Incidence of brain metastasis according to patient race and primary cancer origin: a systematic review.

PURPOSE: A systematic review was conducted to investigate differences in incidence and primary origin of synchronous brain metastasis (sBM) in varying racial groups with different primary cancers. METHODS: Adhering to PRISMA 2020 guidelines a search was conducted using PubMed and Ovid databases for publications from January 2000 to January 2023, with search terms including combinations of "brain metastasis," "race," "ethnicity," and "incidence." Three independent reviewers screened for inclusion criteria encompassing studies clearly reporting primary cancer sites, patient demographics including race, and synchronous BM (sBM) incidence. RESULTS: Of 806 articles, 10 studies comprised of mainly adult patients from the United States met final inclusion for data analysis. Higher sBM incidence proportions were observed in American Indian/Alaska native patients for primary breast (p < 0.001), colorectal (p = 0.015), and esophageal cancers (p = 0.024) as well as in Asian or Pacific islanders for primary stomach (p < 0.001), thyroid (p = 0.006), and lung/bronchus cancers (p < 0.001) yet higher proportions in White patients for malignant melanoma (p < 0.001). Compared to White patients, Black patients had higher sBM incidence likelihood in breast cancer (OR = 1.27, p = 0.01) but lower likelihood in renal (OR = 0.46, p < 0.001) and esophageal cancers (OR = 0.31, p = 0.005). American Indian/Alaska native patients had a higher sBM likelihood (OR = 3.78, p = 0.004) relative to White patients in esophageal cancer. CONCLUSIONS: These findings reveal several comparative racial differences in sBM incidence arising from different primary cancer origins, underscoring a need for further research to explain these variations. Identifying the factors contributing to these disparities holds the potential to promote greater equity in oncological care according to cancer type.

Characterization of Induced Current Density During Transcorneal Electrical Stimulation to Promote Neuroprotection in the Degenerating Retina.

OBJECTIVE: Transcorneal electrical stimulation (TES) is a promising approach to delay retinal degeneration by inducing extracellular electric field-driven neuroprotective effects within photoreceptors. Although achieving precise electric field control is feasible in vitro, characterizing these fields becomes intricate and largely unexplored in vivo due to uneven distribution in the heterogeneous body. In this paper, we investigate and characterize electric fields within the retina during TES to assess the potential for therapeutic approaches Methods: We developed a computational model of a rat's head, enabling us to generate predictive simulations of the voltage and current density induced in the retina. Subsequently, an in vivo experimental setup involving Royal College of Surgeon (RCS) rats was implemented to measure the voltage across the retina using identical electrode configurations as employed in the simulations. RESULTS: A stimulation amplitude of 0.2-0.3 mA may be necessary during TES in rats to induce a current density of at least 20 A/m2 in the retina, which is the lower limit for triggering neuroprotective effects according to culture studies on neural cells. Measurement taken from cadaveric pigs' eyes revealed that a stimulation amplitude of 1 mA is necessary for achieving the same current density. CONCLUSION: The computational modeling approach presented in this study was validated with experimental data and can be leveraged for predictive simulations to optimize the electrode design and stimulation parameters of TES. SIGNIFICANCE: Once validated, the flexibility and low research cost of computational models are valuable in optimization studies where testing on live subjects is not feasible.

A comprehensive analysis of minimally differentially methylated regions common to pediatric and adult solid tumors.

Cancer is the second most common cause of death in children aged 1-14 years in the United States, with 11,000 new cases and 1200 deaths annually. Pediatric cancers typically have lower mutational burden compared to adult-onset cancers, however, the epigenomes in pediatric cancer are highly altered, with widespread DNA methylation changes. The rarity of pediatric cancers poses a significant challenge to developing cancer-type specific biomarkers for diagnosis, prognosis, or treatment monitoring. In the current study, we explored the potential of a DNA methylation profile common across various pediatric cancers. To do this, we conducted whole genome bisulfite sequencing (WGBS) on 31 recurrent pediatric tumor tissues, 13 normal tissues, and 20 plasma cell-free (cf)DNA samples, representing 11 different pediatric cancer types. We defined minimal focal regions that were differentially methylated across samples in the multiple cancer types which we termed minimally differentially methylated regions (mDMRs). These methylation changes were also observed in 506 pediatric and 5691 adult cancer samples accessed from publicly available databases, and in 44 pediatric cancer samples we analyzed using a targeted hybridization probe capture assay. Finally, we found that these methylation changes were detectable in cfDNA and could serve as potential cfDNA methylation biomarkers for early detection or minimal residual disease.

Comparative analysis of the spatial distribution of brain metastases across several primary cancers using machine learning and deep learning models.

OBJECTIVE: Brain metastases (BM) are associated with poor prognosis and increased mortality rates, making them a significant clinical challenge. Studying BMs can aid in improving early detection and monitoring. Systematic comparisons of anatomical distributions of BM from different primary cancers, however, remain largely unavailable. METHODS: To test the hypothesis that anatomical BM distributions differ based on primary cancer type, we analyze the spatial coordinates of BMs for five different primary cancer types along principal component (PC) axes. The dataset includes 3949 intracranial metastases, labeled by primary cancer types and with six features. We employ PC coordinates to highlight the distinctions between various cancer types. We utilized different Machine Learning (ML) algorithms (RF, SVM, TabNet DL) models to establish the relationship between primary cancer diagnosis, spatial coordinates of BMs, age, and target volume. RESULTS: Our findings revealed that PC1 aligns most with the Y axis, followed by the Z axis, and has minimal correlation with the X axis. Based on PC1 versus PC2 plots, we identified notable differences in anatomical spreading patterns between Breast and Lung cancer, as well as Breast and Renal cancer. In contrast, Renal and Lung cancer, as well as Lung and Melanoma, showed similar patterns. Our ML and DL results demonstrated high accuracy in distinguishing BM distribution for different primary cancers, with the SVM algorithm achieving 97% accuracy using a polynomial kernel and TabNet achieving 96%. The RF algorithm ranked PC1 as the most important discriminating feature. CONCLUSIONS: In summary, our results support accurate multiclass ML classification regarding brain metastases distribution.

CHEK2 Founder Variants and Thyroid Cancer Risk.

Background: Germline pathogenic variants in CHEK2 are associated with a moderate increase in the lifetime risk for breast cancer. Increased risk for other cancers, including non-medullary thyroid cancer (NMTC), has also been suggested. To date, data implicating CHEK2 variants in NMTC predisposition primarily derive from studies within Poland, driven by a splice site variant (c.444 + 1G>A) that is uncommon in other populations. In contrast, the predominant CHEK2 variants in non-Polish populations are c.1100del and c.470T>C/p.I157T, representing 61.1% and 63.8%, respectively, of all CHEK2 pathogenic variants in two large U.S.-based commercial laboratory datasets. To further delineate the impact of common CHEK2 variants on thyroid cancer, we aimed to investigate the association of three CHEK2 founder variants (c.444 + 1G>A, c.1100del, and c.470T>C/p.Ile157Thr) on NMTC susceptibility in three groups of unselected NMTC patients. Methods: The presence of three CHEK2 founder variants was assessed within three groups: (1) 1544 NMTC patients (and 1593 controls) from previously published genome-wide association study (GWAS) analyses, (2) 789 NMTC patients with germline exome sequencing (Oncology Research Information Exchange Network [ORIEN] Avatar), and (3) 499 NMTC patients with germline sequence data available in The Cancer Genome Atlas (TCGA). A case-control study design was utilized with odds ratios (ORs) calculated by comparison of all three groups with the Ohio State University GWAS control group. Results: The predominant Polish variant (c.444 + 1G>A) was present in only one case. The proportion of patients with c.1100del was 0.92% in the GWAS group, 1.65% in the ORIEN Avatar group, and 0.80% in the TCGA group. The ORs (with 95% confidence intervals [CIs]) for NMTC associated with c.1100del were 1.71 (0.73-4.29), 2.64 (0.95-7.63), and 2.5 (0.63-8.46), respectively. The proportion of patients with c.470T>C/p.I157T was 0.91% in the GWAS group, 0.76% in the ORIEN Avatar group, and 0.80% in the TCGA group, respectively. The ORs (with CIs) for NMTC associated with c.470T>C/p.I157T were 1.75 (0.74-4.39), 1.52 (0.42-4.96), and 2.31 (0.58-7.90), respectively. Conclusions: Our analyses of unselected patients with NMTC suggest that CHEK2 variants c.1100del and c.470T>C/p.I157T have only a modest impact on thyroid cancer risk. These results provide important information for providers regarding the relatively low magnitude of thyroid cancer risk associated with these CHEK2 variants.

OvaPrint-A Cell-free DNA Methylation Liquid Biopsy for the Risk Assessment of High-grade Serous Ovarian Cancer.

PURPOSE: High-grade serous ovarian carcinoma (HGSOC) is the most lethal epithelial ovarian cancer (EOC) and is often diagnosed at late stage. In women with a known pelvic mass, surgery followed by pathologic assessment is the most reliable way to diagnose EOC and there are still no effective screening tools in asymptomatic women. In the current study, we developed a cell-free DNA (cfDNA) methylation liquid biopsy for the risk assessment of early-stage HGSOC. EXPERIMENTAL DESIGN: We performed reduced representation bisulfite sequencing to identify differentially methylated regions (DMR) between HGSOC and normal ovarian and fallopian tube tissue. Next, we performed hybridization probe capture for 1,677 DMRs and constructed a classifier (OvaPrint) on an independent set of cfDNA samples to discriminate HGSOC from benign masses. We also analyzed a series of non-HGSOC EOC, including low-grade and borderline samples to assess the generalizability of OvaPrint. A total of 372 samples (tissue n = 59, plasma n = 313) were analyzed in this study. RESULTS: OvaPrint achieved a positive predictive value of 95% and a negative predictive value of 88% for discriminating HGSOC from benign masses, surpassing other commercial tests. OvaPrint was less sensitive for non-HGSOC EOC, albeit it may have potential utility for identifying low-grade and borderline tumors with higher malignant potential. CONCLUSIONS: OvaPrint is a highly sensitive and specific test that can be used for the risk assessment of HGSOC in symptomatic women. Prospective studies are warranted to validate OvaPrint for HGSOC and further develop it for non-HGSOC EOC histotypes in both symptomatic and asymptomatic women with adnexal masses.

An extraocular electrical stimulation approach to slow down the progression of retinal degeneration in an animal model.

Retinal diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are characterized by unrelenting neuronal death. However, electrical stimulation has been shown to induce neuroprotective changes in the retina capable of slowing down the progression of retinal blindness. In this work, a multi-scale computational model and modeling platform were used to design electrical stimulation strategies to better target the bipolar cells (BCs), that along with photoreceptors are affected at the early stage of retinal degenerative diseases. Our computational findings revealed that biphasic stimulus pulses of long pulse duration could decrease the activation threshold of BCs, and the differential stimulus threshold between ganglion cells (RGCs) and BCs, offering the potential of targeting the BCs during the early phase of degeneration. In vivo experiments were performed to evaluate the electrode placement and parameters found to target bipolar cells and evaluate the safety and efficacy of the treatment. Results indicate that the proposed transcorneal Electrical Stimulation (TES) strategy can attenuate retinal degeneration in a Royal College of Surgeon (RCS) rodent model, offering the potential to translate this work to clinical practice.

Florida-California Cancer Research, Education and Engagement (CaRE2) Health Equity Center: Structure, Innovations, and Initial Outcomes.

INTRODUCTION: The Florida-California Cancer Research, Education, and Engagement (CaRE2) Health Equity Center is a triad partnership committed to increasing institutional capacity for cancer disparity research, the diversity of the cancer workforce, and community empowerment. This article provides an overview of the structure, process innovations, and initial outcomes from the first 4 years of the CaRE2 triad partnership. METHODS: CaRE2 serves diverse populations in Florida and California using a "molecule to the community and back" model. We prioritize research on the complex intersection of biological, environmental, and social determinants health, working together with scientific and health disparities communities, sharing expertise across institutions, bidirectional training, and community outreach. Partnership progress and outcomes were assessed using mixed methods and four Program Steering Committee meetings. RESULTS: Research capacity was increased through development of a Living Repository of 81 cancer model systems from minority patients for novel cancer drug development. CaRE2 funded 15 scientific projects resulting in 38 publications. Workforce diversity entailed supporting 94 cancer trainees (92 URM) and 34 ESIs (32 URM) who coauthored 313 CaRE2-related publications and received 48 grants. Community empowerment was promoted via outreaching to more than 3000 individuals, training 145 community cancer advocates (including 28 Community Scientist Advocates), and publishing 10 community reports. CaRE2 members and trainees together have published 639 articles, received 61 grants, and 57 awards. CONCLUSION: The CaRE2 partnership has achieved its initial aims. Infrastructure for translational cancer research was expanded at one partner institution, and cancer disparities research was expanded at the two cancer centers.

Transperineal vs transrectal magnetic resonance and ultrasound image fusion prostate biopsy: a pair-matched comparison.

The objective of this study was to compare transperineal (TP) versus transrectal (TR) magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS) fusion prostate biopsy (PBx). Consecutive men who underwent prostate MRI followed by a systematic biopsy. Additional target biopsies were performed from Prostate Imaging Reporting & Data System (PIRADS) 3-5 lesions. Men who underwent TP PBx were matched 1:2 with a synchronous cohort undergoing TR PBx by PSA, Prostate volume (PV) and PIRADS score. Endpoint of the study was the detection of clinically significant prostate cancer (CSPCa; Grade Group ≥ 2). Univariate and multivariable analyses were performed. Results were considered statistically significant if p < 0.05. Overall, 504 patients met the inclusion criteria. A total of 168 TP PBx were pair-matched to 336 TR PBx patients. Baseline demographics and imaging characteristics were similar between the groups. Per patient, the CSPCa detection was 2.1% vs 6.3% (p = 0.4) for PIRADS 1-2, and 59% vs 60% (p = 0.9) for PIRADS 3-5, on TP vs TR PBx, respectively. Per lesion, the CSPCa detection for PIRADS 3 (21% vs 16%; p = 0.4), PIRADS 4 (51% vs 44%; p = 0.8) and PIRADS 5 (76% vs 84%; p = 0.3) was similar for TP vs TR PBx, respectively. However, the TP PBx showed a longer maximum cancer core length (11 vs 9 mm; p = 0.02) and higher cancer core involvement (83% vs 65%; p < 0.001) than TR PBx. Independent predictors for CSPCa detection were age, PSA, PV, abnormal digital rectal examination findings, and PIRADS 3-5. Our study demonstrated transperineal MRI/TRUS fusion PBx provides similar CSPCa detection, with larger prostate cancer core length and percent of core involvement, than transrectal PBx.

ATM-Inhibitor AZD1390 Is a Radiosensitizer for Breast Cancer CNS Metastasis.

PURPOSE: Limited effective treatments are currently available for central nervous system (CNS) metastasis (CM). This is largely driven by the inability of current therapeutics to penetrate the blood brain barrier (BBB) and the lack of preclinical models for testing new therapies. Here we study the efficacy of AZD1390, a BBB penetrating ataxia-telangiectasia mutated inhibitor, as a radiosensitizer for breast cancer CM treatment. EXPERIMENTAL DESIGN: Three patient-derived xenograft (PDX) tumors including 2 HER2+ and 1 triple-negative breast cancer harboring DNA damage response (DDR) gene mutations, were implanted subcutaneously in the flank of mice to assess tumor growth inhibition by AZD1390 combined with radiation. Animal survival was further assessed by implanting the best responding PDX model orthotopically in the brain. RESULTS: Pretreatment with AZD1390 followed by radiation therapy inhibited growth of PDX tumors implanted in the flank, and improved survival in orthotopic models with average survival of 222 days compared with 123 days in controls. Administration of AZD1390 posttreatment for 21 days had no further benefits. While the combination therapy resulted in sustained tumor inhibition, sporadic regrowth was observed in some mice 50 to 100 days posttreatment in all models. Gene expression comparing these tumors with complete responders demonstrated changes in upregulation of oncogenic proteins, which are potential drivers of tumor growth after treatment. CONCLUSIONS: Our results demonstrate that AZD1390 effectively sensitizes breast cancer CM to radiation therapy in DDR mutant tumors. This study demonstrates the potential of using AZD1390 as a novel therapeutic agent for patients with breast cancer CM.

A quantitative characterization of the spatial distribution of brain metastases from breast cancer and respective molecular subtypes.

PURPOSE: Brain metastases (BM) remain a significant cause of morbidity and mortality in breast cancer (BC) patients. Specific factors promoting the process of BM and predilection for selected neuro-anatomical regions remain unknown, yet may have major implications for prevention or treatment. Anatomical spatial distributions of BM from BC suggest a predominance of metastases in the hindbrain and cerebellum. Systematic approaches to quantifying BM location or location-based analyses based on molecular subtypes, however, remain largely unavailable. METHODS: We analyzed stereotactic Cartesian coordinates derived from 134 patients undergoing gamma- knife radiosurgery (GKRS) for treatment of 407 breast cancer BMs to quantitatively study BM spatial distribution along principal component axes and by intrinsic molecular subtype (ER, PR, Herceptin). We used kernel density estimators (KDE) to highlight clustering and distribution regions in the brain, and we used the metric of mutual information (MI) to tease out subtle differences in the BM distributions associated with different molecular subtypes of BC. BM location maps according to vascular and anatomical distributions using Cartesian coordinates to aid in systematic classification of tumor locations were additionally developed. RESULTS: We corroborated that BC BMs show a consistent propensity to arise posteriorly and caudally, and that Her2+ tumors are relatively more likely to arise medially rather than laterally. To compare the distributions among varying BC molecular subtypes, the mutual information metric reveal that the ER-PR-Her2+ and ER-PR-Her2- subtypes show the smallest amount of mutual information and are most molecularly distinct. The kernel density contour plots show a propensity for triple negative BC to arise in more superiorly or cranially situated BMs. CONCLUSIONS: We present a novel and shareable workflow for characterizing and comparing spatial distributions of BM which may aid in identifying therapeutic or diagnostic targets and interactions with the tumor microenvironment. Further characterization of these patterns with larger multi-institutional data-sets may have major impacts on treatment or management of cancer patients.

Anatomical and topographical variations in the distribution of brain metastases based on primary cancer origin and molecular subtypes: a systematic review.

BACKGROUND: While it has been suspected that different primary cancers have varying predilections for metastasis in certain brain regions, recent advances in neuroimaging and spatial modeling analytics have facilitated further exploration into this field. METHODS: A systematic electronic database search for studies analyzing the distribution of brain metastases (BMs) from any primary systematic cancer published between January 1990 and July 2020 was conducted using PRISMA guidelines. RESULTS: Two authors independently reviewed 1957 abstracts, 46 of which underwent full-text analysis. A third author arbitrated both lists; 13 studies met inclusion/exclusion criteria. All were retrospective single- or multi-institution database reviews analyzing over 8227 BMs from 2599 patients with breast (8 studies), lung (7 studies), melanoma (5 studies), gastrointestinal (4 studies), renal (3 studies), and prostate (1 study) cancers. Breast, lung, and colorectal cancers tended to metastasize to more posterior/caudal topographic and vascular neuroanatomical regions, particularly the cerebellum, with notable differences based on subtype and receptor expression. HER-2-positive breast cancers were less likely to arise in the frontal lobes or subcortical region, while ER-positive and PR-positive breast metastases were less likely to arise in the occipital lobe or cerebellum. BM from lung adenocarcinoma tended to arise in the frontal lobes and squamous cell carcinoma in the cerebellum. Melanoma metastasized more to the frontal and temporal lobes. CONCLUSION: The observed topographical distribution of BM likely develops based on primary cancer type, molecular subtype, and genetic profile. Further studies analyzing this association and relationships to vascular distribution are merited to potentially improve patient treatment and outcomes.

Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer.

BACKGROUND: The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC). METHODS: We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes. RESULTS: In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS. CONCLUSIONS: TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.

Cancer-Associated Fibroblast Subpopulations With Diverse and Dynamic Roles in the Tumor Microenvironment.

Close interactions between cancer cells and cancer-associated fibroblasts (CAF) have repeatedly been reported to support tumor progression. Yet, targeting CAFs has so far failed to show a real benefit in cancer treatment, as preclinical studies have shown that such a strategy can enhance tumor growth. Accordingly, recent paradigm-shifting data suggest that certain CAF subpopulations could also show tumor-inhibitory capabilities. The present review aims to provide an in-depth description of the cellular heterogeneity of the CAF compartment in tumors. Through combining information from different cancer types, here we define 4 main CAF subpopulations that might cohabitate in any tumor microenvironment (TME). In addition, a model for the evolution of CAFs during tumor development is introduced. Moreover, the presence of tumor-inhibitory CAFs in the TME as well as their molecular characteristics are extensively discussed. Finally, the potential cellular origins of these distinct CAF subpopulations are reviewed. To our knowledge, this is the first attempt at establishing a broad but comprehensive classification of CAF subpopulations. Altogether, the present manuscript aims to provide the latest developments and innovative insights that could help refine future therapeutic targeting of CAFs for cancer treatment.

Targeted DNA methylation from cell-free DNA using hybridization probe capture.

Cell-free (cf)DNA signatures are quickly becoming the target of choice for non-invasive screening, diagnosis, treatment and monitoring of human tumors. DNA methylation changes occur early in tumorigenesis and are widespread, making cfDNA methylation an attractive cancer biomarker. Already a proven technology for targeted genome sequencing, hybridization probe capture is emerging as a method for high-throughput targeted methylation profiling suitable to liquid biopsy samples. However, to date there are no reports describing the performance of this approach in terms of reproducibility, scalability, and accuracy. In the current study we performed hybridization probe capture using the myBaits® Custom Methyl-seq kit on 172 plasma samples and standards to evaluate its performance on cfDNA methylation analysis. The myBaits® assay showed high target recovery (>90%), demonstrated excellent reproducibility between captures (R 2 = 0.92 on average), and was unaffected by increasing the number of targets in a capture. Finally, myBaits® accurately replicated 'gold standard' beta values from WGBS (average R 2 = 0.79). The results of this study show that custom targeted methylation sequencing with myBaits® offers a cost-effective, reliable platform to profile DNA methylation at a set of discrete custom regions, with potential applicability to liquid biopsies for cancer monitoring.

Molecular drivers of tumor progression in microsatellite stable APC mutation-negative colorectal cancers.

The tumor suppressor gene adenomatous polyposis coli (APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance of aberrant regulation of intracellular WNT signaling in CRC development. Recent studies have found that early-onset CRC exhibits an increased proportion of tumors lacking an APC mutation. We set out to identify mechanisms underlying APC mutation-negative (APCmut-) CRCs. We analyzed data from The Cancer Genome Atlas to compare clinical phenotypes, somatic mutations, copy number variations, gene fusions, RNA expression, and DNA methylation profiles between APCmut- and APC mutation-positive (APCmut+) microsatellite stable CRCs. Transcriptionally, APCmut- CRCs clustered into two approximately equal groups. Cluster One was associated with enhanced mitochondrial activation. Cluster Two was strikingly associated with genetic inactivation or decreased RNA expression of the WNT antagonist RNF43, increased expression of the WNT agonist RSPO3, activating mutation of BRAF, or increased methylation and decreased expression of AXIN2. APCmut- CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and RSPO3. APCmut- CRCs comprise two groups of tumors characterized by enhanced mitochondrial activation or increased sensitivity to extracellular WNT, suggesting that they could be respectively susceptible to inhibition of these pathways.

Large-scale analysis of KMT2 mutations defines a distinctive molecular subset with treatment implication in gastric cancer.

Frequent mutations of genes in the histone-lysine N-methyltransferase 2 (KMT2) family members were identified in gastric cancers (GCs). Understanding how gene mutations of KMT2 family affect cancer progression and tumor immune microenvironment may provide new treatment strategies. A total of 1245 GCs were analyzed using next-generation sequencing, whole transcriptome sequencing, immunohistochemistry (Caris Life Sciences, Phoenix, AZ). The overall mutation rate of genes in the KMT2 family was 10.6%. Compared to KMT2-wild-type GCs, genes involved in epigenetic modification, receptor tyrosine kinases/MAPK/PI3K, and DNA damage repair (DDR) pathways had higher mutation rates in KMT2-mutant GCs (p < 0.05). Significantly higher rates of high tumor mutational burden, microsatellite instability-high/mismatch-repair deficiency (dMMR), and PD-L1 positivity were observed in KMT2-mutant GCs (p < 0.01), compared to KMT2-wild-type GCs. The association between PD-L1 positivity and KMT2 mutations remained significant in the proficient-MMR and microsatellite stable subgroup. Based on transcriptome data from the TCGA, cell cycle, metabolism, and interferon-α/ß response pathways were significantly upregulated in KMT2-mutant GCs than in KMT2-wild-type GCs. Patients with KMT2 mutation treated with immune checkpoint inhibitors had longer median overall survival compared to KMT2-wild-type patients with metastatic solid tumors (35 vs. 16 months, HR = 0.73, 95% CI: 0.62-0.87, p = 0.0003). In conclusion, this is the largest study to investigate the distinct molecular features between KMT2-mutant and KMT2-wild-type GCs to date. Our data indicate that GC patients with KMT2 mutations may benefit from ICIs and drugs targeting DDR, MAPK/PI3K, metabolism, and cell cycle pathways.

Authorship Patterns in Cancer Genomics Publications Across Africa.

PURPOSE: Authorship is a proxy indicator of research capacity. Understanding the research capacity is imperative for developing population-specific cancer control strategies. This is particularly apropos for African nations, where mortality from cancer is projected to surpass that from infectious disease and the populations are critically under-represented in cancer and genomics studies. Here, we present an analysis and discussion of the patterns of authorship in Africa as they pertain to cancer genomics research across African countries. METHODS: PubMed metadata of relevant cancer genomics peer-reviewed publications on African populations, published between January 1, 1990, and December 31, 2019, were retrieved and analyzed for patterns of authorship affiliation using R packages, RISmed, and Pubmed.mineR. RESULTS: The data showed that only 0.016% (n = 375) of cancer publications globally were on cancer genomics of African people. More than 50% of the first and last authors of these publications originated from the North African countries of Tunisia, Morocco, Egypt, and Algeria. South Africa (13.6% and 12.7%) and Nigeria (2.2% and 1.9%) were the Sub-Saharan African countries most represented by first and last authorship positions, respectively. The United States contributed 12.6% of first and last authored papers, and nearly 50% of all African countries had no contributing author for the publications we reviewed. CONCLUSION: This study highlights and brings awareness to the paucity of cancer genomics research on African populations and by African authors and identifies a need for concerted efforts to encourage and enable more research in Africa, needed for achieving global equity in cancer outcomes.