Citations

Background. The VPS35 p.D620N variant causes autosomal dominant Parkinson's disease (PD) and has been shown to activate the LRRK2 kinase pathway, resulting in increased Rab substrate phosphorylation in peripheral immune cells and elevated urinary bis(monoacylglycero)phosphate (BMP) levels. Recently, a VPS35 variant of unknown significance (c.959C>T; p.A320V) was described in two late-onset sporadic PD patients. Methods. We ascertained a family from the Canary Islands in which six siblings were chronically exposed to high doses of pesticides. Three siblings developed levodopa-responsive, akinetic-rigid PD, while the other three remained unaffected. Whole-exome sequencing was performed in the three affected siblings. The frequency of the resulting candidate variant was assessed in 23,327 PD patients and 9,235 controls from four independent cohorts. Members of this pedigree and unrelated controls were assessed for LRRK2 kinase activity in monocytes and neutrophils and BMP levels in urine. Results. The three affected siblings were all heterozygous for p.A320V, whereas the three unaffected siblings did not carry the variant. In the combined PD case-control cohort, p.A320V was identified in six patients and one control. However, unlike p.D620N, heterozygous carrier status for p.A320V was not associated with increased LRRK2 kinase activity or elevated urine BMP levels. Conclusions. While VPS35 p.A320V co-segregated with PD in this family, it did not exhibit the characteristic LRRK2-associated biomarker signature observed in VPS35 p.D620N carriers. It is possible that p.A320V exerts a subtle effect on VPS35 function that was not captured by the assays performed and that chronic pesticide exposure contributed to disease penetrance in this pedigree.

Abstract Background Molecular underpinnings and clinical characteristics of ERBB2/HER2-mutated colorectal cancers (CRCs) remain poorly understood. We aimed to comprehensively characterize the genomic landscape and clinical features of ERBB2/HER2-mutated CRC and to compare them with those of ERBB2/HER2-amplified CRC. Patients and methods We analyzed cBioPortal data from 4348 CRC patients with available ERBB2/HER2 profiling. Clinicodemographic features, microsatellite instability (MSI), tumor mutational burden, and alterations in 94 cancer-associated genes were evaluated using chi-square/Fisher’s exact test, Kruskal–Wallis test, and hierarchical clustering. Results ERBB2/HER2 putative driver mutations were identified in 95 patients (2.2%), amplifications in 87 (2.0%), and wild-type status in 4166 (95.8%). In the overall cohort, ERBB2/HER2-mutated tumors demonstrated significant KRAS enrichment (50.5%) compared to wild-type (37.7%; P = .014) and amplified tumors (18.4%; P < .001), alongside MSI enrichment (37.2% vs 1.6%; P < .001), elevated tumor mutational burden, and right-sided predominance. ERBB2/HER2-mutated tumors also showed broad driver co-alterations largely reflecting their MSI background. In contrast, ERBB2/HER2-amplified tumors exhibited left-sided predominance, with microsatellite stable (MSS)-restricted analyses revealing selective mutual exclusivity with KRAS (Log2 OR = −1.58; q = 0.019) and TP53 co-occurrence (Log2 OR = 2.04; q = 0.019). Hierarchical clustering confirmed that mutated and amplified tumors consistently occupy separate clusters across anatomical sites. Conclusion ERBB2/HER2 mutations and amplifications represent molecularly and clinically distinct subgroups. ERBB2/HER2-mutated tumors are characterized by an MSI-enriched, hypermutated background with frequent concurrent KRAS alterations, whereas amplified tumors exhibit selective KRAS mutual exclusivity and TP53 co-occurrence. These exploratory findings support alteration-specific therapeutic strategies in CRC.

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.

Abstract Background The most compelling advantage that photon counting detectors (PCDs) currently have over energy integrating detectors (EIDs) for CT applications may be their improved spatial resolution. However, PCDs are difficult to manufacture. Next‐generation EIDs using conventional scintillator sensors could be easier to mass produce, but their spatial resolution is thought to be limited by fill factor considerations. Specifically, each EID pixel comprises a block of scintillator surrounded by inactive, optically reflective septa. The minimum width of optically reflective septa is ∼0.1 mm, and unless this is shrunk, decreases in pixel pitch inevitably cause an increasing fraction of dead space. Purpose To propose a modified system geometry in which the detector pixels are tilted by a few degrees, such that rays that are incident on reflective septa would later encounter scintillator. Because reflective septa are nearly transparent to x‐rays compared to scintillator, this geometry restores much of the lost fill factor. Methods Tilting can be achieved in several different ways. We discuss three implementation options: individual detector modules may be tilted, with gaps between modules that are seamless from the perspective of the x‐ray source; the whole detector can be arranged to point towards a “false” focal spot that is offset slightly from the true focal spot; the scintillator wafer can structured differently, e.g. by sawing it at an angle. The pros and cons of each option are discussed. Tilting introduces blurring, but a smaller pixel size improves resolution, and the combination of both improves both resolution and fill factor. We used Monte Carlo simulations to compare a conventional detector with 1.0 mm, 0.75, or 0.5 mm pixel pitch to a tilted detector with 0.5 mm pixel pitch. We assumed negligible optical crosstalk and electronic noise, that the scintillator was 1.5 mm thick with attenuation similar to gadolinium oxysulfide, that the reflective septa was 0.1 mm wide at standard resolution or 0.08 mm at higher resolutions and composed of a low‐attenuating polymer similar to acrylic infused with 20% titanium content. We also compared this to a simple model of a CdTe detector with 1.6 mm thickness, 0.3 mm pixel pitch, and Gaussian charge sharing. Results Tilt increases the aperture of the pixel in an energy‐dependent fashion. With a 1D ASG (85% fill factor) and at 120 kVp, the detection efficiencies (DQE(0)) of a conventional detector at 1.0 mm, conventional detector at 0.5 mm pixel pitch, CdTe detector, and tilted detector at 0.5 mm pixel pitch are 65%, 55%, 66%, and 64%, respectively. With a sparse 2D ASG (1.5 × 3.0 mm openings, 86% fill factor), the DQE(0) of a tilted detector with 0.75 mm is 69%. The DQE(0) of all detectors decreases at higher energy because of punch‐through. Conclusions By tilting detector modules a few degrees, energy‐integrating detectors can provide increases in spatial resolution without the expected losses in fill factor. This architecture could bring the resolution improvements associated with photon counting CT into the domain of energy‐integrating detectors equipped with conventional scintillator sensors.

210 Background: ERBB2/HER2 amplification defines a rare but clinically distinct subtype of colorectal cancer (CRC), associated with favorable responses to HER2-targeted therapies. In contrast, ERBB2/HER2 -mutant CRCs show limited therapeutic benefit, and their clinical and molecular features remain poorly defined. This study investigated the molecular and clinical features of ERBB2/HER2 -mutant CRCs to provide insight into the molecular basis of their differential therapeutic vulnerabilities compared to amplified CRC. Methods: CRC cases were identified from cBioPortal studies with available clinical and ERBB2/HER2 genomic data. After quality control and deduplication, the cohort included 4407 unique cases: 97 with driver mutation(s) only (2.2%), 86 with amplification only (2%), and 4224 wild-type (95.9%). Demographic, clinical, and molecular features, including microsatellite instability (MSI), tumor mutational burden (TMB), and alterations in 94 oncogenic pathway genes, were compared across groups. Statistical analyses used chi-square/Fisher’s exact tests for categorical data, Kruskal-Wallis tests for continuous variables, and the Benjamini-Hochberg correction for multiple comparisons. Odds ratios and FDR-adjusted p-values were calculated to assess associations. Results: Across groups, the distributions of gender, race, and primary cancer site (colon or rectal cancer) were comparable. However, significant differences were observed in age (mean 58.7 ± 15.0 years for ERBB2/HER2 -mutant, 55 ± 13.9 for amplified, and 59 ± 14.8 for wild-type; p = 0.035) and tumor sidedness (among ERBB2/HER2 -mutant cases: right-colon 30.8%, left-colon 15.2%; among ERBB2/HER2 -amplified: right-colon 12.1%, left-colon 37.9%, p = 0.011). KRAS alterations were significantly more common in ERBB2/HER2 -mutant CRCs (50.5%) compared with both amplified (19.8%) and wild-type (37.6%). MSI-H was detected in 34.5% of ERBB2/HER2 -mutant cases, whereas no MSI-H was observed among amplified tumors (p < 0.001). Expectedly, ERBB2/HER2 -mutant tumors exhibited a hypermutated phenotype, with significantly higher TMB (30.3 ± 45.5) and total mutation count (232.8 ± 926.0), compared to amplified (6.1 ± 9.7 and 15.3 ± 28.4) and wild-type (10.5 ± 20.3 and 126.3 ± 424.5; both p < 0.001). Conversely, ERBB2/HER2 -amplified tumors had the highest fraction of overall genomic alterations including chromosomal changes (0.24 ± 0.17 in amplified vs 0.14 ± 0.17 in mutants and 0.20 ± 0.16 in wild-type; p < 0.001). Hierarchical clustering demonstrated that ERBB2/HER2 -mutant tumors form a distinct molecular cluster, whereas amplified tumors cluster closely with wild-type CRC. Conclusions: ERBB2/HER2 - mutant and amplified CRCs show highly distinct genomic and clinical features, supporting the need for tailored treatment approaches.