relevant tissues with greater kinase selectivity. In a randomized phase 3 study (ALPINE; NCT03734016), zanubrutinib was compared head-to-head with ibrutinib as treatment for R/R CLL/SLL. At predefined response analyses, zanubrutinib demonstrated superior overall response rate (ORR); data from the predefined final PFS analysis are reported here. Methods: Patients (pts) with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib until disease progression or unacceptable toxicity. Stratification was based on age, refractory status, geographical region, and del(17p)/TP53 mutation status. As the primary endpoint of ORR was superior with zanubrutinib, the key secondary efficacy endpoint of PFS was tested for noninferiority under hierarchical testing when 205 PFS events were observed. If PFS noninferiority between zanubrutinib and ibrutinib was demonstrated, superiority of zanubrutinib vs ibrutinib could be tested and claimed if the 2-sided P-value was <.04996. Other endpoints included overall survival (OS), ORR including PR with lymphocytosis (PR-L) or better, and safety parameters including atrial fibrillation/flutter. Results: Pts (N=652) from 15 countries were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). Demographic and disease characteristics were balanced between zanubrutinib and ibrutinib arms (age ≥65 yrs [61.5 vs 61.5%]; male [65.1 vs 71.4%]; unmutated IGHV [73.1 vs 73.5%]; del(17p) [13.8 vs 15.4%]; TP53 mutated without del(17p) [9.2 vs 7.7%]). Across the study population, median age was 67 and 68 yrs, respectively; in both arms, median prior lines of therapy was 1. With a median follow-up of 29.6 mo (data cutoff, 8 Aug 2022), zanubrutinib PFS, assessed by independent review committee (PFSIRC), was superior to ibrutinib in the ITT population (HR: 0.65 [95% CI, 0.49-0.86]; 2-sided P=.0024 [Fig 1]); identical statistical values were reported when assessed by investigator (INV). Median PFSIRC was 35.0 mo (95% CI, 33.2-44.3) for ibrutinib-treated pts but not reached for zanubrutinib-treated pts. In a predefined subgroup of pts with del(17p)/TP53 mutation, longer PFSIRC was demonstrated with zanubrutinib than ibrutinib (Fig 2). PFS, regardless of IRC or INV assessment, consistently favored zanubrutinib across other major predefined subgroups, including IGHV status. Compared with ibrutinib, zanubrutinib had a higher ORRIRC (86.2 vs 75.7%, nominal 2-sided P=.0007), with a rate of PR-L or better of 91.7% vs 83.1% (nominal 2-sided P=.001). Treatment discontinuation rate was lower with zanubrutinib (26.3%) vs ibrutinib (41.2%) with most due to AEs (16.2 vs 22.8%) or progressive disease (7.3 vs 12.9%); discontinuation rates due to cardiac disorders were 0.3% vs 4.3%. Rates of grade ≥3 AEs (67.3 vs 70.4%), serious AEs (42.0% vs 50.0%), dose interruption (50.0% vs 56.8%), and dose reduction (12.3 vs 17.0%) were also lower with zanubrutinib vs ibrutinib. Rate of atrial fibrillation/flutter was lower with zanubrutinib compared with ibrutinib (5.2% vs 13.3%); rates of other AEs of special interest were similar between treatments. There were no grade 5 AEs due to cardiac disorders with zanubrutinib vs 6 (1.9%) with ibrutinib. Overall, 48 (14.7%) pts treated with zanubrutinib and 60 (18.5%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.51-1.11]). Conclusions: As ALPINE is the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors, zanubrutinib has now proven superiority to ibrutinib in both ORR and PFS in pts with R/R CLL/SLL. Efficacy benefits with zanubrutinib were observed across all major subgroups, including high-risk pts. Zanubrutinib had a favorable safety profile compared with ibrutinib, with a lower rate of treatment discontinuation and fewer cardiac disorder events, including fewer cardiac events leading to death. These data suggest zanubrutinib is more efficacious and better tolerated than ibrutinib as treatment for R/R CLL/SLL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Analysis of Intrinsic Breast Cancer Subtypes: The Clinical Utility of Epigenetic Biomarkers and TP53 Mutation Status in Triple-Negative Cases

This study aimed at analyzing the DNA methylation pattern and TP53 mutation status of intrinsic breast cancer (BC) subtypes for improved characterization and survival prediction. DNA methylation of 17 genes was tested by methylation-specific PCR in 116 non-familial BRCA mutation-negative BC and 29 control noncancerous cases. At least one gene methylation was detected in all BC specimens and a 10-gene panel statistically significantly separated tumors from noncancerous breast tissues. Methylation of FILIP1L and MT1E was predominant in triple-negative (TN) BC, while other BC subtypes were characterized by RASSF1, PRKCB, MT1G, APC, and RUNX3 hypermethylation. TP53 mutation (TP53-mut) was found in 38% of sequenced samples and mainly affected TN BC cases (87%). Cox analysis revealed that TN status, age at diagnosis, and RUNX3 methylation are independent prognostic factors for overall survival (OS) in BC. The combinations of methylated biomarkers, RUNX3 with MT1E or FILIP1L, were also predictive for shorter OS, whereas methylated FILIP1L was predictive of a poor outcome in the TP53-mut subgroup. Therefore, DNA methylation patterns of specific genes significantly separate BC from noncancerous breast tissues and distinguishes TN cases from non-TN BC, whereas the combination of two-to-three epigenetic biomarkers can be an informative tool for BC outcome predictions.

P53 immunostaining pattern is a useful surrogate marker for TP53 gene mutations

BackgroundTP53 is the most frequently mutated gene in the human cancer, and the awareness of its mutational status is useful in the diagnosis and treatment of cancer patients. In the present study, we investigated the association between TP53 gene mutations and p53 immunohistochemical staining (IHC) patterns and non-genetic effect of MDM2 as a negative regulator of p53. MethodsA total of 135 solid cancer cases with next generation sequencing data were subjected to p53 IHC and classified as overexpression, null type or usual pattern. ResultsTP53 mutation was observed in 104 out of 135 cases (77.0%). When the TP53 mutations were annotated into DISRUPTED (truncations, frameshifts, splice site mutations, and deep deletions) and IF-DBD (in-frame mutations in the DNA binding domain), the null type p53 IHC pattern was associated with DISRUPTED mutations (sensitivity 86.2%, specificity 97.2%) while the overexpression pattern was associated with IF-DBD mutations (sensitivity 100%, specificity 81.7%). The specificity of p53 IHC usual pattern predicting wild type TP53 was also as high as 100%. Regardless of MDM2 amplification, p53 IHC pattern showed a perfect association with TP53 mutation pattern. Conclusionsp53 IHC pattern (overexpression, null type, usual) reasonably predicted TP53 mutational status (DISRUPTED, IF-DBD), and MDM2 amplification status did not have any impact on the p53 IHC pattern.

Integrative characterization of intraductal tubulopapillary neoplasm (ITPN) of the pancreas and associated invasive adenocarcinoma

Pancreatic intraductal tubulopapillary neoplasm (ITPN) is a recently recognized intraductal neoplasm. This study aimed to clarify the clinicopathologic and molecular features of this entity, based on a multi-institutional cohort of 16 pancreatic ITPNs and associated adenocarcinomas. The genomic profiles were analyzed using histology-driven multi-regional sequencing to provide insight on tumor heterogeneity and evolution. Furthermore, an exploratory transcriptomic characterization was performed on eight invasive adenocarcinomas. The clinicopathologic parameters and molecular alterations were further analyzed based on survival indices. The main findings were as follows: 1) the concomitant adenocarcinomas, present in 75% of cases, were always molecularly associated with the intraductal components. These data definitively establish ITPN as origin of invasive pancreatic adenocarcinoma; 2) alterations restricted to infiltrative components included mutations in chromatin remodeling genes ARID2, ASXL1, and PBRM1, and ERBB2-P3H4 fusion; 3) pancreatic ITPN can arise in the context of genetic syndromes, such as BRCA-germline and Peutz–Jeghers syndrome; 4) mutational profile: mutations in the classical PDAC drivers are present, but less frequently, in pancreatic ITPN; 5) novel genomic alterations were observed, including amplification of the Cyclin and NOTCH family genes and ERBB2, fusions involving RET and ERBB2, and RB1 disruptive variation; 6) chromosomal alterations: the most common was 1q gain (75% of cases); 7) by transcriptome analysis, ITPN-associated adenocarcinomas clustered into three subtypes that correlate with the activation of signaling mechanism pathways and tumor microenvironment, displaying squamous features in their majority; and 8) TP53 mutational status is a marker for adverse prognosis. ITPNs are precursor lesions of pancreatic cancer with a high malignant transformation risk. A personalized approach for patients with ITPN should recognize that such neoplasms could arise in the context of genetic syndromes. BRCA alterations, ERBB2 and RET fusions, and ERBB2 amplification are novel targets in precision oncology. The TP53 mutation status can be used as a prognostic biomarker.

TYK2 correlates with immune infiltration: A prognostic marker for head and neck squamous cell carcinoma.

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in immune and inflammatory signaling. TYK2 is overexpressed in several types of cancers and promotes the invasion and proliferation of cancer cells. Nevertheless, the roles of TYK2 in the prognosis and immune infiltration of head and neck squamous cell carcinoma (HNSCC) remain to be elucidated. In this study, the expression of TYK2 in HNSCC was evaluated based on the data retrieved from multiple databases and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The prognostic potential of TYK2 in patients with HNSCC was analyzed by Kaplan-Meier curves and Cox regression analysis. A TYK2-related risk assessment model was subsequently constructed by Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis and stepwise multivariate Cox regression analysis. The association between the expression of TYK2 and the tumor immune microenvironment, immune checkpoints, and drug sensitivity was explored various packages in R. Cell function assays were finally used for exploring the effects of TYK2 on the growth and metastasis of HNSCC tumors. The expression of TYK2 was significantly upregulated in HNSCC and was found to be closely correlated with HPV status, gender, clinical grade, and TP53 mutation status. Survival analysis suggested that TYK2 is associated with better survival outcomes and acts as an independent prognostic indicator of HNSCC. The model constructed herein also performed well in terms of predicting patient prognosis. The expression of TYK2 was positively associated with the population of tumor-infiltrating immune cells, expression of immune checkpoint genes, and antitumor drug susceptibility. Functionally, TYK2 knockdown significantly promoted the proliferation, migration, and invasion of HNSCC cell lines in vitro. The findings demonstrated that TYK2 could serve as a suppressor of tumor growth and holds significant promise as a novel biomarker for assessing the prognosis of patients with HNSCC and aid in immunotherapy against HNSCC.

Value of p53 sequencing in the prognostication of head and neck cancer: a systematic review and meta-analysis

This review aimed to examine the relationship between TP53 mutational status, as determined by genomic sequencing, and survival in squamous cell carcinoma of the head and neck. The databases Medline, Embase, Web of Science (core collection), Scopus and Cochrane Library were searched from inception to April 2021 for studies assessing P53 status and survival. Qualitative analysis was carried out using the REMARK criteria. A meta-analyses was performed and statistical analysis was carried out to test the stability and reliability of results. Twenty-five studies met the inclusion criteria, of which fifteen provided enough data for quantitative evaluation. TP53 mutation was associated with worse overall survival (HR 1.75 [95% CI 1.45–2.10], p < 0.001), disease-specific survival (HR 4.23 [95% CI 1.19–15.06], p = 0.03), and disease-free survival (HR 1.80 [95% CI 1.28–2.53], p < 0.001). Qualitative assessment identified room for improvement and the pooled analysis of all anatomical subsites leads to heterogeneity that may erode the validity of the observed overall effect and its subsequent extrapolation and application to individual patients. Our systematic review and meta-analysis supports the utility of TP53 mutational as a prognostic factor for survival in head and neck squamous cell carcinoma. A well designed prospective, multi-centre trial is needed to definitively answer this question.

Abstract A003: Clinico-molecular real world data demonstrates prognostic significance of a three-gene biomarker for colorectal liver oligometastases

Abstract Background: Colorectal liver oligometastases (CLO) represents a subset of metastatic colorectal cancer (mCRC) patients who may be eligible to undergo curative intent resection which can improve survival. However, given the heterogeneity of this population, prognostic stratification of CLO patients is poorly understood, with a highly variable 5 year survival rate of 25-58%. A three-gene prognostic biomarker based on pathogenic mutations in RAS (KRAS or NRAS), SMAD4, and TP53 was previously described. Here, we validate the prognostication of this three-gene biomarker in a CLO real world data (RWD) cohort. Methods: We leveraged clinico-molecular real world data to develop a retrospective, de-identified cohort of CLO patients for the assessment and development of prognostic biomarkers. Inclusion criteria include curative intent liver resections with negative or unknown surgical margins, tumor samples collected from the colon or liver, metastasis to only the liver at time of sample collection, and minimum 30 days follow up following resection. All samples were profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500x coverage). Real-world time to progression (rwTTP) was used to assess the prognostic value of the three-gene biomarker using a Cox proportional hazard model, treating gene mutations as both a continuous variable (the total number of genes mutated 0-3) and as categorical variables, while also controlling for neoadjuvant therapy, adjuvant therapy, and metachronous vs. synchronous colorectal cancer. Results: We identified 276 patients that met the inclusion criteria for this study. Of these patients, 27 had three genes with mutations, 85 with two, 155 with one, and 9 with zero mutations. The three-gene biomarker represented as a continuous variable had a rwTTP hazard ratio (HR) of 1.42 (95% confidence interval 1.15-1.77, p=0.001). Comparing three mutations to zero mutations resulted in a HR of 10.60 (95% CI 2.2-50.8, p=0.003, n=36), HR=2.55 (95% CI 1.54-4.22, p=0.0003, n=182) compared to one mutation, and HR=2.47 (95% CI 1.44-4.22, p=0.001, n=112) compared to two mutations. Median rwTTP for patients with mutations in all three genes was 3.7 months compared to 31.0 months for patients with zero mutations from the three-gene biomarker, and 10.0 months for all patients in the cohort. Conclusions: A novel clinico-molecular RWD cohort allowed independent rwTTP validation of a three-gene biomarker in the CLO setting. Although future prospective studies are warranted, the significance of the three-gene biomarker as a prognostic factor suggests that mutation status of RAS, SMAD4, and TP53 may be helpful to guide treatment decisions surrounding curative surgery. Citation Format: Alia Zander, Caroline Epstein, Kabir Manghnani, Ben Terdich, Sun Hae Hong, Justin Guinney, Halla Nimeiri, Martin Stumpe, Timothy Taxter, Kyle A. Beauchamp. Clinico-molecular real world data demonstrates prognostic significance of a three-gene biomarker for colorectal liver oligometastases [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A003.

PIK3CA somatic mutations as potential biomarker for immunotherapy in elder or TP53 mutated gastric cancer patients.

Immune checkpoint inhibitors (ICIs) improve overall survival in patients with advanced gastric cancer (GC). However, the molecular characterization of GC in ICIs responders is unclear. A total of 288 advanced GC patients were included in this study. Next-generation sequencing analysis was performed on tumor tissue and paired blood to screen for somatic mutants in 639 tumor-associated genes. We demonstrated that ARID1A, HER2/3/4, KMT2C/2D, LRP1B, PIK3CA, SPTA1, and TP53 mutations were significantly correlated with high tumor mutation burden (TMB) score, as well as HER2 amplification. For HER2 and PIK3CA mutations types, this relationship was statistically significant with age and TP53 mutation status, which was also found in the CDH1 gene. These results were confirmed by sequencing 873 GC cases in the cBioPortal database. PIK3CA mutations appear to be associated with longer survival in elderly population and TP53 mutant subtypes. For the first time, we found that GC patients ≥60 years old or with TP53 mutated type and PIK3CA mutations were associated with higher TMB and better ICI response. Building upon the age and TP53 mutation status, this study suggested a novel stratification approach to GC patients and explored the correlations between genetic somatic mutations and TMB score.

Prognostic value of KRAS mutations, TP53 mutations and PD-L1 expression among lung adenocarcinomas treated with immunotherapy

AimsThe aim of this study was to investigate the association between oncogenic alterations and programmed cell death ligand 1 (PD-L1) expression in lung adenocarcinomas, as well as the prognostic value...