FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study

Background: In preclinical gastric cancer (GC) models, FGFR2 amplification was associated with increased tumour cell proliferation and survival, and drugs targeting this pathway are now in clinical trials. Methods: FGFR2 FISH was performed on 961 GCs from the United Kingdom, China and Korea, and the relationship with clinicopathological data and overlap with HER2 amplification were analysed. Results: The prevalence of FGFR2 amplification was similar between the three cohorts (UK 7.4%, China 4.6% and Korea 4.2%), and intratumoral heterogeneity was observed in 24% of FGFR2 amplified cases. FGFR2 amplification was associated with lymph node metastases (Po0.0001). FGFR2 amplification and polysomy were associated with poor overall survival (OS) in the Korean (OS: 1.83 vs 6.17 years, P ¼ 0.0073) and UK (OS: 0.45 vs 1.9 years, Po0.0001) cohorts, and FGFR2 amplification was an independent marker of poor survival in the UK cohort (P ¼ 0.0002). Co-amplification of FGFR2 and HER2 was rare, and when high-level amplifications did co-occur these were detected in distinct areas of the tumour. Conclusion: A similar incidence of FGFR2 amplification was found in Asian and UK GCs and was associated with lymphatic invasion and poor prognosis. This study also shows that HER2 and FGFR2 amplifications are mostly exclusive

Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62

Funding Information: The authors recognize and appreciate the patients and families who contributed to the current study. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the Icelandic cancer patients. We thank deCODE genetics for access to data and facilities, assistance with data analysis and helpful discussions. This work was supported by the National Institutes of Health [P01HG000205 to SUG and HPJ, 1U01CA15192001-A1 to HPJ, 1U01CA176299 to HPJ, HG006137-07 to HPJ, R01 CA116468NIH to DAJ, 5K08CA166512 to LDN]; Intermountain Healthcare to SUG, JC and HPJ; a Research Scholar Grant from the American Cancer Society [RSG-13-297-01-TBG to JC and HPJ]; Clayville Foundation to HPJ; Gastric Cancer Foundation to HPJ and LDN; the Samuel Waxman Cancer Research Foundation to DAJ; Oklahoma Center for Adult Stem Cell Research (OCASCR) to DAJ; Oklahoma Medical Research Foundation (OMRF) to DAJ; the Conquer Cancer Foundation (Young Investigator Award) to LDN; the Carl Kawaja Foundation to LDN; the Research Fund of Iceland [130230-0529 to ES and MHO, 184861-052 to ES, 184727-051 to MHO]; and a grant from the Icelandic Cancer Society Research Fund to MHO. Publisher Copyright: © 2022, The Author(s).Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development.Peer reviewe

Genome-wide meta-analysis identifies nine loci associated with higher risk of hepatocellular carcinoma development

Background &amp; Aims: The genetic underpinnings of hepatocellular carcinoma (HCC) remain largely unknown. Thus, we aimed to identify new genetic risk loci for HCC. Methods: We performed a genome-wide association study (GWAS) meta-analysis of 11 cohorts with validation in two independent cohorts. The identified variants were tested for effects on other hepatobiliary endpoints, and on incident HCC stratified by underlying risk factors. Mendelian randomization was used to assess the causal effects of a range of traits on the risk of HCC. Results: In meta-analyses totaling 6,540 cases and 2,096,759 controls, we identified 10 associations with HCC, of which five (in KLF15, HSD17B13, APOE, HFE, and MTARC1) have not previously been implicated in HCC at genome-wide statistical significance. Known associations in PNPLA3, TM6SF2, TERT, IFNL4, and HLA-DP1 were confirmed. All associations except KLF15 were validated in independent cohorts totaling 7,630 cases and 733,689 controls. The largest per-allele effect was seen for TM6SF2 (beta = 0.61) followed by PNPLA3 (0.55), HFE (0.45), IFNL4 (0.31), APOE (0.27), HSD17B13, HLA-DP1, and TERT (all 0.21), and MTARC1 (0.17). The identified variants had comparable effects on incident HCC in individuals with prevalent obesity, a high alcohol intake, diabetes, or cirrhosis. Mendelian randomization analyses confirmed the causal role of obesity in HCC. We found strong correlations between genetic effects on HCC and hepatic steatosis (r2 = 0.75), and HCC and cirrhosis (r2 = 0.69), whereas only three loci (APOE, HFE, and TERT) had concordant effects on HCC and biliary tract cancer. Conclusions: We identified and validated nine genetic variants associated with an increased risk of HCC development. Impact and implications: The genetic underpinnings of HCC remain largely unknown. In this genome-wide association meta-analysis totaling 6,540 cases with HCC and 2.1 million controls, we identified and validated nine genetic loci to associate with the risk of HCC. A deeper insight into genetic factors that affect the risk of HCC could improve our ability to predict and ultimately prevent or treat this deadly cancer.</p

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.</p

Securitization and the Fixed-Rate Mortgage

Fixed-rate mortgages (FRMs) dominate the U.S. mortgage market, with important consequences for household risk management, monetary policy, and systemic risk. In this paper, we show that securitization is a key driver of FRM supply. Our analysis compares the agency and nonagency mortgage-backed-securities (MBS) markets, exploiting the freeze in nonagency MBS liquidity in the third quarter of 2007. Using exogenous variation in access to the agency MBS market, we find that when both market segments are liquid they perform similarly in terms of supporting FRM supply. However, after the nonagency market freezes, the share of FRMs is sharply higher among mortgages eligible to be securitized through the still-liquid agency MBS market. Our interpretation is that securitization is particularly important for FRMs because of the prepayment and interest rate risk embedded in these loans. We highlight policy implications for ongoing reform of the U.S. mortgage finance system

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.</p

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Publisher Copyright: © 2023, The Author(s).Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.Peer reviewe

Abstract 4130: Detection of FGFR1 and FGFR2 amplification in triple-negative breast cancer using digital droplet PCR and DNA-based microarrays.

Abstract Background: Triple-negative breast cancers (TNBC) lack targeted therapeutic strategies and identification of potential oncogenic targets is imperative. Fibroblast growth factor (FGF) pathway has been implicated in mammary tumorigenesis and is a potential target in TNBC. Amplification of FGFR2 (fibroblast growth factor receptor 2), identified using genomic studies, has been reported in 4% of TNBCs. Selective FGFR inhibitors are in clinical development and patient selection for these trials is important. Preclinical data suggests that cell lines with FGFR amplification are sensitive to FGFR inhibitors. The aim of this study was to identify FGFR1 and FGFR2 amplification in TNBCs using a quantitative and sensitive methodology of digital droplet polymerase chain reaction (ddPCR) and compare to our results from a DNA-based microarray analysis. Methods: Fresh-frozen breast tumor core biopsies were collected from patients enrolled onto a TNBC neoadjuvant clinical trial. DNA from each tumor and matched germline-derived sample (n=56 pairs) was hybridized to Affymetrix Molecular Inversion Probe (MIP) array to determine copy number variation (CNV). ddPCR was used to assess amplification in FGFR1 and FGFR2 in 11 and 53 tumor/ germline DNA sample pairs respectively. The ddPCR technology utilizes TaqMan chemistry PCR primers and probes specific for FGFR1 and FGFR2. It quantitates copy number by streaming emulsion droplets single-file into a capillary that leads past a two-color detector, where the positive droplets for the target and reference genes are quantified. Copy numbers for target genes are calculated by comparing to an internal control (ultra-conserved region of chromosome 1). Results: CNV in FGFR1 and FGFR2 was assessed in 56 TNBCs. No FGFR1 amplifications were identified in any of the samples. FGFR2 amplifications were identified in 2/56 (4%) tumor samples. ddPCR was used to assess quantitative copy number in 53 paired tumor/ germline DNA samples for FGFR2 and 11 paired samples for FGFR1. High amplifications with 6-8 copies of FGFR2 were identified in 2/53 (4%) of the TNBCs. These two samples were the same as the ones identified to have a high copy gain by CNV analysis. No FGFR1 amplifications were identified by ddPCR and this was consistent with our CNV analysis result. Conclusions: Our FGFR amplification results were in congruence using two different methodologies. No FGFR1 amplification was identified in the TNBC samples assessed and FGFR2 amplification was identified in 4%. ddPCR was done on fresh-frozen TNBCs in this study but this technology can be applied to formalin fixed paraffin embedded tumors as well. ddPCR can detect multiple cancer genome amplifications and has a potential for large scale application. There are several FGFR inhibitors in clinical trials and ddPCR methodology is a clinically applicable strategy for identifying patients with FGFR amplification. Citation Format: Shaveta Vinayak, Lincoln D. Nadauld, Laura Miotke, Rowza T. Rumma, Melinda L. Telli, Hanlee P. Ji, James M. Ford. Detection of FGFR1 and FGFR2 amplification in triple-negative breast cancer using digital droplet PCR and DNA-based microarrays. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4130. doi:10.1158/1538-7445.AM2013-4130</jats:p