Search Results (96)

Background: The profile of germline genetic variants among colorectal cancer patients in Panama has not yet been explored. Methods: We recruited 95 patients with colorectal cancer in an Oncology Reference Hospital Unit in the Azuero region of central Panama, which exhibited the highest prevalence of colorectal cancer in Panama. DNA analysis was performed with a panel of 113 genes with germline mutations for cancer (TruSight^® Cancer Sequencing Panel from Illumina, San Diego, CA, USA). Results: Among the 95 cases, 10 pathogenic/likely pathogenic variants (P/LP) were identified in the MUTYH, TP53, CHEK2, PALB2, ATM, and BARD1 genes, representing 10% of the total. The variant 1103G>A (p.Gly368Asp) in MUTYH was the most prevalent. The variant at c.1675_1676delCAinsTG (p.Gln559Ter) in PALB2 is new and is reported for the first time in this study. Variants were most frequently detected in the MUTYH and CHEK2 genes, affecting four and two patients, respectively. Notably, none of the 95 Panamanian patients in the initial colorectal cancer cohort had mutations in mismatch repair (MMR) genes. These genes are among the most frequently mutated in other cohorts around the world. Conclusions: The atypical profile of germline genetic variants in this population may be related to the unique characteristics of the Azuero population in Panama’s central region. This profile may partly explain the high prevalence of colorectal cancer among its inhabitants. Full article

Background/Objectives: Endometrial cancer (EC) is the most common malignancy of the female genital tract. In 2013, The Cancer Genome Atlas analyzed the molecular profile of endometrial tumors identifying four risk classes (POLE ultramutated, mismatch repair-deficient, copy-number low-microsatellite stable, and copy-number high-serous-like. This classification is reshaping the current understanding of EC, enabling more refined risk stratification and uncovering potential therapeutic targets tailored to specific molecular subgroups. In the context of these four categories, it is possible to identify different molecular alterations that correlate with different prognoses. Methods and Results: We retrospectively analyzed tissue samples from eighty-five EC patients, performing multigene profiling using a 50-gene next-generation sequencing (NGS) panel to categorize them into distinct molecular subtypes; we observed the following distribution: 5.9% POLE, 25.8% mismatch repair-deficient/microsatellite instability (MMRd/MSI), 11.8% p53abn/TP53mut, and 56.5% NSMP. A favorable concordance (97.6%) was shown in MSI NGS-based analysis and MMR IHC results, and the agreement rate of p53 IHC and TP53 mutation was 92.3%. When we analyzed the correlation between molecular subtypes and clinicopathological features, we found that molecular subtypes significantly differentiated by grade, FIGO stage, and lymphovascular invasion (LVSI). These findings seem to support the effectiveness of our NGS-based classifier and its reliability in distinguishing both MSI and TP53 mutated cancers. This study also explored mutations in PIK3CA, PTEN, KRAS, ERBB2, and ESR1 genes, noting their potential as targets for treatments. PIK3CA mutations were linked to favorable features, such as early disease stage and absence of LVSI. Conclusions: Our study highlights the potential of a medium-complexity NGS panel for supporting the molecular classification of endometrial cancer, complementing the existing diagnostic algorithms. By identifying additional biomarkers, we provided valuable insights into the genomic landscape of EC. However, further exploration of the molecular profiles is needed to validate these findings and improve the identification of patients at a higher risk of unfavorable outcomes. Full article

Colorectal cancer (CRC), the third most common cancer worldwide, is one of the deadliest cancers. CRC is known as a cold tumor, characterized by a low immune response that makes it difficult for immune cells to infiltrate and exhibits strong resistance to immunotherapy with checkpoint inhibition. This restricted response is largely attributed to signature gene mutations including mismatch repair (MMR) genes, KRAS, BRAF, APC, and TP53, which are also the main oncogenes in CRC. Mutated signature genes continuously upregulate abnormal signaling pathways, leading to excessive proliferation, cancer progression, and metastasis. Furthermore, it reorganizes the tumor microenvironment (TME) by recruiting immunosuppressive cells. However, the mutation can produce neoantigens that can provoke an immune response, making it a potential target for immunotherapy. In particular, cancer vaccines that leverage the strong neoantigenic properties of these mutations are considered promising for overcoming immune resistance and eliciting anti-tumor responses. In this review, we will describe signature gene mutations in CRC and focus on cancer vaccines targeting these mutations as potential therapies for CRC. Full article

Background and Objectives: Lynch syndrome (LS), an autosomal dominant condition arising from germline mutations in mismatch repair (MMR) genes, is a major cause of hereditary early-onset colorectal cancer (CRC). Although patients diagnosed before age 50 represent a critical subgroup where Lynch syndrome might be more prevalent, data on the precise frequency, clinical outcomes, and molecular correlates remain heterogeneous across studies. This systematic review was conducted to (1) estimate the prevalence of MMR deficiency (dMMR) and confirmed LS in patients diagnosed with CRC before the age of 50, and (2) examine immunohistochemistry (IHC) mismatch repair testing patterns and associated molecular findings (BRAF mutations, MLH1 promoter hypermethylation, somatic MMR gene alterations). Methods: Following a predefined search strategy in PubMed, Scopus, and Web of Science, five relevant studies were identified (n = 5). Each study comprised patients younger than 50 who underwent IHC-based tumor screening. Data extraction covered demographic details, number of patients tested, proportion with abnormal IHC, frequency of somatic or germline MMR gene mutations, and method of classification into sporadic dMMR vs. LS. Quality assessment was performed using recommended scales for observational studies. Results: Among 5 studies totaling 960 early-onset CRC patients, the frequency of dMMR CRC ranged from 8.4% to 19.1%. The confirmed prevalence of LS among all young-onset CRC was between 5.0% and 5.9% in three studies but reached 8.9% in another and 5.1% in yet another. Across all studies, the presence of right-sided tumors and histopathological features such as tumor-infiltrating lymphocytes were more common in dMMR cancers. Incorporation of MLH1-promoter hypermethylation and/or BRAF V600E mutation testing aided discrimination of sporadic dMMR CRC from germline LS cases. Conclusions: The prevalence of LS in CRC patients younger than 50 is clinically significant, at approximately 5–9%. Routine IHC-based MMR screening is both feasible and effective for detecting LS in early-onset CRC. Further research is needed to standardize universal testing protocols, delineate the role of additional molecular assays, and ensure comprehensive genetic counseling for at-risk individuals. Full article

Recent clinical trials have suggested that solid cancers with mismatch repair (MMR) deficiency are highly responsive to immunotherapy, regardless of cancer types. Previous MMR-related studies on breast cancer have predominantly focused on germline variants. However, the somatic MMR alterations have not been comprehensively characterized in breast cancer. In this study, we integrated genomic, transcriptomic, and clinical data from over 3000 breast cancer cases across six public cohorts. Our findings revealed that 1.2% of breast cancers harbored oncogenic somatic MMR alterations, with triple-negative breast cancer (TNBC) demonstrating the highest mutation rate at 3.1%. Additionally, somatic MMR alterations were significantly associated with microsatellite instability-high (MSI-H) and MMR-related mutational signatures, indicating that somatic MMR alterations led to impaired function of the MMR system. Biallelic inactivation of MMR genes resulted in a more pronounced loss of MMR function compared to monoallelic inactivation. Importantly, these MMR alterations significantly increased the tumor mutational burden (TMB) and neoantigen load in breast cancer, regardless of MSI-H status. These findings indicate that the frequency of MMR alterations is highest in TNBC and that MMR alterations in breast cancer can lead to MMR functional deficiencies, suggesting that some patients harboring such alterations may benefit from immunotherapy. Full article

Background and Objectives: Despite the well-established role of the BRCA and mismatch repair (MMR) genes in DNA damage repair pathways, a substantial proportion of familial cancer cases still lack pathogenic variants in those genes. Next Generation Sequencing (NGS) panels have emerged as a powerful tool to identify hereditary cancer at-risk individuals and subsequently provide them with accurate management. Materials and Methods: Families harbouring PVs in RAD50, RAD51C, RAD51D, and BRIP1 were identified by analysing a cancer-predisposing genes panel using Ion S5 system technology. A retrospective cohort of 155 families tested only for the BRCAs of MMR genes were reanalysed, prompted by an increase in familial cases or new cancer diagnoses among index cases. Results: We identified 40 families through molecular reanalysis (33 with Hereditary Breast and Ovarian Cancer (HBOC) and 7 with Lynch Syndrome (LS)), with positive test results among 155 families lacking BRCA or MMR mutations. The most frequently mutated genes after ATM and CHEK2 were BRIP1, RAD51D, and RAD51C with 16, 13, and 9 positive families, respectively. The phenotype–genotype correlations not only revealed ovarian and HER-negative breast cancer predispositions but also other cancer types, particularly lung and gastric, and individuals with a second or third distinct cancer episode. Conclusions: Broader ranges of malignancies, including gastric, lung, and bladder, have been identified among BRIP1, RAD51D, and RAD51C positive families. The results generated using NGS provide a comprehensive genetic landscape in each patient that could explain the diversity of phenotypes shown in PV families that, combined with non-genetic factors, might enable accurate surveillance and personalized treatments. NGS reanalysis doubled our diagnostic yield and was a good strategy to identify hereditary cancer families that would otherwise be overlooked. Full article

Lynch syndrome (LS)—also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC)—is caused by pathogenic germline mutations in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Although it accounts for only 1–5% of all colorectal cancers (CRCs), LS presents with a particularly high lifetime cancer risk and often occurs at younger ages. Identifying LS in patients under 60 years old is crucial for targeted surveillance and early interventions. Variations in clinical presentation and prognosis may exist based on the specific gene mutated, yet these patterns are not fully elucidated. This review aims to synthesize data on clinical outcomes among LS patients under 60, with an emphasis on how different MMR gene mutation patterns might influence prognosis, survival, and treatment decisions. Five population-based studies examining CRC patients younger than 60 years were included according to predefined eligibility criteria. Two independent reviewers screened and extracted data focusing on MMR deficiency detection methods (microsatellite instability [MSI] and/or immunohistochemistry [IHC]), rates of confirmed germline mutations, frequency of BRAF testing, and clinical endpoints such as stage distribution, survival outcomes, and recurrence. Risk of bias was assessed using standardized tools appropriate to each study design. The synthesis focused on comparing outcomes among individuals with MLH1, MSH2, MSH6, and PMS2 mutations, as well as delineating the proportion of patients with sporadic MSI under 60 years of age. Across the five studies, MSI positivity in CRC patients under 60 years ranged from 7.5% to 13%. The frequency of confirmed germline MMR mutations varied between 0.8% and 5.2% in specific cohorts, aligning with LS prevalence estimates of 1–5%. Different mutation patterns correlated with some variation in clinical presentation. Cases with MSH2 and MLH1 mutations more frequently exhibited synchronous or metachronous tumors, while MSH6 and PMS2 mutations displayed more heterogeneous IHC patterns. Where survival data were provided, LS patients under 60 years had better overall survival compared to MMR-proficient individuals, though some studies also noted a potential lack of benefit from standard 5-fluorouracil adjuvant therapy in MMR-deficient tumors. Screening by MSI or by IHC—supplemented with BRAF mutation testing to exclude sporadic MSI—facilitates early detection of LS in CRC patients under 60 and highlights notable differences between mutation types. Although overall outcomes for LS patients can be favorable, especially for stage II disease, the precise impact of each specific mutated gene on clinical course remains heterogeneous. Future large-scale prospective studies are needed to clarify optimal screening protocols and individualized treatment strategies for LS patients under 60. Full article

Ovarian cancer (OC) is a highly heterogeneous malignancy, often characterized by complex genomic alterations that drive tumor progression and therapy resistance. In this paper, we report a novel de novo BRCA2 germline variant NM_000059.3:c.(8693_8695delinsGT) associated with early-onset OC that featured two regions with differential MMR (Mismatch Repair) gene expression. To date, only six cases of de novo BRCA2 variants have been reported, none of which were associated with early-onset high-grade serous OC. The immunohistochemical analysis of MMR genes revealed two distinct tumor areas, separated by a clear topographic boundary, with the heterogeneous expression of MLH1 and PMS2 proteins. Seventy-five percent of the tumor tissue showed positivity, while the remaining 25% exhibited a complete absence of expression, underscoring the spatial variability in MMR gene expression within the tumor. Integrated comparative spatial genomic profiling identified several tumor features associated with the genetic variant as regions of loss of heterozygosity (LOH) that involved BRCA2 and MLH1 genes, along with a significantly higher mutational tumor burden in the tumor area that lacked MLH1 and PMS2 expression, indicating its further molecular evolution. The following variants were acquired: c.6572C>T in NOTCH2, c.1852C>T in BCL6, c.191A>T in INHBA, c.749C>T in CUX1, c.898C>A in FANCG, and c.1712G>C in KDM6A. Integrated comparative spatial proteomic profiles revealed defects in the DNA repair pathways, as well as significant alterations in the extracellular matrix (ECM). The differential expression of proteins involved in DNA repair, particularly those associated with MMR and Base Excision Repair (BER), highlights the critical role of defective repair mechanisms in driving genomic instability. Furthermore, ECM components, such as collagen isoforms, Fibrillin-1, EMILIN-1, Prolargin, and Lumican, were found to be highly expressed in the MLH1/PMS2-deficient tumor area, suggesting a connection between DNA repair deficiencies, ECM remodeling, and tumor progression. Thus, the identification of the BRCA2 variant sheds light on the poorly understood interplay between DNA repair deficiencies and ECM remodeling in OC, providing new insights into their dual role in shaping tumor evolution and suggesting potential targets for novel therapeutic strategies. Full article

Ionizing radiation is mutagenic and carcinogenic, and it is reported to induce primary and secondary tumors with intestinal tumors being one of the most commonly observed. However, the pathological and molecular mechanism(s) underlying the radiation-associated tumorigenesis remain unclear. A link between radiation and somatic tumorigenesis partly through genetic, epigenetic alteration and/or regulation of mismatch repair (MMR) genes has been hypothesized for the first time within this review. Clinical observations and experimental findings provide significant support for this association including MMR mutations as well as altered MMR RNA and protein expressions that occurred post-exposure, although existing evidence in published literature is sparse in this niche area. Some speculative mechanisms are suggested with this review to inform future research. Further studies are needed to understand the roles of the MMR system in response to radiation and to test this possible connection which could potentially provide useful and urgently needed information for clinical guidance. Full article

Lynch syndrome, one of the most common genetic syndromes predisposing to cancer, is associated with a series of malignant conditions, among which the most frequent is colorectal cancer, but gynecologic cancers (especially endometrial) are also quite common. Despite the significant progress made in understanding this condition over time, there are still aspects in managing this condition that have not demonstrated clear benefits. This article aims to summarize the recommendations of international societies and present the latest developments in managing Lynch syndrome, focusing on gynecologic cancer screening and possible prevention strategies. Advances in genetic testing procedures and discoveries related to the association between oncological pathology frequency and the affected pathogenic variant type will probably lead to personalized medicine focused on the individual patient in the coming years. Although various screening methods for gynecological cancers in patients with Lynch syndrome have been used over time, they have not shown significant survival benefits. This highlights the need for studying and implementing new screening and diagnostic methods, which have been under investigation in recent years and are mentioned in this article. Full article

Predictive biomarkers for immune checkpoint inhibitors (ICIs) in solid tumors such as melanoma, hepatocellular carcinoma (HCC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial carcinoma, renal cell carcinoma (RCC), or urothelial carcinoma (UC) include programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), defective deoxyribonucleic acid (DNA) mismatch repair (dMMR), microsatellite instability (MSI), and the tumor microenvironment (TME). Over the past decade, several types of ICIs, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, anti-programmed cell death 1 (PD-1) antibodies, anti-programmed cell death ligand 1 (PD-L1) antibodies, and anti-lymphocyte activation gene-3 (LAG-3) antibodies have been studied and approved by the Food and Drug Administration (FDA), with ongoing research on others. Recent studies highlight the critical role of the gut microbiome in influencing a positive therapeutic response to ICIs, emphasizing the importance of modeling factors that can maintain a healthy microbiome. However, resistance mechanisms can emerge, such as increased expression of alternative immune checkpoints, T-cell immunoglobulin (Ig), mucin domain-containing protein 3 (TIM-3), LAG-3, impaired antigen presentation, and alterations in the TME. This review aims to synthesize the data regarding the interactions between microbiota and immunotherapy (IT). Understanding these mechanisms is essential for optimizing ICI therapy and developing effective combination strategies. Full article

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAF^V600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types. Full article

Germline (Lynch syndrome, LS) and somatic deficiencies of mismatch repair proteins (MMRd) are linked to colorectal and endometrial cancer; however, their prognostic impact in Asian populations remains unclear. This prospective cohort study aimed to determine the prevalence and outcome of germline and somatic MMRd in cancer patients suspected of LS. Patients with colorectal or endometrial cancer suspected of LS were enrolled and underwent gene sequencing for germline MMRd (gMMRd) and immunohistochemistry staining of MMR proteins in a subset of the pathological samples (pMMRd). Among the 451 enrolled patients, 36 patients were gMMRd (+). Compared with gMMRd (−) patients, the 10-year relapse-free survival in gMMRd (+) patients was significantly higher (100% vs. 77.9%; p = 0.006), whereas the 10-year overall survival was similar (100% vs. 90.9%; p = 0.12). Among the 102 gMMRd (−) patients with available pMMR status, 13.7% were pMMRd (+). The 5-year relapse-free survival was 62.9% in gMMRd (−) pMMRd (+) patients and 35.0% in gMMRd (−) pMMRd (−) patients, both lower than gMMRd (+) patients (100%; p < 0.001). This study showed that having LS confers a favorable outcome in colorectal and endometrial cancer patients and highlights the importance of germline genetic testing following the detection of somatic MMRd. Full article

Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR deficiency (MMR-D). Here, we estimated the prevalence of MSI in PC, investigated germline and somatic mutations in the three MMR genes (MLH1, MSH2, and MSH6), and assessed the relationship between MMR genes mutations and MSI status in PC. Clinical specimens from PC patients were analyzed using targeted next-generation sequencing, including paired normal and tumor specimens from 155 patients, tumor-only specimens from 86 patients, and normal-only specimens from 379 patients. The MSI status of 235 PCs was assessed via PCR. Pathogenic/likely pathogenic (P/LP) germline variants in the MMR genes were identified in 1.1% of patients, while somatic variants were found in 2.6% of patients. No MSI-H tumors were detected. One patient carried two variants (P (VAF = 0.57) and LP (VAF = 0.25)) simultaneously; however, their germline/somatic status remains unknown due to the investigation focusing solely on the tumor and MSI analysis was not performed for this patient. MSI is rare in PC, even in tumors with MMR genes mutations. Our findings underscore the importance of assessing tumor MMR-D status in PC patients with confirmed Lynch syndrome when deciding whether to prescribe immunotherapy. Full article

Endometriosis is a frequent, estrogen-dependent, chronic disease, characterized by the presence of endometrial glands and stroma outside of the uterine cavity. Although it is not considered a precursor of cancer, endometriosis is associated with ovarian cancer. In this review, we summarized the evidence that clear-cell and endometrioid ovarian carcinomas (endometriosis-associated ovarian carcinoma—EAOC) may arise in endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interaction domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in phosphatidylinositol 3-kinase (PI3K) which frequently coexist. Recent studies have also suggested the simultaneous role of the PTEN tumor-suppressor gene in the early malignant transformation of endometriosis and the contribution of deficient MMR (mismatch repair) protein status in the pathogenesis of EAOC. In addition to activating and inactivating mutations in cancer driver genes, the complex pathogenesis of EAOC involves multiple other mechanisms such as the modulation of cancer driver genes via the transcriptional and post-translational (miRNA) modulation of cancer driver genes and the interplay with the inflammatory tissue microenvironment. This knowledge is being translated into the clinical management of endometriosis and EAOC. This includes the identification of the new biomarkers predictive of the risk of endometriosis and cancer, and it will shape the precision oncology treatment of EAOC. Full article