Search Results (133)

Background: The identification of pathogenic variants in the Breast Cancer Genes 1 and 2 (BRCA1/2) is a critical predictive biomarker for poly (ADP-ribose) polymerase inhibitor (PARPi) therapy in epithelial ovarian cancer (EOC). The aim of this study is to define real-world rates and determinants of germline and somatic BRCA1/2 testing and subsequent PARPi utilisation in Australia using a national clinical quality registry. Methods: This multi-centre cohort study analysed data from 1503 women with non-mucinous EOC diagnosed between May 2017 and July 2022, captured by the Australian National Gynae-Oncology Registry (NGOR). We evaluated rates of germline and somatic testing and PARPi use, using multivariate logistic regression to identify associated clinical and demographic factors. Results: Overall germline and somatic testing rates were 68% and 32%, respectively. For the high-grade serous ovarian cancer (HGSOC) cohort, rates were higher, at 78% and 39%, respectively. Germline testing was significantly less likely for women aged >80 years (OR 0.49), those in regional areas (OR 0.61), and those receiving single-modality treatment. Somatic testing uptake increased significantly following public reimbursement for PARPi (p = 0.004). Among eligible women with a newly diagnosed BRCA pathogenic variant and advanced disease (n = 110), 52% commenced first-line maintenance PARPi. Conclusions: This national study offers valuable insights into Australian ovarian cancer care, highlighting opportunities to enhance testing equity for older women (aged >80) and regional patients. Furthermore, it identifies the translation of a positive test into PARPi therapy as a complex area that warrants further collaborative investigation to optimise patient outcomes. Full article

Background: Genetic insights from diverse populations are key to advancing cancer detection, treatment, and prevention. Unlike other Latin American countries, Colombia lacks a centralized registry for germline and somatic mutations in breast and ovarian cancer. This study describes the country’s first national variant registry, and the occurrence of recurrent mutations and potential founder effects in Colombia. Methods: To address this gap, we implemented the first capturing protocol using the REDCap system. In a group of 213 breast and/or ovarian cancer patients harboring genetic mutations, we collected genetic, clinical, and demographic data from 13 regional centers across Colombia. Statistical analyses assessed variant distribution and patient demographics. Results: Among 229 identified variants (105 germline, 124 somatic), most were classified as pathogenic or likely pathogenic (72.4% germline, 87% somatic). BRCA1 and BRCA2 accounted for the majority of recurrent mutations. Germline recurrent variants (seen >3 times) were recorded for BRCA1 (77.7%; 21/27) and BRCA2 (22.3%; 6/27). Similarly, recurrent somatic variants were identified for BRCA1 (82.6%; 38/46) and BRCA2 (17.4%; 8/46). Notably, four recurrent variants were previously reported as founder mutations: BRCA1 c.1674del (14.3% germline and 23.7% somatic), BRCA1 c.3331_3334del (33.3% germline and 52.6% somatic), BRCA1 c.5123C>A (52.4% germline and 23.7% somatic), and BRCA2 c.2808_2811del (50% germline and 50% somatic). Most cases originated from the Andean region, highlighting regional disparities. Conclusions: This registry offers the first overview of genetic variants in Colombian breast and ovarian cancer patients. Recurrent and region-specific mutations highlight the need for population-focused data to guide targeted screening and personalized care strategies. Full article

Background: Medullary thyroid cancer (MTC), a neuroendocrine tumor originating from thyroid parafollicular C-cells, presents therapeutic challenges, particularly in advanced stages. While RET proto-oncogene mutations are known drivers, a comprehensive understanding of the broader somatic mutation landscape is needed to identify novel therapeutic targets and improve prognostication. This study leveraged the extensive AACR Project GENIE dataset to characterize MTC genomics. Methods: A retrospective analysis of MTC samples from GENIE examined recurrent somatic mutations, demographic/survival correlations, and copy number variations using targeted sequencing data (significance: p < 0.05). Results: Among 341 samples, RET mutations predominated (75.7%, mostly M918T), followed by HRAS (10.0%) and KRAS (5.6%), with mutual exclusivity between RET and RAS alterations. Recurrent mutations included KMT2D (5.3%), CDH11 (5.3%), ATM (5.0%), and TP53 (4.1%). NOTCH1 mutations were enriched in metastatic cases (p = 0.023). Preliminary associations included sex-linked mutations (BRAF/BRCA1/KIT in females, p = 0.028), and survival (ATM associated with longer survival, p = 0.016; BARD1/BLM/UBR5/MYH11 with shorter survival, p < 0.05), though limited subgroup sizes warrant caution. Conclusions: This large-scale genomic analysis confirms the centrality of RET and RAS pathway alterations in MTC and their mutual exclusivity. The association of NOTCH1 mutations with metastasis suggests a potential role in disease progression. While findings regarding demographic and survival correlations are preliminary, they generate hypotheses for future validation. This study enhances the genomic foundation for understanding MTC and underscores the need for integrated clinico-genomic datasets to refine therapeutic approaches. Full article

Background: HRD is a key biomarker in ovarian cancer, predicting response to PARP inhibitors. However, it remains unclear whether HRD-positive patients differ from HRD-negative patients in terms of clinical characteristics in PARP inhibitor-naïve populations. This study aims to evaluate platinum-sensitive PARP-inhibitor naïve ovarian cancer patients’ clinical characteristics and survival outcomes based on HRD status. Secondly, to investigate whether platinum-resistant patients with homologous recombination repair (HRR) gene mutations are HRD-positive. Methods: Two distinct HRD algorithms—an in-house genomic instability score (GIS) and the normalized large-scale state transitions score (nLST)—were used to stratify patients as HRD-positive or HRD-negative. Clinical data and survival in PARP inhibitor-naïve, platinum-sensitive HGSC patients were analyzed. Results: A total of 71 platinum-sensitive PARP-inhibitor naïve patients were analyzed. By in-house GIS, 37 patients (52%) were classified as HRD-positive and 34 (48%) as HRD-negative. Using nLST, 43 (61%) were HRD-positive and 28 (39%) were HRD-negative. Our analysis revealed no significant differences in clinical parameters or survival between HRD-positive and HRD-negative platinum-sensitive patients. The only observed difference was that somatic BRCA1/2-mutated patients were younger. In the subgroup of six platinum-resistant patients harboring HRR gene mutations, four patients (67%) were classified as HRD positive. Conclusions: Our findings suggest that HRD status does not significantly influence clinical characteristics or survival outcomes in platinum-sensitive, PARP inhibitor-naïve HGSC patients. As some platinum-resistant patients with HRR gene mutations were HRD positive; this subgroup may benefit from further investigation into the potential effect of PARP inhibitors. Full article

The integrity of p53 machinery is crucial for platinum activity, while p53 mutation is frequent in high-grade serous ovarian cancer (HGS-OC). This study aimed to evaluate the link between p53 mutations, platinum sensitivity (PS), and the platinum-free interval (PFI) in patients with HGS-OC. We prospectively analyzed 159 consecutive women with ovarian cancer who underwent surgery. The somatic mutational status of BRCA, HRD, and TP53 (according to structural, hotspot, and functional classification) was evaluated. Among enrolled patients, 82.4% of cases were TP53-mutated (MT), and 27.8% were BRCA-MT. The distribution of TP53 mutation categories did not differ significantly between the BRCA-MT and wild-type (WT) cases. In the entire population, the proportion of PS patients was significantly lower in TP53-MT compared to TP53-WT (p = 0.0208), in nonsense/frameshift/splicing compared to missense (p = 0.0319), and in loss-of-function (LOF) compared to GOF (p = 0.0048) MT cases. For the BRCA-MT patients, structural and functional TP53 mutations were not significantly different between the PS and PR patients. Conversely, for the BRCA WT patients, the distribution of structural and functional TP53 mutations significantly differed between PS and PR patients. In a multivariate regression analysis, LOF mutations were found to be independent negative predictors of PS (HR: 0.1717; 95% CI: 0.0661–0.4461; p-value: 0.0003). Kaplan–Meier curves showed a significantly lower PFI in cases with LOF mutations in the overall population (log-rank p = 0.0020) and in BRCA-WT patients (log-rank p = 0.0140). Via multivariate COX testing, it was found that LOF mutations were independently associated with a decreased PFI (p = 0.0036). In conclusion, our data show that HGS-OC harboring p53 LOF mutations is the poorest prognostic subgroup regarding PS and the PFI. Further studies are needed to confirm our findings. Full article

Background/Objectives: Mutations in BRCA1 and/or BRCA2 (BRCAm) and other homologous recombination repair genes (HRRm) are associated with several cancers. We evaluated the prevalence and association with overall survival (OS) of somatic BRCAm and HRRm among patients with advanced solid tumors. Methods: We used deidentified data from the AACR GENIE Biopharma Collaborative dataset derived from patients with tumors genotyped using next-generation sequencing between 1 January 2014 and 31 December 2017. Eligible patients were aged ≥18 years diagnosed with non-small-cell lung, colorectal, breast, bladder, prostate, or pancreatic cancer, with documented BRCA/HRR somatic mutation status. The primary analysis was OS (censored at the start of poly[ADP ribose] polymerase inhibitors [PARPi]/immunotherapy) after initiation of second-line therapy since most patients had sequencing after first-line therapy. Results: Among eligible patients, 242/7022 (3.4%) had BRCAm and 477/5474 (8.7%) had HRRm. Adjusted OS HRs (95% CI) for the primary analysis (using the initiation of second-line therapy as index date) were 0.79 (0.61–1.03) with/without BRCAm (n = 116/n = 3394) and 0.83 (0.69–0.99) with/without HRRm (n = 247/n = 2656); in sensitivity analysis of patients with stage IV disease, HRs were 0.97 (0.68–1.38) with/without BRCAm (n = 58/n = 1847) and 0.92 (0.73–1.18) with/without HRRm (n = 132/n = 1488). Conclusions: Overall, BRCAm and HRRm did not show a strong association with OS, with a trend toward longer OS among patients receiving standard second-line therapies excluding PARPi/immunotherapy. Full article

Background: Chordoma is a rare primary tumor originating from embryonic notochord remnants, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to characterize the genetic alterations in chordoma using a large national patient-level genomic repository, the AACR Project GENIE, to identify potential therapeutic targets and improve disease modeling. Methods: A retrospective analysis of chordoma samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were observed in genes associated with SWI/SNF complex affecting chromatin remodeling (SETD2, PBRM1, ARID1A). Mutations were also common among the TERT promoter regions, and cell cycle regulation (CDKN2A). Significant co-occurrences were identified among PBRM1, BRCA2, and KMT2D mutations. CDKN2A/B deletions were enriched in metastatic tumors, and pediatric cases demonstrated distinct mutation profiles compared to adults. Conclusions: This study provides a genomic profile of chordoma, identifying key mutations and potential therapeutic targets. These findings highlight the roles of chromatin remodeling and cell cycle pathways in chordoma biology, offering insights for future precision medicine approaches and therapeutic interventions. Full article

Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (PRLT) with Lutetium-177 ([¹⁷⁷Lu]Lu-PSMA) is a safe and effective treatment for metastatic castration-resistant prostate cancer (mCRPC). The aim of our study was to evaluate clinical variables of patients with extreme response to PRLT and to assess its immunomodulatory potential. Methods: This retrospective study included 36 patients from two centers achieving extreme response after [¹⁷⁷Lu]Lu-PSMA PRLT. The primary outcomes were the duration of maintained response in months (MR) and improvement post-therapy—clinically, serologically, and on molecular (PET/CT) imaging. We examined several variables, including pathology, gene sequencing, baseline PSA, Gleason score, prior therapies, number of PRLT cycles, and pattern of disease, to identify potential factors that may influence the extreme response. Results: Between 2018 and mid-September 2024, 36 men with mCRPC received a mean of three cycles of [¹⁷⁷Lu]Lu-PSMA PRLT. Patients were subgrouped according to clinical variables versus MR. A total of 17 patients had ≥12 months MR (17/36, 47%). The longest duration of MR was 99 months and a mean of 17.44 months (95% CI 10.05–24.84). Previous lines of treatment were evaluated for MR, p = 0.172. Pattern of disease (bone, lymph node, liver, and peritoneal) was evaluated for MR, p = 0.721. The Gleason score was evaluated for MR, p = 0.871. Patients with known BRCA sequencing status (n = 12) were analyzed with mean MR: BRCA1/2 wild-type, 6/12 (50%), 6.67 months; BRCA 1/2 negative, 1/12 (8.33%), 7 months; BRCA germline negative and somatic positive, 1/12 (8.33%), 36 months; BRCA germline negative, somatic negative, 2/12 (16.67%), 27 months; and BRCA 2 positive, 2/12 (16.67%), 43 months. Conclusions: We propose there may be intrinsic mechanisms suggesting the immunomodulatory enhancement of ionizing radiation, primarily driving extreme responses. Full article

It has been shown that the pathogenic variants (PVs) of the DNA Damage Response (DDR) genes, whether of a germinal or somatic nature, represent a predictive biomarker of high sensitivity to treatment with inhibitors of the enzyme poly-ADP-ribose polymerase (PARP) in patients with hormone-resistant metastatic prostate cancer (HRPCa). Moreover, the detection of PVs of the Homologous Recombination Repair (HRR) genes in PCa patients can help to define the patient’s prognosis and the choice of the therapeutic procedure. Among men with metastatic PCa, the frequency of PVs in HRR genes ranges from 11% to 33%, which is a significantly higher rate compared to non-metastatic PCa, where the incidence is between 5% and 10%. Next-Generation Sequencing (NGS) results were more commonly obtained from newly acquired somatic samples compared to archived samples (prostate biopsy or prostatectomy). We developed an experimental multidisciplinary prospective study in patients with a new diagnosis of high-risk PCa at biopsy. The aim was to evaluate the presence of PVs of different HRR genes in patients with the first diagnosis of PCa in relation to a metastatic or non-metastatic stage, tumor aggressiveness, and early risk of progression. Among 43 initial tumor samples from 22 patients, 25 samples from 12 patients were selected for library preparation based on their DNA concentration and quality. After the NGS, 14 different DNA variants were prioritized. Oncogenetic and likely oncogenetic variants were found in the ATM, BRCA1, PTEN, KMT2D, and CDH1 genes. Moreover, variants of uncertain significance were found in ATM, DDR2, FANCA, FOXA1, PLCB4, PTCH1, and RB1. Full article

Energy metabolism is a fundamental aspect of the aggressiveness and invasiveness of breast cancer (BC), the neoplasm that most affects women worldwide. Nonetheless, the impact of genetic somatic mutations on glycolysis and oxidative phosphorylation (OXPHOS) genes in BC remains unclear. To fill these gaps, the mutational profiles of 205 screened genes related to glycolysis and OXPHOS in 968 individuals with BC from The Cancer Genome Atlas (TCGA) project were performed. We carried out analyses to characterize the mutational profile of BC, assess the clonality of tumors, identify somatic mutation co-occurrence, and predict the pathogenicity of these alterations. In total, 408 mutations in 132 genes related to the glycolysis and OXPHOS pathways were detected. The PGK1, PC, PCK1, HK1, DONSON, GPD1, NDUFS1, and FOXRED1 genes are also associated with the tumorigenesis process in other types of cancer, as are the genes BRCA1, BRCA2, and HMCN1, which had been previously described as oncogenes in BC, with whom the target genes of this work were associated. Seven mutations were identified and highlighted due to the high pathogenicity, which are present in more than one of our results and are documented in the literature as being correlated with other diseases. These mutations are rs267606829 (FOXRED1), COSV53860306 (HK1), rs201634181 (NDUFS1), rs774052186 (DONSON), rs119103242 (PC), rs1436643226 (PC), and rs104894677 (ETFB). They could be further investigated as potential biomarkers for diagnosis, prognosis, and treatment of BC patients. Full article

Serrated polyposis syndrome (SPS) is characterized by the development of multiple colorectal serrated polyps and increased predisposition to colorectal cancer (CRC). However, the molecular basis of SPS, especially in cases presenting family history of SPS and/or polyps and/or CRC in first-degree relatives (SPS-FHP/CRC), is still poorly understood. In a previous study, we proposed the existence of two molecular entities amongst SPS-FHP/CRC families, proximal/whole-colon and distal SPS-FHP/CRC, according to the preferential location of lesions and somatic events involved in tumor initiation. In the present study, we aimed to investigate these distinct subgroups of SPS patients in a larger cohort at the germline level and to identify the genetic defects underlying an inherited susceptibility for these two entities. Next-generation sequencing was performed using multigene analysis with a custom-designed panel in a Miseq platform in 60 SPS patients (with and without/unknown FHP/CRC). We found germline pathogenic variants in 6/60 patients (ATM, FANCM, MITF, RAD50, RAD51C, and RNF43). We also found variants of unknown significance (VUS), with prediction of probable damaging effect in 23/60 patients (ATM, BLM, BRCA1, FAN1, ERCC2, ERCC3, FANCA, FANCD2, FANCL, MSH2, MSH6, NTHL1, PALB2, PDGFRA, PMS2, PTCH1, RAD51C, RAD51D, RECQL4, TSC2, WRN, and XRCC5 genes). Most variants were detected in gene coding for proteins of the Fanconi Anemia (FA) pathway involved in the DNA Interstrand-Cross Link repair (ICLR). Notably, variants in ICLR genes were significantly more frequent in the proximal/whole-colon than in the distal subgroup [15/44 (34%) vs 1/16 (6%), p = 0.025], as opposed to the non-ICLR genes that were slightly more frequent in the distal group [8/44 (18%) vs. 5/16 (31%), p > 0.05]. Germline defects in the DNA-ICLR genes may contribute to increased serrated colorectal polyps/carcinoma risk in SPS patients, particularly in proximal/whole-colon SPS. The inclusion of DNA-ICLR genes in the genetic diagnosis of SPS patients, mainly in those with proximal/whole-colon lesions, should be considered and validated by other studies. In addition, patients with germline defects in the DNA-ICLR genes may be more sensitive to treatment with platinum-based therapeutics, which can have implications in the clinical management of these patients. Full article

Background: Limited data are available regarding the anticancer activity of PARP inhibitors (PARPis) in pancreatic cancer with mutations in HRR genes other than BRCA and PALB2. Methods: We retrospectively reviewed the clinical characteristics and outcomes of 48 patients with advanced pancreatic cancer harboring pathogenic germline and/or somatic HRR mutations who were treated with PARPis. Results: Thirty patients had germline (g)HRR mutations only, twelve had somatic (s)HRR mutations only, and six had concomitant gHRR and sHRR mutations. The objective response rate (ORR) was 22%. The median progression-free survival (mPFS) and overall survival (mOS) were 6.9 and 11.5 months, respectively. Five patients received olaparib in the front-line setting due to borderline performance status. Their ORR was 20%, and their mPFS and mOS were both 11.3 months. The ORR was higher in patients with BRCA or PALB2 mutations (germline or somatic) than in those with non-BRCA/PALB2 mutations. Patients with somatic non-BRCA/PALB2 variants had a shorter mPFS. Patients with concomitant gHRR/sHRR mutations or gHRR mutations alone had a significantly longer mPFS than those with sHRR mutations only. Conclusions: PARP inhibitors may be considered for patients with advanced pancreatic cancer harboring pathogenic alterations of BRCA who cannot tolerate standard chemotherapy. Maintenance PARPis can be considered in selected patients with non-BRCA/non-PALB2 HRR mutations. Full article

Objectives: Acinar cell carcinoma (ACC) accounts for about 1% of pancreatic cancers. The molecular and clinical features of ACC are less characterized than those of pancreatic ductal adenocarcinoma. Methods: We retrospectively evaluated the clinical and molecular features of ACC patients who underwent germline and/or somatic molecular testing at The University of Texas MD Anderson Cancer Center from 2008 to 2022 and two cases from 2023–2024 who underwent RNA and TME analysis by Boston Gene. Patient information was extracted from our institutional database with the approval of the Institutional Review Board. Results: We identified 16 patients with available molecular testing results. Fourteen patients had metastatic disease, one had borderline resectable disease, and one had localized resectable disease at diagnosis. Fifteen patients were wild type for KRAS (one patient had unknown KRAS status). Somatic/germline mutations of DNA damage repair genes (BRCA1/2, PALB2, and ATM) were present in 5 of 12 patients tested for these genes. One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months. The median overall survival (OS) was 24 months for patients with metastatic disease. One of the additional two cases who underwent BostonGene testing was found to have NTRK1 fusion. RNA and TME analysis by Boston Gene of the two cases reported immune desert features and relatively lower RNA levels of CEACAM5, CD47, CD74, and MMP1 and higher RNA levels of CDH6 compared with PDAC. Full article

Background: Comprehensive genomic profiling (CGP) has gained an important role in patients with advanced prostate cancer following the introduction of PARP inhibitors in daily clinical practice. Here, we report an overview of CGP results, specifically of BRCA1 and BRCA2 HRD-repair system genes, from patients with prostate cancer analyzed in our institution, and we compare our results with those available from more recent scientific literature. Methods: The study cohort consisted of 70 patients. Somatic DNA was extracted from Formalin-Fixed Paraffin-Embedded (FFPE) tissue using a MagCore Genomic DNA FFPE One-Step Kit for MagCore System. The DNA was quantified by EasyPGX^® Real-Time qPCR and EasyPGX^® Analysis Software (version 4.0.13). Tissue somatic DNA libraries were prepared with Myriapod^® NGS BRCA1-2 panel-NG035 and sequenced in a Mi-Seq^® System. The sequence alignment in hg19 and the variant calling were performed using Myriapod^® NGS Data Analysis Software version 5.0.8 NG900-SW 5.0.8 with a software detection limit (LoD) of 95%. Variants with a coverage of 500 and VAF% ≥ 5 were evaluated. Results: Tumor tissue NGS was unsuccessful in 46/70 patients (66%). Mutations of the BRCA2 gene were detected in 4 of the samples: (1) BRCA2 ex10 c.1244A>G p.His415Arg VAF = 51.03%; (2) BRCA2 ex11 c.5946delT p.Ser1982fs VAF = 72.1%; (3) BRCA2 ex11 c.3302A>G p.His1101Arg VAF = 52.9%; and (4) BRCA2 ex11 c.3195_3198delTAAT p.Asn1066fs VAF = 51.1%. Conclusions: The results from our internal overview seem to support the data and to confirm the performance of the technical issues reported in the literature. Considering the advanced age of our patients, with 84% of men over the age of 65, the application of alternative and less invasive procedures such as liquid biopsy, could be a more suitable solution for some cases. Full article

Neuroblastoma is the most prevalent solid tumor in early childhood, with a 5-year overall survival rate of 40–60% in high-risk cases. Therefore, the identification of novel biomarkers for the diagnosis, prognosis, and therapy of neuroblastoma is crucial for improving the clinical outcomes of these patients. In this study, we conducted the whole-exome sequencing of 48 freshly frozen tumor samples obtained from the Biobank. Somatic variants were identified and selected using a bioinformatics analysis pipeline. The mutational signatures were determined using the Mutalisk online tool. Cancer driver genes and druggable mutations were predicted using the Cancer Genome Interpreter. The most common mutational signature was single base substitution 5. MUC4, MUC16, and FLG were identified as the most frequently mutated genes. Using the Cancer Genome Interpreter, we identified five recurrent cancer driver mutations spanning MUC16, MUC4, ALK, and CTNND1, with the latter being novel and containing a missense mutation, R439C. We also identified 11 putative actionable mutations including NF1 Q1798*, Q2616*, and S636X, ALK F1174L and R1275Q, SETD2 P10L and Q1829E, BRCA1 R612S, NOTCH1 D1670V, ATR S1372L, and FGFR1 N577K. Our findings provide a comprehensive overview of the novel information relevant to the underlying molecular pathogenesis and therapeutic targets of neuroblastoma. Full article