ATM Mutations Research Articles

P53 pathway genes' mutations as prognostic factors in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A single center study.

771 Background: Mutations (muts) in oncosuppressor genes have been associated with poor prognosis in different solid tumors. This study aims to evaluate the prognostic impact of p53 pathway muts in mPDAC pts. Methods: For each mPDAC pt enrolled in this study a FFPE tumor tissue specimen was collected and Next Generation Sequencing (NGS) was performed by TSO500HT assay (DNA [523 genes], RNA [55 genes]). Primary endpoint was overall survival (OS). The Kaplan–Meier method was used to estimate efficacy outcome; log-rank test, Peto-Peto test and Cox-regression model were used to compare the differences, considering a statistically significant p value < 0.05. Results: A total of 149 mPDAC pts were enrolled; TP53 was mutated in 115/149 (77.2%) pts, CDKN2A in 28 (24.3%), CDKN2B in 8 (5.3%), ATM in 6 (4%), TP53BP1 and MDM2 in 2 pts each (1.3%) and ATR in 1 (0.7%). No mutations were found in MDM4, CHEK1 and CHEK2 genes. Overall, 121 (81.2%) pts had at least one mutation in a gene of p53 signaling pathway (p53sigmut) and 28 pts (19.8%) had none (p53sigwt). The most frequent TP53 alterations were single nucleotide variations (SNVs): R175 (10 pts-8.7%), R248 (9 pts-7.8%) and R273 (8 pts-7%); 27 TP53 muts (18.1%) occurred in exon 7, 26 (17.4%) in exon 5, 19 (12.8%) in exon 8 and 13 (8.7%) in exon 4. Median OS (mOS) was 15 months (mos) (CI 95%: 12.8-18.2) in TP53 mutated pts vs 24.3 mos (CI 95%: 17.3-Not reached) in TP53 wt pts, p=0.03. The site of TP53 alteration was correlated with pts’ survival: mOS was 34.9 mos (CI 95%: 31-Nr) in exon 4-mutated pts, 16.9 mos (CI 95%: 11.2-21.2) in exon 7-mut, 13.8 mos (CI 95%: 11.2-17.8) in exon 5-mut and 10.7 mos (CI 95%: 8.2-Nr) in exon 8-mut, p= 0.018. CDKN2A mutations were also associated with survival: mOS was 17.9 mos (CI 95%: 15.9-24.1) in wt pts vs 13.4 (CI 95%: 10.7-22.2) in mutated pts, p= 0.04. CDKN2B, ATM, TP53BP1, MDM2 and ATR mutations were not associated with OS. Overall, patients with at least one mutation in one of the genes of p53 pathway had a mOS of 15 mos (CI 95%: 12.8-18.2) vs 19.6 months (mos) (CI 95%: 17.3-Not reached) in p53sigwt patients. In terms of comutations, TP53 wt pts had a higher frequency of KRAS mutations: 94% vs 64.5%, p<0.001. Conclusions: Our study suggests an important prognostic role of p53 signaling muts in mPDAC pts; wt pts resulted in a longer OS than mutated pts, although some mutations seem to be associated with a longer survival. Further studies are needed to investigate these findings, including an in-depth analysis of structural proteogenomic.

TP53 Y220C mutations in pancreatic ductal adenocarcinoma (PDAC): A genomic landscape study.

761 Background: A novel targeted therapy designed to restore wild-type function to the p53 Y220C mutant protein has demonstrated promising activity in an early-phase trial (NCT04585750). While the TP53 Y220C mutation is found in < 1% of all solid malignancies, its prevalence is enriched in certain cancers including PDAC. Here we report results of comprehensive genomic profiling (CGP) in a cohort of patients with advanced PDAC, with a focus on TP53 Y220C mutations. Methods: A total of 27,377 cases of clinically advanced PDAC underwent hybrid capture-based CGP to assess all classes of genomic alterations (GAs). Cases were sequenced to a mean coverage depth of 650X. Microsatellite instability (MSI) status and tumor mutation burden (TMB) were determined using sequencing data; PD-L1 expression was measured by immunohistochemistry (Dako 22C3, tumor proportion score [TPS]). Results: TP53 Y220C alterations were identified in 488 (1.8%) PDAC patients (Y220C+). In comparison to PDAC patients lacking the TP53 Y220C alteration (Y220C-), Y220C+ patients were of similar age, but were more likely to be female (52.9% vs 46.8%; p = 0.0008) and harbor KRAS mutations (96.7% vs 92.7%; p = 0.007). Meanwhile, alterations in ATM were more frequent in the Y220C- group (4.0% vs 1.4%; p = 0.0008). Frequencies of other GAs were similar between Y220C+ and Y220C- groups, including alterations in the homologous recombination defect-associated genes BRCA1/2 and RAD21 , as well as ERBB2 , BRAF , MTAP and PIK3CA . MSI-high status and elevated TMB (≥ 10 mutations/Mb) were extremely uncommon in both groups. PD-L1 expression was similar in the Y220C+ and Y220C- groups, with positive PD-L1 expression (TPS ≥ 1) observed in 31.5% and 34.9% of patients, respectively. Conclusions: The potentially targetable TP53 Y220C mutation was identified in close to 2% of clinically advanced PDAC cases. Those with TP53 Y220C mutations were more likely to be female and harbor KRAS mutations, and less likely to harbor ATM mutations. However, TP53 Y220C mutations were not associated with other distinct genomic characteristics. These findings are consistent with previous reports of interactions between TP53 and KRAS alterations in PDAC. Given the emergence of drugs aimed at restoring p53 function in cases with the Y220C mutation, further study of this alteration in PDAC is warranted. Age, number of genomic alterations (GA) per tumor, and alteration frequency of select commonly altered genes based on TP53 Y220C status. TP53 Y220C+ (n = 488) TP53 Y220C- (n = 26,889) P Value Median Age, years (range) 66 (36-89+) 66 (21-89+) NS GA/tumor 5.2 5.0 NS KRAS 96.7% 92.7% 0.007 CDKN2A 60.1% 56.6% NS CDKN2B 28.6% 29.5% NS MTAP 24.4% 23.8% NS ARID1A 7.8% 8.7% NS ATM 1.4% 4.0% 0.0008 BRCA2 2.3% 3.1% NS NS = non-significant.

Metabolic reprogramming, malignant transformation and metastasis: Lessons from chronic lymphocytic leukaemia and prostate cancer.

Metabolic reprogramming is a hallmark of cancer, crucial for malignant transformation and metastasis. Chronic lymphocytic leukaemia (CLL) and prostate cancer exhibit similar metabolic adaptations, particularly in glucose and lipid metabolism. Understanding this metabolic plasticity is crucial for identifying mechanisms contributing to metastasis. This review considers glucose and lipid metabolism in CLL and prostate cancer, exploring their roles in healthy and malignant states and during disease progression. In CLL, lipid metabolism supports cell survival and migration, with aggressive disease characterised by increased fatty acid oxidation and altered sphingolipids. Richter's transformation and aggressive lymphoma, however, exhibit a metabolic shift towards increased glycolysis. Similarly, prostate cell metabolism is unique, relying on citrate production in the healthy state and undergoing metabolic reprogramming during malignant transformation. Early-stage prostate cancer cells increase lipid synthesis and uptake, and decrease glycolysis, whereas metastatic cells re-adopt glucose metabolism, likely driven by interactions with the tumour microenvironment. Genetic drivers including TP53 and ATM mutations connect metabolic alterations to disease severity in these two malignancies. The bone microenvironment supports the metabolic demands of these malignancies, serving as an initiation niche for CLL and a homing site for prostate cancer metastases. By comparing these malignancies, this review underscores the importance of metabolic plasticity in cancer progression and highlights how CLL and prostate cancer may be models of circulating and solid tumours more broadly. The metabolic phenotypes throughout cancer cell transformation and metastasis, and the microenvironment in which these processes occur, present opportunities for interventions that could disrupt metastatic processes and improve patient outcomes.

Spectrum of BRCA1, BRCA2, PALB2, ATM and TP53 Mutations in Breast Cancer and Ovarian Cancer Patients from Kabardino-Balkaria

Введение. У больных раком молочной железы (РМЖ) и раком яичников (РЯ) — представительниц народностей с относительно компактным проживанием и выраженным «эффектом основателя» анализ этноспецифических мутаций BRCA1 и BRCA2 может быть приемлемой альтернативой секвенированию полной кодирующей последовательности этих генов. Цель. Характеристика спектра РМЖ- и РЯ-ассоциированных патогенных вариантов у пациенток кабардинской и балкарской национальностей, проживающих в Кабардино-Балкарской Республике (КБР) и выявление повторяющихся аллелей. Материалы и методы. В исследование включено 273 больных РМЖ (n = 200) и РЯ (n = 73): 221 кабардинка, 44 балкарки и 8 пациенток со смешанным кабардино-балкарским происхождением. Информация об этнической принадлежности предоставлялась пациентками. Кодирующие последовательности генов BRCA1 и BRCA2, а также PALB2, ATM и TP53 были проанализированы методом таргетного высокопроизводительного секвенирования. Результаты. В исследованной группе выявлено 39 патогенных вариантов BRCA1/BRCA2. В группе РМЖ было обнаружено 26 носителей мутаций (13 %); в спектре мутаций преобладали аллели BRCA2 (BRCA1: 6/200 (3 %) vs. BRCA2: 20/200 (10 %), p = 0,007). Среди РЯ было обнаружено 8/73 (11 %) мутаций BRCA1 и 5/73 (6,8 %) мутаций BRCA2. В спектре патогенных аллелей 84 % вариантов были повторяющимися. Самым частым аллелем, обнаруженным как у пациенток кабардинского (n = 6), так и балкарского происхождения (n = 3), являлся миссенс-вариант BRCA2 c.7868A>G [p.His2623Arg]. К другим повторяющимся в этом регионе патогенным вариантам относились BRCA1 c.5266dupC (n = 5), c.1961delA (n = 4), BRCA2 c.993_994delAA (n = 4), c.8437G>T [G2813X] (n = 4), c.6486_6489delACAA (n = 4), c.8009C>A [p.Ser2670Ter] (n = 2). У балкарцев единственным повторяющимся аллелем был BRCA2 c.7868A>G. Патогенные аллели ATM были обнаружены у 8 пациенток (3,0 %), при этом только один патогенный вариант встретился более одного раза (ATM c.8874_8877del [rs770704493]). Патогенные и вероятно патогенные варианты TP53 и PALB2 обнаружены не были. Выводы. Таким образом, спектр РМЖ/РЯ-ассоциированных мутаций в исследуемом регионе характеризуется выраженным «эффектом основателя» (founder-effect) в отношении гена BRCA2. Можно утверждать, что мутация BRCA2 c.7868A>G [p.His2623Arg] — это мажорный founder-вариант у кабардинцев, и, вероятно, у балкарцев.

Arabidopsis thaliana DNA Damage Response Mutants Challenged with Genotoxic Agents-A Different Experimental Approach to Investigate the TDP1α and TDP1β Genes.

Background/Objectives: DNA damage response (DDR) is a highly conserved and complex signal transduction network required for preserving genome integrity. DNA repair pathways downstream of DDR include the tyrosyl-DNA phosphodiesterase1 (TDP1) enzyme that hydrolyses the phosphodiester bond between the tyrosine residue of topoisomerase I (TopI) and 3'-phosphate end of DNA. A small TDP1 subfamily, composed of TDP1α and TDP1β, is present in plants. The aim of this work was to investigate the role of the two TDP1 genes in the DDR context. Methods: A series of Arabidopsis thaliana DDR single and double mutants defective in the sog1, e2fb, pol2A, atm, and atr genes, treated with the genotoxic agents camptothecin (CPT, inhibitor of TopI) and NSC120686 (NSC, inhibitor of TDP1), were used. These compounds were specifically used due to their known impact on the TDP1 function. The effect of the treatments was assessed via phenotypic analyses that included germination percentage, speed, and seedling growth. Subsequently, the expression of the TDP1α and TDP1β genes was monitored through qRT-PCR. Results: Overall, the gathered data indicate that the atm mutant was highly sensitive to NSC120686, both phenotypically and concerning the TDP1α gene expression profiles. Alternatively, the upregulation of TDP1β in e2fb, pol2a, and atr supports its implication in the replication stress response. Conclusions: The current study demonstrates that genotoxic stress induced by CPT and NSC has a genotype-dependent effect reflected by a differential expression of TDP1 genes and early phenotypic development.

Comparison of genetic mutations of gastric cancer diagnosed before or after H. pylori eradication and between differentiated and undifferentiated types using next-generation sequencing.

Genetic abnormalities specific to post-H. pylori eradication gastric cancer (GC), especially those associated with undifferentiated post-eradication GC, are unknown. We conducted next-generation sequencing of GC diagnosed either before or after eradication to investigate the carcinogenesis of post-eradication GC. Five cases of post-eradication differentiated GC [HP(-)-D group], five cases of H. pylori-positive differentiated GC [HP(+)-D group], four cases of post-eradication undifferentiated GC [HP(-)-U group)], and six cases of H. pylori-positive undifferentiated GC [HP(+)-U group)] underwent analysis. DNA was extracted from tumor samples, and non-tumor samples of all subjects. Next-generation target sequencing was conducted using the Ion AmpliSeq Library Kit 2.0 with the Ion AmpliSeq Cancer Hotspot Panel v2. Next-generation targeted sequencing results of the cancer part were subtracted from the results of the non-cancer part. The HP (-)-D group displayed significantly fewer SNPs in hotspot than the other groups (P < 0.01). Definitive DNA mutations were identified by sequencing of cancerous and non-cancerous tissues. 5 of 20 patients had specific somatic mutations, with different TP53 mutations in the HP(+)-D and HP(-)-U groups, CTNNB1 mutations in the HP(+)-U group, and ATM mutations in the HP(+)-U group, but no mutations in the HP(-)-D group. Several definite genetic mutations involved in GC were observed. Mutations were less frequent in post-eradication differentiated GC. However, because of small number of cases analyzed to identify carcinogenic differences, further analysis with a large number of cases and with strictly grading GC samples is needed.

PARP inhibitor-based treatment in metastatic, castration-resistant prostate cancer (mCRPC): A systematic review and meta-analysis.

We present a systematic review and meta-analysis of randomized clinical trials (RCTs) with PARPi either as monotherapy or in combination with an androgen receptor-targeted agent (ARTA) in first- and second-line settings. Primary endpoints are radiographic progression free survival (rPFS) and overall survival (OS) in patients with mCRPC and either unselected, homologous recombination repair wild-type (HRR-), homologous recombination repair mutated (HRR+) or with BRCA1, BRCA2, or ATM mutation. The effect of PARPi + ARTA in the second-line setting is also explored. Safety is a secondary end-point. A total of five phase III (first line: MAGNITUDE, PROpel, TALAPRO-2; second line: PROfound, TRITON3) and two phase II RCTs (second line: NCT01972217, NCT01576172) were selected. In the first-line setting, rPFS was significantly improved in PARPi + ARTA arm in all comers (HR 0.70, p < 0.00001), HRR- (HR 0.76, p = 0.005), HRR+ (HR 0.57, p = 0.0003), and BRCA1/2-mutated patients (HR: 0.33, p < 0.00001). OS was improved in the population with HRR+ status (HR 0.76, p = 0.02) but not statistically significant in BRCA1/2-mutated patients (HR 0.57, 95% CI 0.30-1.08, p = 0.08). In the second line, PARPi improves rPFS (HR for BRCA2 0.31, p = 0.002) and OS (HR for BRCA1/2 0.71, p = 0.01) only in such patients. In this setting, no advantage was reported by adding a PARPi to an ARTA. The arm with PARPi either as monotherapy or in combination with ARTA showed a significantly higher toxicity profile. PARPi-based therapy represents a compelling treatment option for HRR+ mCRPC, mainly BRCA1/2-mutated patients. However, further biomarker analysis are needed in order to identify other responsive patients across the different disease settings.

Clonal Hematopoiesis of Indeterminant Potential as a Predictor of Colorectal Cancer Risk: Insights from the UK Biobank Cohort.

Clonal hematopoiesis of indeterminate potential (CHIP) has been shown to be associated with the occurrence of solid tumors, but its relationship with colorectal cancer still needs to be studied. We conducted a prospective matched case-control study using data from the UK Biobank, including 5,310 incident colorectal cancer (CRC) cases and 26,550 controls matched for age, sex, and body mass index (BMI). Analysis of the UK Biobank data revealed that the presence of CHIP was associated with an increased risk of CRC. The odds ratio (OR) for CRC in the presence of CHIP was 1.20 (P = 0.006). This association remained significant even after excluding participants with a family history of bowel cancer (multivariate OR, 1.19, P = 0.007). Subgroup analyses demonstrated that CHIP independently increased the risk of CRC in females (multivariate OR, 1.25, P = 0.018) and in individuals older than 60 years (multivariate OR, 1.17; P=0.046). Gene-specific analyses revealed that mutations in TET2 and ATM were particularly significant in relation to CRC risk, with OR of 1.62 (P = 0.002) for TET2 and 2.98 (P < 0.001) for ATM. Our findings indicate that CHIP is associated with an increased risk of CRC, particularly in individuals over 60 years of age or in females. Screening for CHIP in the population may improve the early detection and diagnosis rates of CRC.

A Comparative Study on the Progression of Neuroendocrine Carcinomas and Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms.

The prognostic differences between neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) remain unclear. This study aimed to compare the prognostic outcomes of NEC and MiNEN by analyzing the clinicopathological features of these diseases and exploring factors affecting progression after radical surgery. Additionally, we employed whole-exome sequencing to investigate the molecular mechanisms influencing the prognosis of both conditions. Among the 252 patients followed, 163 underwent surgical treatment. The median time to tumor progression was 16 months (range: 9-56 months). Tumor pathology type (p = 0.007), lymph node metastasis (p < 0.0001), and distant metastasis (p < 0.0001) were identified as independent factors affecting disease progression in NEC and MiNEN patients. MiNEN patients without lymph node or distant metastasis generally had a better prognosis. First-line chemotherapy regimens did not show a significant impact on disease progression (p = 0.160, median progression-free survival [mPFS]: 36 vs. 13 vs. 23 vs. 15 months). However, the etoposide plus cisplatin (EP) regimen has shown good efficacy in gastric neuroendocrine neoplasms (NENs) (p = 0.048, mPFS: 45 vs. 12 vs. 32 vs. 16 months), especially in gastric MiNENs (p = 0.022, mPFS: Undefined vs. 11 vs. 52 vs. 37 months). Further investigation into the genetic mutation differences between NECs and MiNENs revealed that among previously sequenced data, rectal NECs commonly exhibited mutations in MUC16, SPTA1, ATM, PDGFB, NF1, FAT4, AR, APC, ANTXR2, and ADGRA2. In contrast, rectal MiNENs showed common mutations in NOTCH2, ZNRF3, CARD11, TP53, OBSCN, FPR1, APC, ANGPT2, ARID1A, and AR. Mutations in ANGPT2 and OBSCN were present in two rectal MiNEN cases, while NF1 and PDGFB mutations were found in two rectal NEC cases but not in MiNENs. The JAK-STAT signaling pathway appears to be specific to rectal NECs and may be involved in tumor progression. EP regimen remains the most effective chemotherapy option for neuroendocrine tumor patients. There were prognostic differences between NECs and MiNENs, as well as differences in genetic mutations and signaling pathways. This study provided new insights into the prognosis assessment and treatment strategies for NENs, particularly highlighting the importance of personalized treatments and the development of novel targeted therapies.

Association of Specific Gene Mutations with Immunoglobulin Heavy-Chain Variable Region and Chromosomal Alterations in Chronic Lymphocytic Leukemia Patients in India.

Chronic lymphocytic leukemia (CLL) is a less common hematological malignancy in Indian people. It accounts for less than 5% of all leukemias. Information on genomic alteration in CLL is limited immunoglobulin heavy-chain variable region (IGHV) mutational status is considered the most reliable prognostic marker. In this study, we performed mutation analysis of significantly mutated genes of CLL and correlated them with the IGHV mutational status and cytogenetic alterations. We included 97 patients in this study; 36 were IGHV hypermutated, and 61 were IGHV unmutated. We observed frequent mutations in TP53 (16.4%), ATM (19.5%), SF3B1 (18.5%), and NOTCH1 (14.2%). NOTCH1 mutations were significantly observed in patients with unmutated IGHV. We observed that patients with no mutations in ATM, NOTCH1, or TP53 had chromosomal alterations (del 11q, del 13q, del 17q, and trisomy 21) identified by FISH. Our results have shown mutations in essential genes and their association with IGHV status. Overall, specific gene mutations, IGHV status, and chromosomal alterations can provide information on prognosis.

Phase II Trial of Risk-Enabled Therapy After Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer (RETAIN 1).

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Mutations in DNA damage repair genes are associated with pathologic downstaging after NAC. We hypothesized that a combination of biomarker selection and clinical staging would identify patients for cystectomy-sparing active surveillance (AS). We conducted a single-arm, phase II, noninferiority trial to evaluate a risk-adapted approach for MIBC. Patients with cT2-T3N0M0 MIBC underwent NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC). Pre-NAC transurethral bladder tumor specimens were sequenced for mutations in ATM, ERCC2, FANCC, and RB1. Patients with ≥1 mutation and cT0 post-NAC began AS. The primary end point was metastasis-free survival (MFS) at 2 years for the entire cohort with the null hypothesis rejected if the lower bound exact one-sided 95% CI exceeds 64%. Seventy patients were enrolled, 33 (47%) had a mutation, and 25 (36%) began per-protocol AS. With a median follow-up of 40 months, the 2-year MFS for all patients was 72.9% (lower bound exact one-sided 95% CI, 62.8). The 2-year MFS was 76.0% in the AS group (95% CI, 54.2 to 88.4) and 71.1% (95% CI, 55.5 to 82.1) in the remaining patients. In the AS group, 17 patients (68%) had some recurrence and 12 (48%) were metastasis-free with an intact bladder. The 2-year overall survival (OS) was 84.3% (95% CI, 73.4 to 91.0); OS was 88.0% (95% CI, 67.3 to 96.0) and 82.2% (95% CI, 67.6 to 90.7) in the AS and not-AS groups, respectively. Patients with MIBC treated with AMVAC followed by a risk-adapted approach to local consolidation achieved a 2-year MFS rate of 73%. The primary end point was not met, but 17% of all enrolled patients and 48% of the AS group avoided cystectomy without metastatic disease.

Characterizing Nodal Gamma-Delta T-Cell Lymphoma: Clinicopathological and Molecular Insights.

Peripheral T-cell lymphomas with gamma-delta phenotype (GDTCL) are rare lymphoid malignancies. Beyond the well-recognized entities of extranodal lymphomas with gamma-delta phenotype as defined by the 5th edition of the WHO Classification of Hematolymphoid Tumors and 2022 International Consensus Classification, there is a group of poorly-defined gamma-delta T-cell lymphomas with predominantly nodal presentation, termed as nodal GDTCL (nGDTCL). In this study, we present a series of 12 cases of EBV-negative nGDTCL, highlighting the clinical, histopathological and molecular features of this rare entity. Seven cases reported in the literature were included for the analysis. Of the 12 cases, nGDTCL shows an increased incidence in elderly males with a median age of 65.5 years. All cases presented primarily with enlarged lymph nodes and 4 cases (4/12; 33.3%) showed involvement of extranodal sites, including skin, liver, spleen and bone marrow. Histologically, 9 cases showed a diffuse and monomorphic proliferation of mostly medium to large lymphoid cells while 3 cases demonstrated a lymphoepithelioid morphology. All cases (12/12, 100%) were positive for CD3 and TCRγδ. CD4, CD8 and CD56 were positive in 66.7% (8/12), 25% (3/12) and 8.3% (1/11) of cases, respectively. Most cases (8/12, 66.7%) showed a non-cytotoxic phenotype. Using immunohistochemistry, the majority of cases (6/8, 75.0%) belonged to the PTCL-GATA3 subtype with GATA3 and/or CCR4 expression and a non-cytotoxic CD4-positive phenotype. Two cases (2/8, 25%) belonged to the PTCL-TBX21 subtype, of which 1 displayed a cytotoxic CD8-positive phenotype. Next-generation sequencing was performed on 9 cases and TP53 mutation was detected in 66.7% (6/9) of cases. Mutations of ATM and KSR2 were identified in 2 cases each. It remains uncertain if nGDTCL represents a distinct entity, and further studies are needed for better characterization. Nonetheless, nodal-based GDTCL should be distinguished from secondary nodal involvement by other extranodal GDTCL and EBV-positive T/NK-cell lymphoproliferative diseases.

A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors.

Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ATM, genes conferring replication stress (RS), or SDH. Patients were recruited to 4 cohorts: T1: ATRX-mutant leiomyosarcoma; T2: ATM-mutant solid tumors; T3: solid tumors with mutations in RS-associated genes; and T4: SDH-deficient GIST. Patients were treated with berzosertib 240 mg/m2 IV twice per week. Pre and on-treatment biopsies were obtained in cohorts T1-T3. Patients with SDH-mutant GIST had the longest median progression-free survival (PFS) (229 days) with stable disease as the best response. Patients in the other cohorts experienced progressive disease within 4 months. There was no significant difference in PFS comparing outcomes in patients with/without mutations in ATM or RS genes. Decreased pS345-CHK1 in on-treatment biopsies indicated target engagement by berzosertib and were accompanied by substantial increases in levels of DNA damage (g-H2AX) and RS (pKAP1) markers in a subset of patients. However, these biomarker changes did not translate to clinical benefit. In contrast, in cohorts T1-T3, increased expression of SFLN11 on treatment correlated with clinical benefit (HR = 0.045; 95%CI 0.005-0.400). Across cohorts, only SDH-mutant GIST patients experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.

Leveraging Tumor Mutation Profiles to Forecast Immune Checkpoint Blockade Resistance in Melanoma, Lung, Head and Neck, Bladder and Renal Cancers

Immune checkpoint blockade (ICB), radiotherapy, chemotherapy and surgery are currently used as therapeutic strategies against melanoma, lung, bladder and renal cancers, but their efficacy is limited. Thus, I need to predict treatment response and resistance to address this challenge. In this study, I analyzed 350 lung cancer, 320 melanoma, 215 bladder cancer, 139 head and neck cancer and 151 renal carcinoma patients treated with ICB to identify tumor mutations associated with response and resistance to treatment. I identified several tumor mutations linked with a difference in survival outcomes following ICB. In lung cancer, missense mutations in ABL1, ASXL1, EPHA3, EPHA5, ERBB4, MET, MRE11A, MSH2, NOTCH1, PAK7, PAX5, PGR, ZFHX3, PIK3C3 and REL genes were indicative of favorable responses to ICB. Conversely, mutations in TGFBR2, ARID5B, CDKN2C, HIST1H3I, RICTOR, SMAD2, SMAD4 and TP53 genes were associated with shorter overall survival post-ICB treatment. In melanoma, mutations in FBXW7, CDK12, CREBBP, CTNNB1, NOTCH1 and RB1 genes predict resistance to ICB, whereas missense mutations in FAM46C and RHOA genes are associated with extended overall survival. In bladder cancer, mutations in HRAS genes predict resistance to ICB, whereas missense mutations in ERBB2, GNAS, ATM, CDKN2A and LATS1 genes, as well as nonsense mutations in NCOR1 and TP53 genes, are associated with extended overall survival. In head and neck cancer, mutations in genes like PIK3CA and KRAS correlated with longer survival, while mutations in genes like TERT and TP53 were linked to shorter survival. In renal carcinoma, mutations such as EPHA5, MGA, PIK3R1, PMS1, TSC1 and VHL were linked to prolonged overall survival, while others, including total splice mutations and mutations in B2M, BCOR, JUN, FH, IGF1R and MYCN genes were associated with shorter overall survival following ICB. Then, I developed predictive survival models by machine learning that correctly forecasted cancer patient survival following ICB within an error between 5 and 8 months based on their distinct tumor mutational attributes. In conclusion, this study advocates for personalized immunotherapy approaches in cancer patients.

PIK3CA Mutations and Co-Mutations in Operated Non-Small Cell Lung Carcinoma.

Background: Understanding PIK3CA mutations and co-mutations in non-small cell lung carcinoma (NSCLC) is critical to developing personalized treatment strategies. Therefore, this study aims to investigate PIK3CA mutations and the accompanying somatic variations in NSCLC. Methods: This retrospective study included 98 patients over 18 years of age who were diagnosed with NSCLC, operated on, and referred to the Molecular Pathology Laboratory between January 2019 and June 2024 for next-generation sequencing panel tests and ALK-ROS1 FISH analysis. Results: All patients were found to carry PIK3CA mutations. Among the 98 NSCLC patients analyzed, 16 (16.33%) were female and 82 (83.67%) were male. The average age of the patients was 64.53 ± 9.63 years, with an age range of 38-84 years, and the majority were 50 years or older. Of the cases, 51 presented the adenocarcinoma subtype, while the remaining 47 showed the squamous cell carcinoma subtype. A smoking history was present in 77 (78.57%) patients, while 21 (21.43%) had no smoking history. The most frequently detected pathogenic or likely pathogenic PIK3CA variations were c.1633G>A p.E545K (32.65%), c.1624G>A p.E542K (11.22%), c.3140A>G p.H1047R (11.22%), c.3140A>T p.H1047L (5.10%), c.1357G>C p.E453Q (4.08%), and c.3143A>G p.H1048R (2.04%). The top 10 mutations that most commonly accompanied PIK3CA variations were KRAS, NF1, TP53, EGFR, PTEN, BRAF, KIT, CDKN2A, SMARCA4, and ATM mutations, respectively. Conclusions:PIK3CA variations, along with other gene variations, may influence cancer progression and thus may play a crucial role in the determination of targeted treatment strategies.

Real-world efficacy and safety of combined first-line treatment with PARP inhibitors and novel hormonal therapy in mCRPC patients with HRR gene mutations.

This study evaluated the real-world efficacy and safety of combining PARP inhibitors with novel hormonal therapy (NHT) as a first-line treatment in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations. We enrolled 41 mCRPC patients who received at least 1month of combined treatment with PARP inhibitors and NHT. Patients were divided into two groups: Cohort A (mutations in BRCA1, BRCA2, or ATM genes) and Cohort B (mutations in other HRR genes). The primary endpoint was imaging-based progression-free survival (PFS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), overall survival (OS), PSA50 response, and adverse events (AEs). To ensure accurate research results and control confounding factors, we will employ multivariate Cox proportional hazards models to evaluate key variables affecting mCRPC patient survival outcomes. This study enrolled 41 patients, 22 in Cohort A and 19 in Cohort B. The median PFS for all patients was 21.8months, and the median OS had yet to be reached. The overall ORR was 48.8%, and the DCR was 61.0%. Specifically, the median PFS for Cohort A was 21.8months compared to 14.5months for Cohort B. The median OS had yet to be reached for either cohort. Regarding efficacy, 81.8% of patients in Cohort A and 73.7% in Cohort B achieved a PSA50 response. Imaging assessments showed ORRs of 54.6% for Cohort A and 42.1% for Cohort B, with DCRs of 72.7% and 47.4%, respectively. 85.4% of patients experienced grade 1 or 2 adverse events, and 51.2% encountered grade 3 or 4. In the multivariate Cox regression analysis focusing on PFS, the Gleason score was identified as a significant predictor (HR = 5.8, 95% CI: 1.65-20.2, p = 0.006). Combined first-line treatment with PARP inhibitors and NHT is effective and well-tolerated in mCRPC patients with HRR gene mutations, particularly those with BRCA1, BRCA2, or ATM mutations. These findings underscore the potential of this therapeutic combination in managing mCRPC in the Chinese population, suggesting a favorable outcome for those with specific genetic backgrounds.

Endometrial endometrioid adenocarcinoma with a malignant squamous component: is the unusual metastatic pattern unique of these tumors?

The FIGO scheme is currently applied for tumor grading of endometrioid adenocarcinoma. The current report presents a series of ten cases of endometrioid carcinomas that when applying the FIGO grading does not fully convey the true biological nature of the disease. The squamous component of these tumors is malignant; it constitutes the predominant invasive component, and it often metastasizes to unconventional sites. Half of the cohort developed distant disease recurrence within 2 years, even those with early-stage disease. Somatic mutations were analyzed, targeting 101 genes in all ten cases, and mutations in PTEN, MMR, PIK3CA, ATM, RB1, and TP53 genes were detected, often multiple mutations in the same case. None of the cases revealed unique molecular signatures or previously unreported gene mutations. Immunohistochemical staining for beta-catenin showed aberrant nuclear staining in eight of ten cases and remaining two showed cytoplasmic and membranous staining. Aggressive behavior and unusual sites of metastases are observed in this series even in low-grade tumor. The FIGO grading on smaller samples may be deceptive for these cases. Even if FIGO is applied, the pathology report should emphasize the malignant squamous component and its potential significance so that the gynecologic oncology team can formulate appropriate adjuvant treatment upfront. This case series argues that this histology should be regarded as a high-grade endometrioid carcinoma and can show unusual metastatic patterns. Further research is needed with more cases within this histologic subtype to guide recommendations on adjuvant therapies for this aggressive tumor type.

Phase II Trial of the PARP Inhibitor, Niraparib, in BAP1 and Other DNA Damage Response Pathway-Deficient Neoplasms.

BRCA1-associated protein 1 (BAP1) is a critical cell cycle and DNA damage response (DDR) regulator with mutations (mBAP1) causing a functional protein loss. PARP inhibitors (PARPis) demonstrate synthetic lethality in mBAP1 preclinical models, independent of underlying BRCA status. This study aimed to explore the clinical activity of niraparib in patients with advanced tumors likely to harbor mBAP1. This was a phase II multicenter trial in which refractory solid tumor patients were assigned to cohort A (histology-specific tumors likely to harbor mBAP1) or cohort B (histology-agnostic tumors with other known non-BRCA-confirmed DDR mutations). All patients received niraparib 300 mg orally once daily on a 28-day cycle. The primary end point was objective response rate, and secondary end points included progression-free survival (PFS) and overall survival. From August 2018 through December 2021, 37 patients were enrolled with 31 evaluable for response (cohort A, n = 18; cohort B, n = 13). In cohort A, the best response was one partial response (PR; 6%), eight stable disease (SD; 44%), and nine progressive disease (PD; 50%). This cohort stopped at the first stage following the prespecified Simon's design. mBAP1 was confirmed in 7/9 patients (78%) with PR or SD but in only 3/9 (33%) in those with PD. The median PFS in patients with mBAP1 (n = 10) was 6.7 months (95% CI, 1.0 to 9.2) versus 1.8 months (95% CI, 0.9 to 4.5) for wild-type (n = 8; P = .020). In cohort B, the best response was six SD (46%) and seven PD (54%), with SD in those with ATM, CHEK2, PTEN, RAD50, and ARID1A mutations. Niraparib failed to meet the prespecified efficacy end point for response. However, clinical benefit was suggested in a proportion of patients who had a confirmed mBAP1, supporting further investigation.

ATR inhibition potentiates FOLFIRINOX cytotoxic effect in models of pancreatic ductal adenocarcinoma by remodelling the tumour microenvironment.

In pancreatic ductal adenocarcinoma (PDAC), the dense stroma rich in cancer-associated fibroblasts (CAFs) and the immunosuppressive microenvironment confer resistance to treatments. To overcome such resistance, we tested the combination of FOLFIRINOX (DNA damage-inducing chemotherapy drugs) with VE-822 (an ataxia-telangiectasia and RAD3-related inhibitor that targets DNA damage repair). PDAC spheroid models and organoids were used to assess the combination effects. Tumour growth and the immune and fibrotic microenvironment were evaluated by immunohistochemistry, single-cell analysis and spatial proteomics in patient-derived xenograft (PDX) and orthotopic immunocompetent KPC mouse models. The FOLFIRINOX and VE-822 combination had a strong synergistic effect in several PDAC cell lines, whatever their BRCA1, BRCA2 and ATM mutation status and resistance to standard chemotherapy agents. This was associated with high DNA damage and inhibition of DNA repair signalling pathways, leading to increased apoptosis. In immunocompetent and PDX mouse models of PDAC, the combination inhibited tumour growth more effectively than FOLFIRINOX alone. This was associated with tumour microenvironment remodelling, particularly decreased proportion of fibroblast activated protein-positive CAFs and increased anti-tumorigenic immune cell infiltration and interaction. The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.

Investigating the influence of germline ATM variants in chronic lymphocytic leukemia on cancer vulnerability.

Chronic lymphocytic leukemia (CLL) patients have an increased risk of secondary cancers, along with predisposition to CLL in their relatives. We have previously identified germline ATM variants as associated with CLL risk; here, we present their impact on predisposition to secondary neoplasms in CLL patients and their relatives. Patients enrolled in our tissue bank who had germline ATM status available were mailed a questionnaire between April 2022 and May 2023. Of the 333 patients who replied to the questionnaire, 283 patients (85%) reported at least one relative with a cancer history. The prevalence of family history of B-cell lymphoproliferative disorders was significantly higher (p=0.02) in patients with germline ATM variants (32%) compared to those without germline ATM variants (21%) including familial CLL (25% vs 18%) (p=0.04). No significant difference in the prevalence of secondary cancers was found between patients with and without germline ATM variants (p=0.73), although the role for individual ATM variants in other malignancies could not be excluded given the small sample size. Time to first CLL treatment (TTFT) was shorter in patients harboring somatic ATM events while no difference was observed in patients with germline ATM variants. In conclusion, we demonstrate a higher prevalence of B-cell lymphoproliferative disorders, including familial CLL, in relatives of CLL patients carrying germline ATM variants. The presence of these germline variants did not impact TTFT compared to patients harboring somatic ATM mutations.