Search

Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic “two-hit” model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.

Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and noncoding cancer driver plexuses from somatic mutations. However, differentiating driver from passenger events among noncoding genetic variants remains a challenge. Herein, we reveal cancer-driver cis-regulatory elements linked to transcription factors previously shown to be involved in development of luminal breast cancers by defining a tumor-enriched catalogue of approximately 100,000 unique cis-regulatory elements from 26 primary luminal estrogen receptor (ER)+ progesterone receptor (PR)+ breast tumors. Integrating this catalog with somatic mutations from 350 publicly available breast tumor whole genomes, we uncovered cancer driver cistromes, defined as the sum of binding sites for a transcription factor, for ten transcription factors in luminal breast cancer such as FOXA1 and ER, nine of which are essential for growth in breast cancer with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of noncoding mutations over cis-regulatory elements concatenated into a functional unit.Implications:Mapping the accessible chromatin of luminal breast cancer led to discovery of an accumulation of mutations within cistromes of transcription factors essential to luminal breast cancer. This demonstrates coopting of regulatory networks to drive cancer and provides a framework to derive insight into the noncoding space of cancer.

Supplementary Figure from Mutations in Noncoding Cis-Regulatory Elements Reveal Cancer Driver Cistromes in Luminal Breast Cancer

Supplementary Table from Mutations in Noncoding Cis-Regulatory Elements Reveal Cancer Driver Cistromes in Luminal Breast Cancer

Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and noncoding cancer driver plexuses from somatic mutations. However, differentiating driver from passenger events among noncoding genetic variants remains a challenge. Herein, we reveal cancer-driver cis-regulatory elements linked to transcription factors previously shown to be involved in development of luminal breast cancers by defining a tumor-enriched catalogue of approximately 100,000 unique cis-regulatory elements from 26 primary luminal estrogen receptor (ER)+ progesterone receptor (PR)+ breast tumors. Integrating this catalog with somatic mutations from 350 publicly available breast tumor whole genomes, we uncovered cancer driver cistromes, defined as the sum of binding sites for a transcription factor, for ten transcription factors in luminal breast cancer such as FOXA1 and ER, nine of which are essential for growth in breast cancer with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of noncoding mutations over cis-regulatory elements concatenated into a functional unit. Implications: Mapping the accessible chromatin of luminal breast cancer led to discovery of an accumulation of mutations within cistromes of transcription factors essential to luminal breast cancer. This demonstrates coopting of regulatory networks to drive cancer and provides a framework to derive insight into the noncoding space of cancer.

A person’s germline genome strongly influences their risk of developing cancer. Yet the molecular mechanisms linking the host genome to the specific somatic molecular phenotypes of individual cancers are largely unknown. We quantified the relationships between germline polymorphisms and somatic mutational features in prostate cancer. Across 1,991 prostate tumors, we identified 23 co-occurring germline and somatic events in close 2D or 3D spatial genomic proximity, affecting 10 cancer driver genes. These driver quantitative trait loci (dQTLs) overlap active regulatory regions, and shape the tumor epigenome, transcriptome and proteome. Some dQTLs are active in multiple cancer types, and information content analyses imply hundreds of undiscovered dQTLs. Specific dQTLs explain at least 16.7% ancestry-biases in rates ofTMPRSS2-ERGgene fusions and 67.3% of ancestry-biases in rates ofFOXA1point mutations. These data reveal extensive influences of common germline variation on somatic mutational landscapes.

Lorises are a group of globally threatened strepsirrhine primates that exhibit many unusual physiological and behavioral features, including a low metabolic rate, slow movement, and hibernation. Here, we assembled a chromosome-level genome sequence of the pygmy loris ( Xanthonycticebus pygmaeus ) and resequenced whole genomes from 50 pygmy lorises and 6 Bengal slow lorises ( Nycticebus bengalensis ). We found that many gene families involved in detoxification have been specifically expanded in the pygmy loris, including the GSTA gene family, with many newly derived copies functioning specifically in the liver. We detected many genes displaying evolutionary convergence between pygmy loris and koala, including PITRM1. Significant decreases in PITRM1 enzymatic activity in these two species may have contributed to their characteristic low rate of metabolism. We also detected many evolutionarily convergent genes and positively selected genes in the pygmy loris that are involved in muscle development. Functional assays demonstrated the decreased ability of one positively selected gene, MYOF, to up-regulate the fast-type muscle fiber, consistent with the lower proportion of fast-twitch muscle fibers in the pygmy loris. The protein product of another positively selected gene in the pygmy loris, PER2 , exhibited weaker binding to the key circadian core protein CRY, a finding that may be related to this species’ unusual circadian rhythm. Finally, population genomics analysis revealed that these two extant loris species, which coexist in the same habitat, have exhibited an inverse relationship in terms of their demography over the past 1 million years, implying strong interspecies competition after speciation.

BackgroundLatino men who have sex with men (MSM) in San Diego have poor HIV testing and prevention outcomes compared with non-Latino White men. Peer navigation (PN) is a promising evidence-based intervention to reduce disparities but needs tailoring for Latino MSM.SettingsHealth centers near the US-Mexico border.MethodsUsing the Exploration, Preparation, Implementation, Sustainment Framework, we conducted mixed-methods implementation science study. In phase I, we conducted interviews with Latino men (n = 15), focus groups with staff (n = 7), and surveys with all to understand the Exploration, Preparation, Implementation, Sustainment factors associated with HIV testing and care linkage. In phase II, we conducted 31 web-based surveys with Latino men and staff to rank intervention and implementation strategies from phase I. Quantitative data were analyzed descriptively, integrated with qualitative data, and reviewed by our community-academic partnership to develop an implementation model.ResultsLatino men (N = 15) were 94% Spanish speaking, 67% gay identified, 27% US born, and their suggestions were to have navigators use peer referral to address barriers such as stigma; use the Latino social network to expand reach, leverage social media for peer-led intervention, and disseminate HIV information. Staff (N = 26) were 77% Spanish speaking, 35% gay-identified, 96% trained in cultural competency, and suggested including culturally appropriate HIV educational materials in Spanish, status and identity neutral programs, administrative/supervisorial/training structure for PNs, and PN compensation and team integration. Overall, results emphasized a need for a formalized PN model centered on referrals and using existing Latino community social networks.ConclusionsFindings can be packaged for future implementation of PN programs for Latino MSM.

Inherited genetic variation profoundly influences cancer risk and outcome. While the impact of germline single nucleotide polymorphisms has been well-studied in several cancer types, the effects of germline structural variants (gSVs) on cancer biology and clinical outcomes is largely unknown. From our cohort of 300 men with localized, intermediate risk prostate cancer, we identified 6,003 gSVs present in at least 3% of patients; 48 were associated with recurrent somatic alterations or clinical outcome. Of these, approximately 50% were associated with expression of nearby genes or intersected with exons or regulatory regions. Using external cohorts, we validated three gSVs that were strongly associated with poor clinical outcomes, including an inversion at chr14q24.1 present in ~20% of patients. Notably, a strong synergistic effect on outcome was observed in patients with somatic TP53 alterations or high genomic instability, defining a new aggressive prostate cancer subtype with chr14INV as a novel, recurrent biomarker. Citation Format: Nicholas K. Wang, Alexandre Rouette, Kathleen E. Houlahan, Takafumi N. Yamaguchi, Julie Livingstone, Chol-Hee Jung, Peter Georgeson, Michael Fraser, Yu-Jia Shiah, Cindy Q. Yao, Vincent Huang, Natalie S. Fox, Natalie Kurganovs, Katayoon Kasaian, Veronica Y. Sabelnykova, Jay Jayalath, Kenneth Weke, Helen Zhu, Theodorus van der Kwast, Tony Papenfuss, Housheng H. He, Niall M. Corcoran, Robert G. Bristow, Alexandre R. Zlotta, Christopher Hovens, Paul C. Boutros. Germline structural variants shape prostate cancer clinical and molecular evolution. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4305.

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identified binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.

Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and noncoding cancer driver plexuses from somatic mutations. However, differentiating driver from passenger events among noncoding genetic variants remains a challenge. Herein, we reveal cancer-driver

Current knowledge of plesiosaurs of clade Cryptoclidia is constrained by a lack of fossils from outside the Oxford Clay deposits of England. Recent fleldwork in the Sundance Formation of the Bighorn Basin, Wyoming, has resulted in the recovery of significant new fossils of cryptoclidid plesiosaurs, including the small-bodied form Tatenectes laramiensis. A new partial skeleton of this taxon is reported here; it is the most complete and best-preserved example of the taxon found to date, comprising a complete dorsal vertebral series, many ribs and gastralia, and a complete pelvic girdle. This skeleton illuminates several unique features of the taxon, including a novel pattern of midline pachyostosis in the gastralia. In addition, a range of both axial and appendicular morphological features reveals that Tatenectes had a body shape unique among known plesiosaurs, characterized by extreme dorsoventral compression, and modest anteroposterior reduction. The combination of the new skeleton with informati...

A cytoplasmic manganese superoxide dismutase (cMnSOD) cDNA was cloned from the hepatopancreas of the red swamp crawfish, Procambarus clarkii. An initial cDNA fragment was identified by using degenerate primers, and the complete sequence was obtained by using RACE methodology. The full sequence comprises 1140 bp, with an open reading frame of 858 bp encoding a protein of 286 amino acids. Sequence analysis showed that this protein is highly homologous to previously obtained crustacean cMnSODs. Phylogenetic analysis clusters it with all known cMnSODs and in a group distinct from mitochondrial MnSODs. cMnSOD transcripts were detected in the gills, tail muscle, green glands, and hepatopancreas. The data provide additional evidence for the hypothesis that cMnSOD replaced CuZnSOD in crustaceans that use haemocyanin as the respiratory pigment.

Protective wear coatings for disks that incorporate a layer of nitrogenated carbon (CN X ) have recently attracted attention. The thickness and nitrogen content of such a layer affects the electrical resistivity, mechanical wear behavior, as well as lubricity and hydroscopic affinity of a disk. An optical methodology will be presented that can measure the thickness and optical constants of such CN X overcoats. The methodology relies on broad-band spectrophotometry and the Forouhi-Bloomer dispersion equations for refractive index ( n ) and extinction coefficient ( k ). A trend in the optical constants of CN X films will be described that allows rapid quantitative determination of nitrogen content. Measurements of nitrogen content ranging from about 4% to 25% will be presented. Results obtained with this methodology are compared to results from X-ray photoelectron spectroscopy (XPS). Additional outputs of optical spectra are utilized to further elucidate chemical structure.

A series of nitroflavones, 8a-p, and their corresponding aminoflavone hydrochloride salts, 10a-p, was synthesized. The preparation of nitroflavones 8b-i,o,p began with commercially available o-hydroxyacetophenones 2b-f which were converted to o-hydroxynitroacetophenones 3a-h via a variety of nitration methods, followed by condensation with nitrobenzoyl chlorides and cyclization under acidic condition. The nitroflavones 8aj-n were prepared by nitration of the corresponding flavones 7a-e. These new compounds were evaluated for their abilities to inhibit the in vitro protein-tyrosine kinase activities of p56lck, EGFr, and p60v-src, and all of the active compounds were amino-substituted flavones. None of the nitroflavones inhibited the enzymes. The most active substance in this series against p56lck was compound 10j, which had an IC50 of 18 microM. When tested versus EGFr, compounds 10a,m displayed IC50's of 8.7 and 7.8 microM, respectively. Against p60v-src, 10a,m showed IC50 values of 28.8 and 38.4 microM, respectively.

Reduction of the thickness of the diamond-like-carbon (DLC) overcoat deposited on media and head, plays an important role in enhancing areal density. This is because the DLC layer contributes directly to the spacing between media and head and increases in areal density are achieved by reducing this spacing. In fact, nowadays DLC thicknesses of the order of 50 Angstrom are required. With such ultra-thin DLC overcoats, quick and accurate thickness measurements are becoming a must. In this article, an optical technique for measuring the DLC thickness, rapidly and nondestructively is presented. The technique, termed the 'n&k Method,' is based on broad band reflectance spectrophotometry and Forouhi-Bloomer dispersion equations in the data analysis. Results for samples with DLC thicknesses ranging from approximately 25 Angstrom to 300 Angstrom are given. In addition, a typical uniformity map of DLC on a magnetic disk is presented, whereby the thickness ranges from 46 Angstrom to 50 Angstrom, with a mean value of 50 Angstrom, and standard deviation of 2 Angstrom. The determined thicknesses obtained using the 'n&k Method' is compared with those from step height measurements using stylus and atomic force microscopy (AFM). The results are consistent within the measurement error and the optical measurement has by far much better precision and repeatability.

not Available.