Malignant melanoma in a 12-year-old boy 17 months after completing hepatoblastoma treatment.

BACKGROUND: Melanoma is rare as a secondary malignant neoplasm among childhood cancer survivors. CASE: We report a case of a 12-year-old boy who developed malignant melanoma with systemic metastases 17 months after completing treatment for hepatoblastoma. The diagnosis was made unexpectedly based on a bone marrow examination. The patient did not respond to immune checkpoint inhibitor therapy and died 6 weeks after being diagnosed with melanoma. Whole-exome sequencing to examine 103 genes associated with cancer predisposition did not identify any germ-line variants. CONCLUSION: This case study provides a unique example of melanoma in a childhood cancer survivor following hepatoblastoma treatment but does not identify any candidate variant to link hepatoblastoma and melanoma.

MicroRNAs as Prognostic Biomarkers and Therapeutic Targets in Chondrosarcoma.

Chondrosarcoma, the second most common primary malignant bone tumor, originates from cartilaginous tissue and accounts for almost 20% of all primary bone tumors. The management of chondrosarcoma remains challenging due to its diverse clinical course and prognosis, which can range from benign to highly aggressive with a huge risk of metastasis. Emerging research has demonstrated the importance of microRNA (miRNA) dysregulation in the pathogenesis of chondrosarcoma. MiRNAs are small, noncoding RNA molecules that play an essential role in gene expression regulation by targeting specific messenger RNAs (mRNAs) for degradation or translational repression. This article provides an extensive review of current miRNA research in chondrosarcoma, focusing on diagnostic strategies, cell cycle regulation, drug resistance, biomarkers of progression, and stem cell phenotype. We will examine recent studies identifying differentially expressed miRNAs in chondrosarcoma compared to normal cartilage tissue, exploring their potential as diagnostic and prognostic biomarkers. Furthermore, we will discuss the role of miRNAs in regulating cell cycle progression and their potential as therapeutic targets to overcome drug resistance. We will also investigate the prospective utility of miRNAs as biomarkers of progression and their role in modulating the stem cell phenotype of chondrosarcoma cells. This article offers a comprehensive analysis of current miRNA research in chondrosarcoma, focusing on its potential as diagnostic and prognostic biomarkers, therapeutic targets, and regulators of disease progression. By integrating the latest discoveries in this field, we aim to contribute to the development of novel approaches to the prevention, diagnosis, and treatment of chondrosarcoma, ultimately enhancing patient outcomes.

Clonal analysis of metachronous double biliary tract cancers.

The molecular mechanisms underpinning the development of metachronous tumors in the remnant bile duct following surgical resection of primary biliary tract carcinomas (BTCs) are unknown. This study aimed to elucidate these mechanisms by evaluating the clinicopathologic features of BTCs, the alterations to 31 BTC-related genes on targeted sequencing, and the aberrant expression of p53, p16, SMAD4, ARID1A and ß-catenin on immunohistochemistry. Twelve consecutive patients who underwent resection of metachronous BTCs following primary BTC resection with negative bile duct margins were enrolled. Among the 12 metachronous tumors, six exhibited anterograde growth in the lower portion and six exhibited retrograde growth in the upper portion of the biliary tree. Surgical resection of metachronous BTCs resulted in recurrence-free survival in seven, local recurrence in five, and death in two patients. Nine achieved 5-year overall survival after primary surgery. Molecular analyses revealed that recurrently altered genes were: TP53, SMAD4, CDKN2A, ELF3, ARID1A, GNAS, NF1, STK11, RNF43, KMT2D and ERBB3. Each of these was altered in at least three cases. A comparison of the molecular features between 12 paired primary and metachronous BTCs indicated that 10 (83%) metachronous tumors developed in clonal association with corresponding primary tumors either successionally or phylogenically. The remaining two (17%) developed distinctly. The successional tumors consisted of direct or evolved primary tumor clones that spread along the bile duct. The phylogenic tumors consisted of genetically unstable clones and conferred a poor prognosis. Metachronous tumors distinct from their primaries harbored fewer mutations than successional and phylogenic tumors. In conclusion, over 80% of metachronous BTCs that develop following primary BTC resection are probably molecularly associated with their primaries in either a successional or a phylogenetic manner. Comparison between the molecular features of a metachronous tumor and those of a preceding tumor may provide effective therapeutic clues for the treatment of metachronous BTC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

When the second comes first- rhabdomyosarcoma preceding heritable retinoblastoma- a case report.

BACKGROUND: Retinoblastoma (rb) is the most frequent intraocular tumor, accounting for 3% of all childhood cancers. Heritable rb survivors are germline carriers for an RB1 mutation and have a lifelong risk to develop non-ocular second primary tumors (SPTs) involving multiple other organs like the bones, soft tissues, or skin. These SPTs usually become manifest several years succeeding the diagnosis of rb. In our instance, however, a non-ocular SPT presented prior to the diagnosis of heritable rb. CASE PRESENTATION: We report a rare case of a monozygotic twin who presented with primary rhabdomyosarcoma (RMS) preceding the manifestation of heritable rb. The rb was diagnosed when the child developed strabismus while already on therapy for the RMS. The child underwent therapy for both as per defined treatment protocols. The rb regressed well on treatment, but the RMS relapsed and the child developed multiple refractory metastatic foci and succumbed to his disease. CONCLUSIONS: Non-ocular SPTs like sarcomas are usually known to manifest in heritable rb survivors with a lag of two to three decades (earlier if exposure to radiation is present) from the presentation of the rb. However, in our case, this seemed to be reversed with the RMS being manifest at an unusual early age and the rb being diagnosed at a later point in time.

Risk of second primary cancers after a diagnosis of first primary cancer: A pan-cancer analysis and Mendelian randomization study.

Background: The risk of second primary cancers (SPC) is increasing after the first primary cancers (FPC) are diagnosed and treated. The underlying causal relationship remains unclear. Methods: We conducted a pan-cancer association (26 cancers) study in the Surveillance, Epidemiology, and End Results (SEER) database (non-Hispanic whites). The standardized incidence ratio (SIR) was estimated as the risk of SPCs in cancer survivors based on the incidence in the general population. Furthermore, the causal effect was evaluated by two-sample Mendelian Randomization (MR, 13 FPCs) in the UK Biobank (UKB, n=459,136,, European whites) and robust analysis (radial MR and Causal Analysis Using Summary Effect estimates, CAUSE). Results: We found 11 significant cross-correlations among different cancers after harmonizing SIR and MR results. Whereas only 4 of them were confirmed by MR to have a robust causal relationship. In particular, patients initially diagnosed with oral pharyngeal cancer would have an increased risk of non-Hodgkin lymphoma (SIRSEER = 1.18, 95%Confidence Interval [CI]:1.05-1.31, ORradial-MR=1.21, 95% CI:1.13-1.30, p=6.00 × 10-3; ORcause = 1.17, 95% CI:1.05-1.31, p=8.90 × 10-3). Meanwhile, ovary cancer was identified to be a risk factor for soft tissue cancer (SIRSEER = 1.72, 95%Confidence Interval [CI]:1.08-2.60, ORradial-MR=1.39, 95% CI:1.22-1.58, p=1.07 × 10-3; ORcause = 1.36, 95% CI:1.16-1.58, p=0.01). And kidney cancer was likely to cause the development of lung cancer (SIRSEER = 1.28, 95%Confidence Interval [CI]:1.22-1.35, ORradial-MR=1.17, 95% CI:1.08-1.27, p=6.60 × 10-3; ORcause = 1.16, 95% CI:1.02-1.31, p=0.05) and myeloma (SIRSEER = 1.54, 95%Confidence Interval [CI]:1.33-1.78, ORradial-MR=1.72, 95% CI:1.21-2.45, p=0.02; ORcause = 1.49, 95% CI:1.04-2.34, p=0.02). Conclusions: A certain type of primary cancer may cause another second primary cancer, and the profound mechanisms need to be studied in the future. Funding: This work was in supported by grants from National Natural Science Foundation of China (Grant No. 81972645), Innovative research team of high-level local universities in Shanghai, Shanghai Youth Talent Support Program, intramural grant of The University of Hong Kong to Dr. Rong Na, and Shanghai Sailing Program (22YF1440500) to Dr. Da Huang.

Better cancer treatment and early detection have increased survival rates among patients with cancer. But some cancer survivors can develop a second cancer called a second primary cancer. Second primary cancers may occur months or years after successful treatment of the primary cancer. They are not caused by the spread of the original tumor like a cancer metastasis. Instead, they appear to occur independently in another location or tissue. Scientists are trying to understand what causes second primary cancers. Genetics, lifestyle, the environment, treatments used for the initial tumor, or other factors may all contribute to individuals developing a second cancer. Learning more about who is at risk of developing a second cancer and why, may lead to new prevention, treatment or screening strategies. Ruan, Huang et al. found that people with some primary cancers have an increased risk of secondary primary cancers in specific tissues. The researchers first looked at the Surveillance, Epidemiology, and End Results (SEER) database that tracks US cancer patients to see if different types of cancers were more likely to lead to a second primary cancer. Then, the team conducted a comprehensive analysis for a causal relationship in a second extensive health database, the UK Biobank, to determine if the primary cancers may have caused the second primary cancer. The study showed that patients diagnosed with mouth or throat cancers were at increased risk of later developing a lymph node cancer called non-Hodgkin lymphoma. Patients diagnosed with ovarian cancer were at increased risk of later developing cancer in one of the body's soft tissues. Kidney cancer is likely the cause of later lung cancers and a type of blood cancer called myeloma. Understanding the relationships between an initial and later cancer diagnosis is essential to improve cancer survivors' care. It is especially important for patients diagnosed early in life. More studies are needed to confirm the links Ruan, Huang et al. identified and to understand the mechanism. If more studies confirm the associations, physicians may want to screen survivors for specific cancers. Scientists may also be able to use the information to develop new strategies to help prevent or treat secondary primary cancers.

BRAF V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis.

In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.

A Phase I Trial of the Dual MET Kinase/OCT-2 Inhibitor OMO-1 in Metastatic Solid Malignancies Including MET Exon 14 Mutated Lung Cancer.

INTRODUCTION: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients' outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors. MATERIALS AND METHODS: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket). RESULTS: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response. CONCLUSION: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients.

High HSPB1 expression predicts poor clinical outcomes and correlates with breast cancer metastasis.

BACKGROUND: Heat shock protein beta-1 (HSPB1) is a crucial biomarker for pathological processes in various cancers. However, the clinical value and function of HSPB1 in breast cancer has not been extensively explored. Therefore, we adopted a systematic and comprehensive approach to investigate the correlation between HSPB1 expression and clinicopathological features of breast cancer, as well as determine its prognostic value. We also examined the effects of HSPB1 on cell proliferation, invasion, apoptosis, and metastasis. METHODS: We investigated the expression of HSPB1 in patients with breast cancer using The Cancer Genome Atlas and immunohistochemistry. Chi-squared test and Wilcoxon signed-rank test were used to examine the relationship between HSPB1 expression and clinicopathological characteristics. RESULTS: We observed that HSPB1 expression was significantly correlated with the stage N, pathologic stages, as well as estrogen and progesterone receptors. Furthermore, high HSPB1 expression resulted in a poor prognosis for overall survival, relapse-free survival, and distant metastasis-free survival. Multivariable analysis showed that patients with poor survival outcomes had higher tumor, node, metastasis, and pathologic stages. Pathway analysis of HSPB1 and the altered neighboring genes suggested that HSPB1 is involved in the epithelial-to-mesenchymal transition. Functional analysis revealed showed that transient knockdown of HSPB1 inhibited the cell migration/invasion ability and promoted apoptosis. CONCLUSIONS: HSPB1 may be involved in breast cancer metastasis. Collectively, our study demonstrated that HSPB1 has prognostic value for clinical outcomes and may serve as a therapeutic biomarker for breast cancer.

Evaluation of Second Primary Cancer Risk Among Chronic Lymphocytic Leukemia Patients: Multicenter Study.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) have an increased risk of developing second primary cancers (SPC). The aim of this study is to determine the frequency of SPC in CLL patients and determine the relationship between these cancers and their treatment status, cytogenetic factors, and other risk factors. METHODS: The study was designed as multicenter and retroprospective. The sample comprised 553 subjects with a CLL diagnosis. Data collection commenced in August 2016, and completed at May 2021. RESULTS: Fifty one of 553 patients followed for CLL, had a history of SPC. SPC development rate was 9.2%. Epithelial tumors were mostly observed. According to the incidence skin, lymphoma, renal, breast, lung, gastrointestinal system, thyroid, malignant melanoma, prostate, Kaposi's sarcoma, neuroendocrine tumor, ovarian, larynx and salivary gland cancers were detected respectively. The 13q deletion was the most common genetic abnormality in those who developed SPC, and the frequency of 13q deletion was found to be increased statistically significant in those with malignancy, compared to those who did not. CONCLUSION: In CLL patients with SPC, the age of diagnosis, 13q and CD38 positivity, and treatment rates with fludarabine and monoclonal antibodies were found to be higher. Also, we determined that SPC frequency increased independently from hemogram values (except hemoglobin values), ß2 microglobulin level on admission, number of treatment lines, and genetic mutations other than 13q, in CLL patients. In addition, the mortality rate was higher in CLL patients with SPC and they were prone to be in advanced stages at the time of diagnosis.

Prevalence of pathogenic variants in cancer-predisposing genes in second cancer after childhood solid cancers.

BACKGROUND: Second malignant neoplasms (SMNs) are one of the most severe late complications after pediatric cancer treatment. However, the effect of genetic variation on SMNs remains unclear. In this study, we revealed germline genetic factors that contribute to the development of SMNs after treatment of pediatric solid tumors. METHODS: We performed whole-exome sequencing in 14 pediatric patients with SMNs, including three brain tumors. RESULTS: Our analysis revealed that five of 14 (35.7%) patients had pathogenic germline variants in cancer-predisposing genes (CPGs), which was significantly higher than in the control cohort (p < 0.01). The identified genes with variants were TP53 (n = 2), DICER1 (n = 1), PMS2 (n = 1), and PTCH1 (n = 1). In terms of the type of subsequent cancer, leukemia and multiple episodes of SMN had an exceptionally high rate of CPG pathogenic variants. None of the patients with germline variants had a family history of SMN development. Mutational signature analysis showed that platinum drugs contributed to the development of SMN in three cases, which suggests the role of platinum agents in SMN development. CONCLUSIONS: We highlight that overlapping effects of genetic background and primary cancer treatment contribute to the development of second cancers after treatment of pediatric solid tumors. A comprehensive analysis of germline and tumor samples may be useful to predict the risk of secondary cancers.

Updates in molecular genetics of therapy-related myeloid neoplasms.

Therapy-related myeloid neoplasms (t-MN) are a heterogeneous group of aggressive myeloid neoplasms that arise following exposure to various cytotoxic therapeutic agents and/or ionizing radiation for treatment of prior non-myeloid malignancy or autoimmune disease. Each therapeutic group has been associated with varying latency intervals from the time of therapy exposure to onset of t-MN, as well as certain recurrent genetic alterations. This review will focus on the molecular genetic alterations that have been described in t-MNs, as well as recent updates regarding diagnostic classification.

Tracking the evolution of therapy-related myeloid neoplasms using chemotherapy signatures.

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Preleukemic clones (ie, clonal hematopoiesis [CH]) are detectable years before the development of these aggressive malignancies, although the genomic events leading to transformation and expansion are not well defined. Here, by leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of prechemotherapy samples, we reconstructed the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy was revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan were hypermutated and enriched for complex structural variants (ie, chromothripsis), whereas neoplasms with nonmutagenic chemotherapy exposures were genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to discrete clinical exposure in each patient's life, we estimated that several complex events and genomic drivers were acquired after chemotherapy was administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected after reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA damage. Overall, we revealed a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select preexisting CH but also promote the acquisition of recurrent genomic drivers.

Therapy-selected clonal hematopoiesis and its role in myeloid neoplasms.

Therapy-related myeloid neoplasms (t-MN) account for approximately 10-15% of all myeloid neoplasms and are associated with poor prognosis. Genomic characterization of t-MN to date has been limited in comparison to the considerable sequencing efforts performed for de novo myeloid neoplasms. Until recently, targeted deep sequencing (TDS) or whole exome sequencing (WES) have been the primary technologies utilized and thus limited the ability to explore the landscape of structural variants and mutational signatures. In the past decade, population-level studies have identified clonal hematopoiesis as a risk factor for the development of myeloid neoplasms. However, emerging research on clonal hematopoiesis as a risk factor for developing t-MN is evolving, and much is unknown about the progression of CH to t-MN. In this work, we will review the current knowledge of the genomic landscape of t-MN, discuss background knowledge of clonal hematopoiesis gained from studies of de novo myeloid neoplasms, and examine the recent literature studying the role of therapeutic selection of CH and its evolution under the effects of antineoplastic therapy. Finally, we will discuss the potential implications on current clinical practice and the areas of focus needed for future research into therapy-selected clonal hematopoiesis in myeloid neoplasms.

Replication stress drives chromosomal instability in fibroblasts of childhood cancer survivors with second primary neoplasms.

New development and optimization of oncologic strategies are steadily increasing the number of long-term cancer survivors being at risk of developing second primary neoplasms (SPNs) as a late consequence of genotoxic cancer therapies with the highest risk among former childhood cancer patients. Since risk factors and predictive biomarkers for therapy-associated SPN remain unknown, we examined the sensitivity to mild replication stress as a driver of genomic instability and carcinogenesis in fibroblasts from 23 long-term survivors of a pediatric first primary neoplasm (FPN), 22 patients with the same FPN and a subsequent SPN, and 22 controls with no neoplasm (NN) using the cytokinesis-block micronucleus (CBMN) assay. Mild replication stress was induced with the DNA-polymerase inhibitor aphidicolin (APH). Fibroblasts from patients with the DNA repair deficiency syndromes Bloom, Seckel, and Fanconi anemia served as positive controls and for validation of the CBMN assay supplemented by analysis of chromosomal aberrations, DNA repair foci (γH2AX/53BP1), and cell cycle regulation. APH treatment resulted in G2/M arrest and underestimation of cytogenetic damage beyond G2, which could be overcome by inhibition of Chk1. Basal micronuclei were significantly increased in DNA repair deficiency syndromes but comparable between NN, FPN, and SPN donors. After APH-induced replication stress, the average yield of micronuclei was significantly elevated in SPN donors compared to FPN (p = 0.013) as well as NN (p = 0.03) donors but substantially lower than for DNA repair deficiency syndromes. Our findings suggest that mild impairment of the response to replication stress induced by genotoxic impacts of DNA-damaging cancer therapies promotes genomic instability in a subset of long-term cancer survivors and may drive the development of an SPN. Our study provides a basis for detailed mechanistic studies as well as predictive bioassays for clinical surveillance, to identify cancer patients at high risk for SPNs at first diagnosis.

Inherited cancer predisposing mutations in patients with therapy-related myeloid neoplasms.

Some patients with therapy-related myeloid neoplasms (t-MN) may have unsuspected inherited cancer predisposition syndrome (CPS). We propose a set of clinical criteria to identify t-MN patients with high risk of CPS (HR-CPS). Among 225 t-MN patients with an antecedent non-myeloid malignancy, our clinical criteria identified 52 (23%) HR-CPS patients. Germline whole-exome sequencing identified pathogenic or likely pathogenic variants in 10 of 27 HR-CPS patients compared to 0 of 9 low-risk CPS patients (37% vs. 0%, p = 0.04). These simple clinical criteria identify t-MN patients most likely to benefit from genetic testing for inherited CPS.

Germline risk factors for second malignant neoplasms after treatment for pediatric hematologic malignancies.

Survivors of childhood hematologic malignancies are at a substantially higher risk of developing subsequent neoplasms (SNs) when compared with the general population. SNs commonly observed in this population include basal cell carcinoma, brain tumors, thyroid cancer, breast cancer, bone tumors, and sarcoma. Radiation is the primary therapeutic exposure associated with the development of these SNs. There is emerging evidence of an association between chemotherapeutic exposures (alkylating agents/anthracyclines) and the development of SNs. Despite a strong dose-dependent association between therapeutic exposures and SN risk, there is significant interindividual variability in the risk for SNs for any given dose of therapeutic exposure. This interindividual variability in risk suggests the role of genetic susceptibility. This article describes the clinical and molecular epidemiology of SNs commonly observed in survivors of childhood hematologic malignancies and also highlights some of the work focusing on the development of risk prediction models to facilitate targeted interventions.