Search Results (1,336)

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with a significant percentage of germline pathogenic variants (GPVs). Unlike in the United States, routine universal genetic testing is not performed in Europe. The aim of the study is to evaluate the diagnostic yield of germline genetic testing in all patients with PDAC. Methods: Individuals with newly diagnosed PDAC from three Spanish hospitals were enrolled, regardless of family history. Thirteen known susceptibility genes for PDAC were studied using a multigene panel or whole-exome sequencing. Results: One hundred seventy-nine PDAC patients underwent genetic testing. Fourteen (7.8%) had a GPV or likely pathogenic variant In the genes studied: six in ATM, six in BRCA2, one in PALB2, and one in TP53. Of these, seven (50%) did not meet the clinical criteria for genetic study and would have been classified as sporadic PDAC. Presenting with a personal history of any other neoplasm was associated with some GPV, with an odds ratio (OR) of 3.5 (1.1–11.5). A family history of PDAC and breast cancer was also associated with some GPV, with oRs of 3.7 (1.08–13.6) and 8.5 (2.6–26.6), respectively. None of the patients over 60 years without a relevant family history of malignancies presented a GPV associated with PDAC. Conclusions: In our PDAC cohort, a noteworthy number of GPVs were identified, and half of these patients would have been classified as sporadic based solely on clinical criteria. Genetic testing should always be considered, particularly in patients under 60 years or those with a history of other malignancies, especially where economic resources need optimization. Full article

Breast cancer is the most prevalent cancer worldwide, affecting both low- and middle-income countries, with a growing number of cases. In 2024, about 310,720 women in the U.S. are projected to receive an invasive breast cancer diagnosis, alongside 56,500 cases of ductal carcinoma in situ (DCIS). Breast cancer occurs in every country of the world in women at any age after puberty but with increasing rates in later life. About 65% of women with the BRCA1 and 45% with the BRCA2 gene variants develop breast cancer by age 70. While these genes account for 5% of breast cancers, their prevalence is higher in certain populations. Advances in early detection, personalised medicine, and AI-driven diagnostics are improving outcomes by enabling a more precise analysis, reducing recurrence, and minimising treatment side effects. Our paper aims to explore the vast applications of artificial intelligence within the diagnosis and treatment of breast cancer and how these advancements can contribute to elevating patient care as well as discussing the potential drawbacks of such integrations into modern medicine. We structured our paper as a non-systematic review and utilised Google Scholar and PubMed databases to review literature regarding the incorporation of AI in the diagnosis and treatment of non-palpable breast masses. AI is revolutionising breast cancer management by enhancing imaging, pathology, and personalised treatment. In imaging, AI can improve the detection of cancer in mammography, MRIs, and ultrasounds, rivalling expert radiologists in accuracy. In pathology, AI enhances biomarker detection, improving HER2 and Ki67 assessments. Personalised medicine benefits from AI’s predictive power, aiding risk stratification and treatment response. AI also shows promise in triple-negative breast cancer management, offering better prognosis and subtype classification. However, challenges include data variability, ethical concerns, and real-world validation. Despite limitations, AI integration offers significant potential in improving breast cancer diagnosis, prognosis, and treatment outcomes. Full article

Poly (ADP-ribose) polymerase inhibitors (PARPis) show cytotoxicity in homologous recombination deficiency (HRD) seen in BRCA-mutant ovarian cancer (OvCa). Despite initial responses, resistance often develops. The reintroduction of different PARPis, such as niraparib or rucaparib, has shown some clinical activity in BRCA mutation-associated OvCa patients with prior olaparib treatment, yet the underlying mechanisms remain unclear. To investigate the differential sensitivity to different PARPis, we established an olaparib-resistant BRCA1-mutant OvCa cell line (UWB-OlaJR) by exposing UWB1.289 cells to gradually increasing concentrations of olaparib. UWB-OlaJR exhibited restored HR capability without BRCA1 reversion mutation or increased drug efflux. We examined cell viability, DNA damage, and DNA replication fork dynamics in UWB-OlaJR treated with various PARPis. UWB-OlaJR exhibits varying sensitivity to PARPis, showing cross-resistance to veliparib and talazoparib, and sensitivity with increased cytotoxicity to niraparib and rucaparib. Indeed, DNA fiber assay reveals that niraparib and rucaparib cause higher replication stress than the others. Moreover, S1 nuclease fiber assay shows that niraparib and rucaparib induce greater DNA single-strand gaps than other PARPis, leading to increased DNA damage and cell death. Our study provides novel insights into differential PARPi sensitivity in olaparib-resistant BRCA-mutant OvCa, which requires further investigation of inter-agent differences in large prospective studies. Full article

The genetic landscape of urologic cancers has evolved with the identification of actionable mutations that impact diagnosis, prognosis, and therapeutic strategies. This narrative review consolidates existing literature on genetic mutations across key urologic cancers, including bladder, renal, prostate, upper tract urothelial, testicular, and penile. The review highlights mutations in DNA damage repair genes, such as BRCA1/2 and PTEN, as well as pathway alterations like FGFR and PD-L1 overexpression. These mutations influence tumor behavior and therapeutic outcomes, emphasizing the need for precision oncology approaches. Molecular profiling, through tools like next-generation sequencing, has revolutionized patient care by enabling targeted treatment strategies, especially in cancers with distinct molecular subtypes such as luminal or basal bladder cancer and clear cell renal carcinoma. Emerging therapies, including FGFR inhibitors and immune checkpoint blockade, offer new treatment avenues, although resistance mechanisms remain a challenge. We also emphasize the importance of biomarker identification for personalized management, especially in metastatic settings where treatment intensification is often required. Future research is needed to further elucidate our understanding of the genetics affecting urologic cancers, which will help develop novel, individualized therapies to enhance oncologic outcomes. Full article

Background: The aim of this study was to determine the differences in diffusion-weighted imaging (DWI) and dynamic contrast enhancement (DCE) parameters between patients with peritoneal high-grade serous ovarian cancer (HGSOC) recurrence with BRCA mutations (BRCAmut) or BRCA wild type (BRCAwt). Materials and Methods: We retrospectively analyzed the abdominal and pelvic magnetic resonance (MR) images of 43 patients suspected of having recurrent HGSOC, of whom 18 had BRCA1/2 gene mutations. Patients underwent MRI examination via a 1.5 T MRI scanner, and the analyzed parameters were as follows: apparent diffusion coefficient (ADC), time to peak (TTP) and perfusion maximum enhancement (Perf. Max. En.). Results: The mean ADC in patients with BRCAwt was lower than that in patients with BRCAmut: 788.7 (SD: 139.5) vs. 977.3 (SD: 103), p-value = 0.00002. The average TTP value for patients with BRCAwt was greater than that for patients with mutations: 256.3 (SD: 50) vs. 160.6 (SD: 35.5), p-value < 0.01. The Perf. Max. En. value was lower in the BRCAwt group: 148.6 (SD: 12.3) vs. 233.6 (SD: 29.2), p-value < 0.01. Conclusion: Our study revealed a statistically significant correlation between DWI and DCE parameters in examinations of peritoneal metastasis in patients with BRCA1/2 mutations. Adding DCE perfusion to the MRI protocol for ovarian cancer recurrence in patients with BRCAmut may be a valuable tool. 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

The lifetime risk of breast and ovarian cancer increases substantially for individuals with mutations in BRCA1/2. The evidence indicates that BRCA1/2 mutation carriers benefit from early cancer detection and prevention strategies. However, data on the patterns of risk-reducing interventions are lacking. This study investigated the patterns of surveillance and risk-reducing interventions among unaffected BRCA1/2 mutation carriers. A cohort of unaffected BRCA1/2 mutation carriers was identified from the Korean Hereditary Breast cAncer (KOHBRA) study database, and a telephone survey was conducted. The survey included questions on the incidence of new cancers, patterns of cancer (breast, ovarian, prostate, other) surveillance, chemoprevention, risk-reducing surgery, and reasons for participating in risk-reducing strategies. Between November 2016 and November 2020, 192 BRCA1/2 mutation carriers were contacted, of which 83 responded. After excluding 37 responders who refused to participate, 46 participants (15 males, 31 females) were included in the analysis. The mean ± SD follow-up time was 103 ± 17 months (median 107, range 68~154), and the mean ± SD age was 31 ± 8 years. Ten BRCA1/2 mutation carriers developed breast cancer, one developed ovarian cancer, and three developed other cancers. Six BRCA1/2 mutation carriers (19.4%) underwent annual breast cancer surveillance as recommended by guidelines, while none underwent ovarian or prostate cancer surveillance. Three carriers (9.7%) used chemoprevention for breast cancer. Risk-reducing salpingo-oophorectomy was performed on only one BRCA1/2 mutation carrier. The rates of breast/ovarian cancer surveillance, chemoprevention, and risk-reducing surgery were low among unaffected Korean BRCA1/2 mutation carriers. Given this cohort’s relatively high risk of developing breast cancer, strategies to encourage active participation in risk reduction are needed. Full article

Familial pancreatic cancer (FPC) represents a significant yet underexplored area in pancreatic cancer research. Basic research efforts are notably limited, and when present, they are predominantly centered on the BRCA1 and BRCA2 mutations due to the scarcity of other genetic variants associated with FPC, leading to a limited understanding of the broader genetic landscape of FPC. This review examines the current state of FPC research, focusing on the molecular mechanisms driving pancreatic ductal adenocarcinoma (PDAC) progression. It highlights the role of homologous recombination (HR) and its therapeutic exploitation via synthetic lethality with PARP inhibitors in BRCA1/2-deficient tumors. The review discusses various pre-clinical models of FPC, including conventional two-dimensional (2D) cell lines, patient-derived organoids (PDOs), patient-derived xenografts (PDXs), and genetically engineered mouse models (GEMMs), as well as new advancements in FPC research. Full article

Fanconi anemia (FA) represents a rare hereditary disease; it develops due to germline pathogenic variants in any of the 22 currently discovered FANC genes, which interact with the Fanconi anemia/breast cancer-associated (FANC/BRCA) pathway to maintain genome integrity. FA is characterized by a triad of clinical traits, including congenital anomalies, bone marrow failure (BMF) and multiple cancer susceptibility. Due to the complex genetic background and a broad spectrum of FA clinical symptoms, the diagnostic process is complex and requires the use of classical cytogenetic, molecular cytogenetics and strictly molecular methods. Recent findings indicate the interplay of inflammation, oxidative stress, disrupted mitochondrial metabolism, and impaired intracellular signaling in the FA pathogenesis. Additionally, a shift in the balance towards overproduction of proinflammatory cytokines and prooxidant components in FA is associated with advanced myelosuppression and ultimately BMF. Although the mechanism of BMF is very complex and needs further clarification, it appears that mutual interaction between proinflammatory cytokines and redox imbalance causes pancytopenia. In this review, we summarize the available literature regarding the clinical phenotype, genetic background, and diagnostic procedures of FA. We also highlight the current understanding of disrupted autophagy process, proinflammatory state, impaired signaling pathways and oxidative genotoxic stress in FA pathogenesis. Full article

Helicobacter pylori, a gram-negative, flagellated, helical bacterium, is a common cause of chronic gastric infection worldwide. According to the World Health Organization, H. pylori infection, a specific carcinogenic factor, was the leading cause of gastric cancer (GC) in 2014 worldwide (80%). H. pylori infection causes GC in >98% of patients in East Asian countries, including Japan. However, only some types of GCs are associated with H. pylori infection. Previous clinical studies have revealed that the bacterium secretes cytotoxin-associated gene A antigen, which inhibits the nuclear translocation of the breast cancer susceptibility gene 1 and 2 (BRCA1/2), a factor involved in DNA damage repair. This indicated an association between hereditary breast and ovarian cancers (HBOCs) and the development of GC. However, the detailed mechanisms underlying the development of GC caused by H. pylori infection remain unclear. Using the information on hereditary cancers obtained based on cancer genomic medicine, this study revealed that the incidence of GC was high in families with HBOC, with a preponderance for men from families with HBOC. Furthermore, the use of poly-adenosine diphosphate-ribose polymerase inhibitors in patients with hereditary GC is considered safe and effective. This study provides substantial evidence for guiding the establishment of early treatment for patients with advanced-stage/metastatic GC who harbored BRCA1/2 mutations. Full article

Purpose: In this study, we aimed to retrospectively investigate the real-world clinical efficacy and adverse events of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in real-world clinical practice among patients with newly diagnosed epithelial ovarian cancer. Methods: We retrospectively reviewed the medical records from hospitals. Patients with epithelial ovarian cancer treated with olaparib or niraparib as frontline maintenance treatment between 1 January 2014 and 31 December 2022 were included. Progression-free survival (PFS) was analyzed using the Kaplan–Meier method, and adverse events associated with PARP inhibitor treatment were investigated. Results: Ninety-six patients treated with PARP inhibitors were identified. The median follow-up period was 21.8 months (95% confidence interval [CI] 19.4–24.0). Twenty (20.1%) patients experienced disease progression, and two patients died. The median PFS was 45.3 months (95% CI 39.4–NA). BRCA1 or BRCA2 gene mutations and primary cytoreductive surgery were associated with better PFS. Adverse events of any grade occurred in 74 (77.1%) patients. Nineteen (19.8%) patients experienced PARP inhibitor therapy interruptions, and 35 (36.5%) patients experienced dose reductions. Only three patients discontinued the drug due to adverse events. Conclusions: In a real-world setting, PARP inhibitors showed efficacy comparable to that reported in published randomized controlled trials and had acceptable safety profiles. Full article

Background: Women undergoing genetic counseling for hereditary breast cancer often experience a high emotional burden. Distress and stress in the initial phases of genetic counseling can be significant predictors of long-term psychological health, influencing quality of life and well-being. Objectives: This study aimed to evaluate the mediating role of psychophysical stress in the relationship of anxiety and depression with quality of life and well-being in women undergoing genetic counseling for BRCA1/2 mutations. Methods: A sample of 193 women from two genetic counseling clinics was assessed using validated questionnaires measuring the psychological variables under study. Sociodemographic and clinical characteristics were also considered. Results: The results of path analyses indicated a mediating role of psychophysical stress on the relationship between emotional distress and mental quality of life and well-being: higher levels of anxiety and depression were associated with increased psychophysical stress, which, in turn, was linked to a reduced perceived mental quality of life and well-being. Depression was the only significant psychological predictor of physical quality of life. Conclusions: These findings indicate that addressing both anxiety and depression in genetic counseling is crucial for enhancing mental and overall well-being. Interventions should focus on stress management to improve the quality of life, emphasizing depression treatment to enhance physical health outcomes. Full article

Breast cancer ranks first in incidence and second in deaths worldwide, presenting alarmingly rising mortality rates. Imaging methodologies and/or invasive biopsies are routinely used for screening and detection, although not always with high sensitivity/specificity. MicroRNAs (miRNAs) could serve as diagnostic and prognostic biomarkers for breast cancer. We have designed a computational approach combining transcriptome profiling, survival analyses, and diagnostic power calculations from 1165 patients with breast invasive carcinoma from The Cancer Genome Atlas (TCGA-BRCA). Our strategy yielded two separate miRNA signatures consisting of four up-regulated and five down-regulated miRNAs in breast tumors, with cumulative diagnostic strength of AUC 0.93 and 0.92, respectively. We provide direct evidence regarding the breast cancer-specific expression of both signatures through a multicancer comparison of >7000 biopsies representing 19 solid cancer types, challenging their diagnostic potency beyond any of the current diagnostic methods. Our signatures are functionally implicated in cancer-related processes with statistically significant effects on overall survival and lymph-node invasion in breast cancer patients, which underlie their strong prognostic implication. Collectively, we propose two novel miRNA signatures with significantly elevated diagnostic and prognostic power as a functionally resolved tool for binary and accurate detection of breast cancer and other tumors of the female reproductive system. Full article

Background: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy is a therapeutic choice for women with advanced ovarian cancer. Whether NACT affects the tumor’s molecular profile has not been determined. Methods: This was a retrospective study of patients with advanced-stage epithelial ovarian cancer treated with NACT at oncology departments affiliated with the Hellenic Cooperative Oncology Group (HeCOG). Tumor molecular profiling was performed on formalin-fixed and paraffin-embedded (FFPE) tumor pre- and post-NACT tissues. Homologous recombination deficiency (HRD), tumor-infiltrating lymphocytes (TILs), tumor molecular alterations, and tumor mutational burden (TMB) via next-generation sequencing analysis were assessed. Results: Overall, tumors from 36 patients were assessed, and molecular profiling was evaluated in 20 paired tumor samples. HRD positivity exhibited no significant change between pre- and post-NACT tumors. The BRCA1/2 mutational status remained constant, irrespective of the treatment administration. Pre-NACT tumors tended to exhibit a lower percentage of intratumoral TILs compared to post-NACT tumors (p = 0.004). Differences in the mutation profile between pre- and post-treatment tissue were observed in 33.33% (6/18) of the cases. The mean tumor cell content (TCC) (p-value: 0.0840) and the mean genomic instability score (p-value: 0.0636) decreased slightly numerically after therapy. A moderate inverse relationship was observed between the pre-NACT TMB and the chemotherapy response score (p-value: 0.038), indicating this correlation is statistically significant. Conclusion: This study provides insights into the effect of NACT on the tumor molecular landscape. While BRCA1/2 and HRD status remained stable, an increase in TIL proportion and changes in the mutational profiles were observed post-treatment. Full article

Growing evidence has demonstrated the role of mutations of tumor biomarkers in diagnosing and treating epithelial ovarian cancer. This review aims to analyze recent literature on the correlation between tumor biomarkers and chemotherapy in nonmucinous ovarian cancer, providing suggestions for personalized treatment approaches. An extensive literature search was conducted to identify relevant studies and trials. BRCA1/2 mutations are central in homologous recombination repair deficiency (HRD) in ovarian cancer, but several other genetic mutations also contribute to varying cancer risks. While the role of MMR testing in ovarian cancer is debated, it is more commonly linked to non-serous ovarian cancer, often associated with Lynch syndrome. A significant proportion of ovarian cancer patients have HRD, affecting treatment decisions in both first-line (especially in advanced stages) and second-line therapy due to HRD’s connection with platinum-based therapy and PARP inhibitors’ response. However, validated genetic tests to identify HRD have not yet been universally implemented. There is no definitive therapeutic algorithm for advanced ovarian cancer, despite ongoing efforts and multiple proposed tools. Future research should focus on expanding the utility of biomarkers, reducing resistance, and increasing the actionable biomarker pool. Full article