TP53 mutations in urothelial carcinoma: not all one and the same†.

Systemic therapy options for urothelial carcinoma have expanded in recent years, with both immunotherapy and cytotoxic chemotherapy being widely available. However, we lack biomarkers to select which drug is likely to work best in individual patients. A new article in this journal by Jin, Xu, Su, et al reports that disruptive versus non-disruptive TP53 mutations may guide these personalised therapy choices. Intriguingly, patients with disruptive TP53 tumour mutations had poor overall survival versus those with non-disruptive TP53 mutations or wild type TP53 but responded particularly well to immunotherapy. Of relevance, an increased tumour mutational burden and increased effector CD8+ T-cell infiltration was seen in tumours with disruptive mutations. The impact of different TP53 mutations on prognosis and therapy choices appears to be tumour- and therapy-type specific, with no clear consensus on overall tumour phenotype according to type of mutation. Nonetheless, profiling of specific types of TP53 mutation is increasingly clinically feasible with targeted sequencing or immunohistochemistry. There is an urgent need for additional studies in urothelial cancer clarifying how the type of TP53 mutation present within a tumour can best be used as a predictive biomarker. Further important remaining questions include the impact of TP53 mutations on other clinically important aspects of the tumour microenvironment, including cancer-associated fibroblasts. Furthermore, the impact of gain-of-function mutations in TP53 and other related genes signalling upstream or downstream of TP53 is of wide interest. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway.

TP53 is the most frequently mutated gene in human cancer. This gene shows not only loss-of-function mutations but also recurrent missense mutations with gain-of-function activity. We have studied the primary bone malignancy osteosarcoma, which harbours one of the most rearranged genomes of all cancers. This is odd since it primarily affects children and adolescents who have not lived the long life thought necessary to accumulate massive numbers of mutations. In osteosarcoma, TP53 is often disrupted by structural variants. Here, we show through combined whole-genome and transcriptome analyses of 148 osteosarcomas that TP53 structural variants commonly result in loss of coding parts of the gene while simultaneously preserving and relocating the promoter region. The transferred TP53 promoter region is fused to genes previously implicated in cancer development. Paradoxically, these erroneously upregulated genes are significantly associated with the TP53 signalling pathway itself. This suggests that while the classical tumour suppressor activities of TP53 are lost, certain parts of the TP53 signalling pathway that are necessary for cancer cell survival and proliferation are retained. In line with this, our data suggest that transposition of the TP53 promoter is an early event that allows for a new normal state of genome-wide rearrangements in osteosarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

p53 protein expression patterns associated with TP53 mutations in breast carcinoma.

PURPOSE: The importance of a TP53 mutation has been demonstrated in several tumor types, including breast cancer (BC). However, the accuracy of p53 protein expression as a predictor of gene mutation has not been well studied in BC. Therefore, we evaluated p53 protein expression associated with TP53 mutations in breast cancers from 64 patients. METHODS: TP53 mutation was examined using next-generation sequencing (NGS). p53 protein expression was examined using immunohistochemistry (IHC). RESULTS: Among the 64 BCs, 55% demonstrated abnormal expression patterns including 27% overexpression, 22% null, 6% equivocal with 45% having a wild-type pattern. A TP53 mutation was present in 53% (34/64) of tumors including 30% (19/64) demonstrating a missense mutation, 11% (7/64) with a frameshift mutation, 11% (7/64) with a nonsense mutation, and 3% (1/64) with a splice site mutation. Abnormal expression of p53 protein was present in 33 of 34 (97%) tumors carrying a TP53 mutation; conversely, a wild-type pattern was present in 28 of 30 (93%) tumors without a detectable mutation (p < 0.0001). The majority of BCs with a p53 IHC overexpression pattern (15/17, 88%) contained a missense TP53 mutation; while the majority of BCs with a null pattern (12/14, 86%) contained a truncating mutation (p < 0.0001). The BCs with a null pattern are associated with a high Nottingham histological grade and a triple-negative phenotype when compared to those demonstrating overexpression (p < 0.05). CONCLUSION: These findings suggest that p53 IHC can be a potential surrogate for TP53 mutations in BC. Different p53 expression patterns may correlate with specific TP53 genetic mutations in BC.

Pedigree analysis exploring the inconsistency between diverse phenotypes and testing criteria for germline TP53 mutations in Chinese women with breast cancer.

PURPOSE: In the present study, we addressed the inconsistency between the testing criteria and diverse phenotypes for germline TP53 mutation in patients with breast cancer in the Chinese population. METHOD: We proposed a new added item (synchronous or metachronous bilateral breast cancer) as one of the testing criteria (aimed at high-penetrance breast cancer susceptibility genes) and applied it for determining TP53 germline mutation status in 420 female patients with breast cancer using multigene panel-based next-generation sequencing, Sanger sequencing, and mass spectrometry. RESULTS: We found that 1.4% of patients carried a pathogenic or likely pathogenic germline TP53 mutation. Compared with BRCA mutation carriers (8.0%) and non-carriers (7.1%), TP53 mutation carriers (33.3%) developed breast cancer earlier. The majority of TP53 mutation carriers (66.7%) developed breast cancer after age 30 and had bilateral breast cancer (33.3%). Pedigree investigation of four TP53 carriers and a patient with a TP53 variant of unknown significance revealed that neither of their parents harbored the same mutations as the probands, indicating that the mutations might occur de novo. CONCLUSION: Our study revealed distinguishing features of TP53 carriers among Chinese women with breast cancer, which is inconsistent with the currently used testing criteria; therefore, the newly proposed testing criteria may be more appropriate.

A Gradual Transition Toward Anaplasia in Wilms Tumor Through Tolerance to Genetic Damage.

Patients with Wilms tumor (WT) in general have excellent survival, but the prognosis of patients belonging to the subgroup of WT with diffuse anaplasia (DA) is poor due to frequent resistance to chemotherapy. We hypothesized that DA WT cells might undergo changes, such as acquiring a persistent tolerance to DNA damage and copy number aberrations (CNAs), which could eventually lead to their resistance to chemotherapy treatment. Tissue sections from chemotherapy-treated DA WTs (n = 12) were compared with chemotherapy-treated nonanaplastic WTs (n = 15) in a tissue microarray system, enabling analysis of 769 tumor regions. All regions were scored for anaplastic features and immunohistochemistry was used to quantify p53 expression, proliferation index (Ki67), and DNA double-strand breaks (γH2AX). CNAs were assessed by array-based genotyping and TP53 mutations using targeted sequencing. Proliferation index and the frequency of DNA double-strand breaks (γH2AX dot expression) increased with higher anaplasia scores. Almost all (95.6%) areas with full-scale anaplasia had TP53 mutations or loss of heterozygosity, along with an increased amount of CNAs. Interestingly, areas with wild-type TP53 with loss of heterozygosity and only one feature of anaplasia (anaplasia score 1) also had significantly higher proliferation indices, more DNA double-strand breaks, and more CNAs than regions without any anaplastic features (score 0); such areas may be preanaplastic cell populations under selective pressure for TP53 mutations. In conclusion, we suggest that chemoresistance of DA WTs may be partly explained by a high proliferative capability of anaplastic cells, which also have a high burden of double-stranded DNA breaks and CNAs, and that there is a gradual emergence of anaplasia in WT.

Exploring p53 protein expression and its link to TP53 mutation in myelodysplasia-related malignancies-Interpretive challenges and potential field of applications.

AIMS: TP53 alterations have a significant prognostic effect in myeloid neoplasms. Our objective was to investigate the TP53 gene mutation status, p53 protein expression and their relationship in dysplasia-related myeloid neoplasms with varying levels of myeloblast counts. METHODS AND RESULTS: A total of 76 bone marrow biopsy samples with different blast counts were analysed. Total and strong (3+) p53 expression was determined. Dual immunohistochemical staining was performed to determine the cell population associated with p53 expression. NGS analysis was performed using the Accel-Amplicon Comprehensive TP53 panel. Both p53 expression and TP53 VAF showed a significant correlation with the myeloblast ratio (P < 0.0001); however, p53 expression was also present in other cell lineages. The VAF value exhibited a significant correlation with p53 expression. A high specificity (0.9800) was observed for TP53 mutation using the ≥ 10% strong (3+) p53 cut-off value, although the sensitivity (0.4231) was low. CONCLUSIONS: Strong (3+) p53 expression using a ≥ 10% cut-off value accurately predicts TP53 mutation but does not reveal the allelic state. The p53 expression is significantly influenced by myeloblast count, and histological interpretation should consider the presence of intermixed non-neoplastic marrow cells with varying physiological p53 expression.

Hematologic malignancies in Li-Fraumeni syndrome: A case report.

Li-Fraumeni syndrome (LFS) is a rare syndrome characterized by an increased lifetime risk of cancer development in multiple organ systems, typically caused by de novo or inherited germline pathogenic variants in the tumor suppressor TP53 gene. LFS is more classically associated with solid tumors; however, it is also associated with hematologic malignancies such as therapy-related acute myeloid leukemia (AML). We present the case of a female patient with a strong family and personal history of cancer who presented to our institution with therapy-related AML with next-generation sequencing showing a pathogenic TP53 mutation. She received several lines of systemic therapy and underwent stem cell transplant using her adult daughter as a haploidentical donor after achieving minimal residual disease (MRD). Her posttransplant bone marrow evaluations demonstrated persistence of the same pathogenic TP53 mutation despite ongoing clinical remission with full donor engraftment and negative MRD. Genetic testing was performed which confirmed the germline origin of the TP53 pathogenic variant in the patient. The patient's adult donor daughter was also identified to have the same pathogenic variant in TP53 consistent with LFS. The presented case highlights the need for increased awareness of LFS in the adult hematologic community, particularly for patients undergoing evaluation for stem cell transplant.

Chromothripsis in myeloid malignancies.

Chromothripsis refers to massive genomic rearrangements developed during a catastrophic event. In total acute myeloid leukemia (AML), the incidence of chromothripsis ranges from 0 to 6.6%, in cases of complex karyotype AML, the incidence of chromothripsis ranges from 27.3 to 100%, whereas in cases of AML with TP53 mutations, the incidence ranges from 11.1 to 90%. For other types of malignancies, the incidence of chromothripsis also varies, from 0 to 10.5% in myelodysplastic syndrome to up to 61.5% in cases of myelodysplastic syndrome with TP53 mutations.Chromothripsis is typically associated with complex karyotypes and TP53 mutations, and monosomal karyotypes are associated with the condition. ERG amplifications are frequently noted in cases of chromothripsis, whereas MYC amplifications are not. Moreover, FLT3 and NPM1 mutations are negatively associated with chromothripsis. Chromothripsis typically occurs in older patients with AML with low leukocyte counts and bone marrow blast counts. Rare cases of patients with chromothripsis who received intensive induction chemotherapy revealed low response rates and poor overall prognosis. Signal pathways in chromothripsis typically involve copy number gain and upregulation of oncogene gene sets that promote cancer growth and a concomitant copy number loss and downregulation of gene sets associated with tumor suppression functions.Patients with chromothripsis showed a trend of lower complete remission rate and worse overall survival in myeloid malignancy. Large-scale studies are required to further elucidate the causes and treatments of the condition.

TP53-mutated acute myeloid leukemia and myelodysplastic syndrome: biology, treatment challenges, and upcoming approaches.

Improved understanding of TP53 biology and the clinicopathological features of TP53-mutated myeloid neoplasms has led to the recognition of TP53-mutated acute myeloid leukemia/myelodysplastic syndrome (TP53m AML/MDS) as a unique entity, characterized by dismal outcomes following conventional therapies. Several clinical trials have investigated combinations of emerging therapies for these patients with the poorest molecular prognosis among myeloid neoplasms. Although some emerging therapies have shown improvement in overall response rates, this has not translated into better overall survival, hence the notion that p53 remains an elusive target. New therapeutic strategies, including novel targeted therapies, immune checkpoint inhibitors, and monoclonal antibodies, represent a shift away from cytotoxic and hypomethylating-based therapies, towards approaches combining non-immune and novel immune therapeutic strategies. The triple combination of azacitidine and venetoclax with either magrolimab or eprenetapopt have demonstrated safety in early trials, with phase III trials currently underway, and promising interim clinical results. This review compiles background on TP53 biology, available and emerging therapies along with their mechanisms of action for the TP53m disease entity, current treatment challenges, and recently published data and status of ongoing clinical trials for TP53m AML/MDS.

TP53 mutations and the association with platinum resistance in high grade serous ovarian carcinoma.

OBJECTIVES: Alterations in the tumor suppressor TP53 gene are the most common mutations in high grade serous ovarian carcinoma. The impact of TP53 mutations on clinical outcomes and platinum resistance is controversial. We sought to evaluate the genomic profile of high grade serous ovarian carcinoma and explore the association of TP53 mutations with platinum resistance. METHODS: Next generation sequencing data was obtained from our institutional database for patients with high grade serous ovarian carcinoma undergoing primary treatment. Sequencing data, demographic, and clinical information was reviewed. The primary outcome analyzed was time to recurrence or refractory diagnosis. Associations between the primary outcome and different classification schemes for TP53 mutations (structural, functional, hot spot, pathogenicity scores, immunohistochemical staining patterns) were performed. RESULTS: 209 patients met inclusion criteria. TP53 mutations were the most common mutation. There were no differences in platinum response with TP53 hotspot mutations or high pathogenicity scores. Presence of TP53 gain-of-function mutations or measure of TP53 gain-of function activity were not associated with platinum resistance. Immunohistochemical staining patterns correlated with expected TP53 protein function and were not associated with platinum resistance. CONCLUSIONS: TP53 hotspot mutations or high pathogenicity scores were not associated with platinum resistance or refractory disease. Contrary to prior studies, TP53 gain-of-function mutations were not associated with platinum resistance. Estimation of TP53 gain-of-function effect using missense mutation phenotype scores was not associated with platinum resistance. The polymorphic nature of TP53 mutations may be too complex to demonstrate effect using simple models, or response to platinum therapy may be independent of initiating TP53 mutation.

Transplant versus no transplant in myelodysplastic syndrome and acute myeloid leukemia with TP53 mutation; a referral center experience.

A remarkably high rate of post-transplant relapse in patients with TP53-mutated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) calls to question the utility of allogeneic stem cell transplant (HSCT). We, therefore, performed a retrospective analysis to compare the outcomes between HSCT (N = 38) versus non-HSCT (N = 45) approaches. Patients in the HSCT cohort were younger (median age 63 vs. 72) while patients in the non-HSCT cohort more commonly had complex karyotype with chromosome 17 aberrancy and 5q deletion (p < .01). A total of 69 TP53 variants including 64 pathogenic variants, and 5 variants of undetermined significance were detected. Nine patients (4 in HSCT and 5 in non-HSCT) had multi-hit TP53 variants. After induction: 57.9% versus 56.6% in the HSCT versus non-HSCT cohort achieved morphologic complete remission. Median time to HSCT was 6 months and median follow-up was 15.1 months for HSCT and 5.7 months for non-HSCT. Median disease-free survival (DFS) and overall survival (OS) were 11.7 and 15.9 months for HSCT, and 4.1 and 5.7 months for non-HSCT cohorts, respectively. Non-relapse mortality at 12 months was 22% versus 44% for HSCT versus non-HSCT. In the HSCT cohort, the rate of grade II-IV acute and chronic graft-versus-host disease (GVHD) was 55% and 18%, respectively. None of the patients from the non-HSCT cohort were alive while four patients from the HSCT cohort were alive, in remission, and without GVHD (GRFS) at the time of abstraction. Better treatment strategies for patients with TP53-mutated MDS/AML remain an area of unmet clinical need.

Myelodysplastic syndromes del(5q): Pathogenesis and its therapeutic implications.

Myelodysplastic syndromes (MDS) encompass a heterogeneous set of acquired bone marrow neoplastic disorders characterized by ineffective hematopoiesis within one or more bone marrow lineages. Nearly half of MDS patients carry cytogenetic alterations, with del(5q) being the most prevalent. Since its first description, del(5q) was consistently correlated with a typical clinical phenotype marked by anemia, thrombocytosis, and a low risk of evolving into acute leukemia. Presently, the World Health Organization (WHO) classification of myeloid neoplasms recognizes a specific subtype of MDS known as "myelodysplastic neoplasm with low blast and isolated del(5q)" identified by the sole presence of 5q deletion or in combination with one other abnormality excluding -7/del(7q). Several studies have sought to unravel the biological processes triggered by del(5q) in the development of MDS, revealing the involvement of various genes localized in specific regions of chromosome 5 referred to as common deleted regions (CDR). This intricate biological landscape makes the MDS cells with del(5q) exceptionally sensitive to lenalidomide. Several studies have confirmed the efficacy of lenalidomide in this context. Regrettably, the response to lenalidomide is not conclusive, prompting ongoing research into biological mechanisms that drive patients toward leukemia and strategies to circumvent lenalidomide resistance and disease progression.

TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Current Guidelines, Therapies, and Future Considerations.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by uncontrolled proliferation and impaired differentiation of myeloid cells in the bone marrow. The tumor suppressor gene TP53 plays a crucial role in maintaining genomic integrity and preventing the development of cancer. TP53 mutations are frequently observed in AML (∼10% of patients) and are associated with aggressive disease behavior, resistance to therapy, and poor prognosis. SUMMARY: Recent changes in classification of TP53-mutated myelodysplastic syndrome (MDS) have occurred related to the allelic status of TP53 and more importantly to harmonize MDS/AML patients as a homogeneous hematological malignancy. Current treatment regimens involve hypomethylating agents +/- venetoclax or intensive chemotherapy although unfortunately independent of treatment regimen the overall survival (OS) of this patient cohort is around 6 months with poor long-term outcomes after allogeneic stem-cell transplantation. Recent developments geared toward the treatment of TP53-mutated MDS/AML have focused on immunotherapies. KEY MESSAGES: Notably, there is optimism surrounding these new therapies that could provide breakthroughs with improving outcomes either as monotherapy or combined with established nonimmune therapies. This paper aims to provide an overview of TP53-mutated MDS/AML, including the underlying mechanisms, clinical implications, and emerging therapeutic strategies targeting this hematologic malignancy.

Tertiary Lymphoid Structures Gene Signature Predicts Prognosis and Immune Infiltration Analysis in Head and Neck Squamous Cell Carcinoma.

Objectives: This study aims to assess the prognostic implications of gene signature of the tertiary lymphoid structures (TLSs) in head and neck squamous cell carcinoma (HNSCC) and scrutinize the influence of TLS on immune infiltration. Methods: Patients with HNSCC from the Cancer Genome Atlas were categorized into high/low TLS signature groups based on the predetermined TLS signature threshold. The association of the TLS signature with the immune microenvironment, driver gene mutation status, and tumor mutational load was systematically analyzed. Validation was conducted using independent datasets (GSE41613 and GSE102349). Results: Patients with a high TLS signature score exhibited better prognosis compared to those with a low TLS signature score. The group with a high TLS signature score had significantly higher immune cell subpopulations compared to the group with a low TLS signature score. Moreover, the major immune cell subpopulations and immune circulation characteristics in the tumor immune microenvironment were positively correlated with the TLS signature. Mutational differences in driver genes were observed between the TLS signature high/low groups, primarily in the cell cycle and NRF2 signaling pathways. Patients with TP53 mutations and high TLS signature scores demonstrated a better prognosis compared to those with TP53 wild-type. In the independent cohort, the relationship between TLS signatures and patient prognosis and immune infiltration was also confirmed. Additionally, immune-related biological processes and signaling pathways were activated with elevated TLS signature. Conclusion: High TLS signature is a promising independent prognostic factor for HNSCC patients. Immunological analysis indicated a correlation between TLS and immune cell infiltration in HNSCC. These findings provide a theoretical basis for future applications of TLS signature in HNSCC prognosis and immunotherapy.

Integrated Bioinformatic Analysis Reveals the Oncogenic, Survival, and Prognostic Characteristics of TPX2 in Hepatocellular Carcinoma.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a well-known mitotic protein, has been linked to carcinogenesis in several cancers. This study investigated the role of TPX2 in hepatocellular carcinoma (HCC) from various aspects using bioinformatic analyses. TPX2 expression and its prognostic value in pan-cancers were analyzed using SangerBox. TPX2 expression and its association with prognosis, immune infiltration, tumor mutations, and signaling pathways in HCC were analyzed using UALCAN, BoxKaplan-Meier Plotter, GEPIA, Human Protein Atlas, TIMER 2.0, and SangerBox. Genes co-expressed with TPX2 in HCC were analyzed using the HCCDB database, followed by functional enrichment using SangerBox. Clinical predictive models were established based on TPX2 and its co-expressed genes using the ACLBI database. TPX2 expression significantly increased in pan-cancers and was associated with survival in nearly half of the cancer types. High TPX2 expression has been linked to poor survival outcomes in patients with HCC. TPX2 expression was positively correlated with abundant infiltration of immune cells (including B cells, CD4 + /CD8 + T cells, macrophages, neutrophils, and dendritic cells), TP53 mutation, and carcinogenesis-related pathways, such as the PI3K/AKT/mTOR pathway, cellular response to hypoxia, and tumor proliferation signature. Nineteen genes were found to be co-expressed with TPX2 in HCC, and these genes showed close positive correlations and were mainly implicated in cell cycle-related functions. A prognostic model established using TPX2 and its expressed genes could stratify HCC patients into high- and low-risk groups, with a significantly shorter survival time in high-risk groups. The prognostic model performed well in predicting 1-, 3-, and 5-year survival of patients with HCC, with areas under the curve of 0.801, 0.725, and 0.711, respectively. TPX2 functions as an oncogene in HCC, and its high expression is detrimental to the survival of patients with HCC. Thus, TPX2 may be a prognostic biomarker and potential therapeutic target for HCC.

Enhancing Therapeutic Approaches in Glioblastoma with Pro-Oxidant Treatments and Synergistic Combinations: In Vitro Experience of Doxorubicin and Photodynamic Therapy.

Glioblastoma (GBM) is an aggressive brain cancer characterized by significant molecular and cellular heterogeneity, which complicates treatment efforts. Current standard therapies, including surgical resection, radiation, and temozolomide (TMZ) chemotherapy, often fail to achieve long-term remission due to tumor recurrence and resistance. A pro-oxidant environment is involved in glioma progression, with oxidative stress contributing to the genetic instability that leads to gliomagenesis. Evaluating pro-oxidant therapies in brain tumors is crucial due to their potential to selectively target and eradicate cancer cells by exploiting the elevated oxidative stress levels inherent in these malignant cells, thereby offering a novel and effective strategy for overcoming resistance to conventional therapies. This study investigates the therapeutic potential of doxorubicin (DOX) and photodynamic therapy (PDT) with Me-ALA, focusing on their effects on redox homeostasis. Basal ROS levels and antioxidant gene expression (NFE2L2, CAT, GSR) were quantitatively assessed across GBM cell lines, revealing significant variability probably linked to genetic differences. DOX and PDT treatments, both individually and in combination, were analyzed for their efficacy in inducing oxidative stress and cytotoxicity. An in silico analysis further explored the relationship between gene mutations and oxidative stress in GBM patients, providing insights into the molecular mechanisms underlying treatment responses. Our findings suggest that pro-oxidant therapies, such as DOX and PDT in combination, could selectively target GBM cells, highlighting a promising avenue for improving therapeutic outcomes in GBM.

Acute Erythroid Leukemia Post-Chemo-Radiotherapy and Autologous Stem Cell Transplantation Due to Multiple Myeloma: Tracing the Paths to Leukemic Transformation.

The clinical impact of therapy-related acute leukemias is increasing with the extension of cancer-related survival; however, the origins remain largely unknown. Acute erythroleukemia (AEL), a rare unfavorable type of myeloid neoplasia, may also develop secondary to cytotoxic therapy. The disorder is featured by specific genetic alterations, most importantly multi-allelic mutations of the TP53 gene. While AEL might appear as a part of the therapy-related MDS/AML, spectrum information regarding the genetic complexity and progression is largely missing. We present two AEL cases arising after cytotoxic therapy and melphalan-based myeloablation/autologous peripheral stem cell transplantation due to multiple myeloma (MM). As stated, multiple pathogenic TP53 variants were present unrelated to preexisting MM, in parallel with uninvolved/wild-type hemopoiesis. Potential mechanisms of leukemic transformation are discussed, which include (1) preexisting preneoplastic hemopoietic stem cells (HSC) serving as the common origin for both MM and AEL, (2) the generation and intramedullary survival of p53-deficient post-chemotherapy HSCs, (3) reinoculation of mobilized autologous TP53 mutated HSCs, and (4) melphalan treatment-related late-onset myelodysplasia/leukemia with newly acquired TP53 mutations.

Breast cancer genomes from CHEK2 c.1100delC mutation carriers lack somatic TP53 mutations and display a unique structural variant size distribution profile.

BACKGROUND: CHEK2 c.1100delC was the first moderate-risk breast cancer (BC) susceptibility allele discovered. Despite several genomic, transcriptomic and functional studies, however, it is still unclear how exactly CHEK2 c.1100delC promotes tumorigenesis. Since the mutational landscape of a tumor reflects the processes that have operated on its development, the aim of this study was to uncover the somatic genomic landscape of CHEK2-associated BC. METHODS: We sequenced primary BC (pBC) and normal genomes of 20 CHEK2 c.1100delC mutation carriers as well as their pBC transcriptomes. Including pre-existing cohorts, we exhaustively compared CHEK2 pBC genomes to those from BRCA1/2 mutation carriers, those that displayed homologous recombination deficiency (HRD) and ER- and ER+ pBCs, totaling to 574 pBC genomes. Findings were validated in 517 metastatic BC genomes subdivided into the same subgroups. Transcriptome data from 168 ER+ pBCs were used to derive a TP53-mutant gene expression signature and perform cluster analysis with CHEK2 BC transcriptomes. Finally, clinical outcome of CHEK2 c.1100delC carriers was compared with BC patients displaying somatic TP53 mutations in two well-described retrospective cohorts totaling to 942 independent pBC cases. RESULTS: BC genomes from CHEK2 mutation carriers were most similar to ER+ BC genomes and least similar to those of BRCA1/2 mutation carriers in terms of tumor mutational burden as well as mutational signatures. Moreover, CHEK2 BC genomes did not show any evidence of HRD. Somatic TP53 mutation frequency and the size distribution of structural variants (SVs), however, were different compared to ER+ BC. Interestingly, BC genomes with bi-allelic CHEK2 inactivation lacked somatic TP53 mutations and transcriptomic analysis indicated a shared biology with TP53 mutant BC. Moreover, CHEK2 BC genomes had an increased frequency of > 1 Mb deletions, inversions and tandem duplications with peaks at specific sizes. The high chromothripsis frequency among CHEK2 BC genomes appeared, however, not associated with this unique SV size distribution profile. CONCLUSIONS: CHEK2 BC genomes are most similar to ER+ BC genomes, but display unique features that may further unravel CHEK2-driven tumorigenesis. Increased insight into this mechanism could explain the shorter survival of CHEK2 mutation carriers that is likely driven by intrinsic tumor aggressiveness rather than endocrine resistance.

Mutation of the TP53 gene in acute lymphoblastic leukemia does not affect survival outcomes after haploidentical hematopoietic stem cell transplantation.

Previous studies have demonstrated that TP53 mutation is correlated with insufficient therapy response and unfavorable prognosis in acute lymphoblastic leukemia (ALL). Few studies have investigated the impact of TP53 mutation in ALL patients after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We completed a retrospective study of 65 ALL patients with available TP53 status who underwent haplo-HSCT. They were divided into a TP53 mutation group (TP53mut ) and a TP53 wild-type (TP53wt ) group. TP53mut showed comparable 2-year cumulative incidence of relapse (CIR) rates (13.1% vs 12.5%, P = .96) and 2-year leukemia-free survival (LFS) (74.2% vs 77.4%, P = .80) with TP53wt . No significant differences in 2-year overall survival (OS) rates (82.9% vs 87.3%, P = .61) or 2-year NRM rates (12.7% vs 10.2%, P = .69) were observed in TP53mut and TP53wt patients. Multivariate analysis suggested that white blood cell (WBC) count at initial diagnosis (>50 × 109 /L: hazard ratio [HR] = 3.860, P = .016) and age (>40 years old: HR = 4.120, P = .012) are independent risk factors for 2-year LFS. Our study showed that TP53 mutations may not be related to the unfavorable impact on survival in ALL patients after treatment with haplo-HSCT. The present results suggested that haplo-HSCT may eliminate the poor prognosis effect of TP53 mutation in ALL.

Disparities in receiving disease-directed therapy, allogeneic stem cell transplantation in non-Hispanic Black patients with TP53-mutated acute myeloid leukemia.

BACKGROUND: Although the clinical outcomes of patients with TP53-mutated acute myeloid leukemia (AML) are dismal, subsets of patients eligible for curative-intent therapies may fare better. Because racial disparities are known to affect outcome in hematologic malignancies, the authors sought to explore disparities among patients with TP53-mutated AML. METHODS: A multicenter, retrospective study was conducted in a cohort of 340 patients who had TP53-mutated AML (275 non-Hispanic White [NHW] and 65 non-Hispanic Black [NHB]) to analyze differences in treatment and outcome among NHW and NHB patients. RESULTS: The median patient age was comparable between NHW and NHB patients (p = .76). A higher proportion of NHB patients had therapy-related AML (31% vs. 20%; p = .08) and had co-mutations (74% vs. 61%; p = .06). A higher proportion of NHW patients received intensive chemotherapy compared with NHB patients (47% vs. 31%; p = .02). Conversely, a higher proportion of NHB patients received low-intensity chemotherapy (9% vs. 5.5%; p = .02) or best supportive care (22% vs. 7%; p < .001). The complete response rate (including complete responses with or without complete count recovery) was 31% versus 24.5% (p = .39) in NHW and NHB patients, respectively. Only 5% of NHB patients received allogeneic stem cell transplantation compared with 15.5% of NHW patients (p = .02). The proportion of patients who were event-free (18.5% vs. 8.5%; p = .49) or who remained alive (24.9% vs. 8.3%; p = .13) at 18 months was numerically higher in NHW versus NHB patients, respectively, but was not statistically significant. CONCLUSIONS: The current study highlights disparities between NHW and NHB patients with TP53-mutated AML. Efforts are warranted to eliminate treatment disparities in minority populations.