Citations

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Background: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. Methods: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18–90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. Results: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC–; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P <.001) and FPC group assignment (odds ratio, 1.57; P <.001; relative to PGV+/FPC–) were independent predictors of harboring a pancreatic cyst. Conclusions: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC– risk groups by surveillance protocols.

Abstract Introduction: Identifying dysregulated gene expression in ovarian cancers has been limited by a deficit of available normal tissues. Here, we generated the largest set of high-grade serous ovarian cancer (HGSOC) tumors with normal precursor tissues for transcriptome analyses to identify lncRNA expression patterns, provide insight into their cellular contexts and functions, and assess their relevance to HGSOC pathogenesis and genetic susceptibility. Methods: We performed RNA sequencing on 220 primary HGSOCs and 116 benign epithelia (micro-dissected fallopian tube, ovarian surface, and inclusion cyst epithelia), and combined samples with 428 HGSOCs from TCGA, 60 HGSOCs from a prior study, and 180 bulk ovary tissues from GTEx. Reads were processed with a uniform bioinformatic and quality control pipeline, combined and batch corrected. Normalized TPM expression values were compared using the Wilcoxon rank sum test with &gt;2-fold change and FDR &lt;1% considered statistically significant. We computed weighted gene co-expression networks for each tissue type and tested for enrichment of differentially expressed genes (DEGs) and gene ontologies within co-expression modules. Results: Transcriptomes included 27,700 expressed genes (8,202 lncRNAs) across 706 HGSOCs, 180 bulk ovary, and 88 ovarian epithelia tissues. Most genes were expressed in all tissues, though 5% each showed HGSOC- or normal tissue-specific expression which comprised ≥50% lncRNA. Comparing HGSOCs to normal tissues identified 11,804 DEGs with 4,522 lncRNAs (DElncRNA) of which ~50% were tissue-specific. DEGs included MUC16 and multiple GWAS/TWAS implicated susceptibility genes including RAD51, BRIP1, BNC2, TIPARP-AS1, PRC1, KANSL1, ANKLE1, CHMP4C, ESRP2, and CCNE1. The most highly expressed DElncRNA in HGSOC were upregulated RMRP (P=1.4 × 10−39), SNHG1 (P=3.0 × 10−27), and HAGLR (P=2.0 × 10−24) at the HOXD risk locus. Lower proportions of lncRNA were seen in the HGSOC co-expression modules compared to those in normal tissues and less (3% vs. 15%) HGSOC modules were considered strongly lncRNA regulated (&gt;50% lncRNA in module). Tissue-specific DElncRNA tended toward upregulation in HGSOC compared to ovarian epithelia with enriched modules associated with cell cycle regulation (P=1.5 × 10−38); and toward downregulation in HGSOC compared to bulk ovary with enriched modules associated with chemokine signaling/response (P=1.7 × 10−113). Conclusions: The lower proportion of lncRNA involved in HGSOC co-expression networks indicates a marked loss of regulation by lncRNA. Preliminary interrogation of HGSOC-dysregulated lncRNA expression revealed tissue-specific differences that highlight unique biological pathways in precursor epithelia and the ovarian microenvironment that contribute to HGSOC pathogenesis. Our results provide additional support for previously nominated risk genes. eQTL analysis has recently been completed and integration with GWAS are underway to elucidate lncRNA and lncRNA-regulated susceptibility genes and will be presented at the conference. Citation Format: Brett M. Reid, Ann Chen, Zhihua Chen, Florian A. Karreth, Peter Kanetsky, Jennifer B. Permuth, Ozlen Saglam, Jamie K. Teer, Xiaoqing Yu, Simon Gayther, Ellen Goode, Paul Pharoah, Thomas A. Sellers, Kate Lawrenson, Jonathan Tyrer. Patterns of lncRNA-regulated gene expression in high-grade serous ovarian carcinomas [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A004.

Background and Aims: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). Approach and Results: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP, rs9842969, (0.51, [0.40–0.65]); 5p15.33, TERT, rs2242652, (0.70, (0.62–0.79]); 19q13.11, TM6SF2, rs58542926, (1.49, [1.29–1.72]); 19p13.11 MAU2, rs58489806, (1.53, (1.33–1.75]); and 22q13.31, PNPLA3, rs738409, (1.66, [1.51–1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74–0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. Conclusions: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

ImportanceWhile the incidence of early-onset metastatic colorectal cancer (mCRC) has been increasing, studies on the age-related disparity in this group of patients are limited.ObjectiveTo evaluate the association of age with treatment-related adverse events and survival in patients with mCRC and explore the potential underlying factors.Design, Setting, and ParticipantsThis cohort study included 1959 individuals. Individual data on 1223 patients with mCRC who received first-line fluorouracil and oxaliplatin therapy in 3 clinical trials, and clinical and genomic data of 736 patients with mCRC from Moffitt Cancer Center were used to assess genomic alterations and serve as an external validation cohort. All statistical analyses were conducted from October 1, 2021, through November 12, 2022.ExposuresMetastatic colorectal cancer.Main Outcomes and MeasuresSurvival outcomes and treatment-related adverse events were compared among patients in 3 age groups: younger than 50 (early onset), 50 to 65, and older than 65 years.ResultsIn the total population of 1959 individuals, 1145 (58.4%) were men. Among 1223 patients from previous clinical trials, 179 (14.6%) in the younger than 50 years group, 582 (47.6%) in the 50 to 65 years group, and 462 (37.8%) in the older than 65 years group had similar baseline characteristics except for sex and race. The younger than 50 years group had significantly shorter progression-free survival (PFS) (hazard ratio [HR], 1.46; 95% CI, 1.22-1.76; P &amp;lt; .001) and overall survival (OS) (HR, 1.48; 95% CI, 1.19-1.84; P &amp;lt; .001) compared with the 50 to 65 years group after adjustment for sex, race, and performance status. Significantly shorter OS in the younger than 50 years group was confirmed in the Moffitt cohort. The younger than 50 years group had a significantly higher incidence of nausea and vomiting (69.3% vs 57.6% [50-65 years] vs 60.4% [&amp;gt;65 years]; P = .02), severe abdominal pain (8.4% vs 3.4% vs 3.5%; P = .02), severe anemia (6.1% vs 1.0% vs 1.5%; P &amp;lt; .001), and severe rash (2.8% vs 1.2% vs 0.4% P = .047). The younger than 50 years group also had earlier onset of nausea and vomiting (1.0 vs 2.1 vs 2.6 weeks; P = .01), mucositis (3.6 vs 5.1 vs 5.7 weeks; P = .05), and neutropenia (8.0 vs 9.4 vs 8.4 weeks; P = .04), and shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks; P = .006). In the younger than 50 years group, severe abdominal pain and severe liver toxic effects were associated with shorter survival. The Moffitt genomic data showed that the younger than 50 years group had a higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%; P = .047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%; P = .005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%; P = .05), but lower prevalence of BRAF mutation (7.7% vs 8.5% vs 16.7%; P = .002).Conclusions and RelevanceIn this cohort study of 1959 patients, those with early-onset mCRC showed worse survival outcomes and unique adverse event patterns, which could be partially attributed to distinct genomic profiles. These findings may inform individualized management approaches in patients with early-onset mCRC.

Abstract Purpose: Identifying dysregulated gene expression in ovarian cancers has been limited by a deficit of available normal tissues. Here, we generated the largest set of high-grade serous ovarian cancer (HGSOC) tumors with normal precursor tissues for transcriptome analyses. Methods: We performed RNA sequencing on 220 primary HGSOCs and 116 benign epithelia (micro-dissected fallopian tube, ovarian surface, and inclusion cysts), and combined samples with 428 HGSOCs from TCGA, 60 HGSOCs from a prior study, and 180 bulk ovary tissues from GTEx. Raw reads were processed with a uniform bioinformatic and quality control pipeline; combined data were batch corrected. We tested for differences in median normalized CPM expression values using the Wilcoxon rank sum test with &gt;2-fold change and a false discovery rate &lt;1% considered statistically significant. We also conducted weighted gene co-expression network analysis in each tissue type. The hypergeometric test was used for enrichment of differentially expressed genes (DEGs) and gene ontologies within modules. Results: Transcriptomes comprised 27,700 expressed genes (8,202 lncRNAs) across 706 HGSOCs, 180 bulk ovary, and 88 ovarian epithelia tissues. Most (~90%) genes were expressed in all tissues; 5% each showed HGSOC- or normal tissue-specific expression and ≥50% were lncRNA. Comparing HGSOCs to ovarian epithelia and to bulk ovary identified 11,804 DEGs with 4,522 lncRNAs (DElncRNA) of which ~50% were tissue-specific. DEGs included MUC16 and multiple GWAS/TWAS implicated susceptibility genes including RAD51, BRIP1, BNC2, TIPARP-AS1, PRC1, KANSL1, ANKLE1, CHMP4C, ESRP2, and CCNE1. The most highly expressed DElncRNA in HGSOC were upregulated RMRP (P=1.4x10-39), SNHG1 (P=3.0x10-27), and HAGLR (P=2.0x10-24) at the HOXD risk locus. The highest expressed DElncRNA in precursor tissues was the HGSOC-downregulated MEG3 (P=1.7x10-67). DEGs were enriched in HGSOC co-expression modules associated with immune response, cell motility/localization, cell cycle regulation, angiogenesis, reproductive development, transcriptional regulation, and metabolic processes. Tissue-specific DElncRNA tended toward upregulation compared to ovarian epithelia with enriched modules associated with cell cycle regulation (hub=BUB1B; top DElncRNA TRPM2-AS, P=1.5x10-38); and toward downregulation compared to bulk ovary with enriched modules associated with chemokine signaling/response (hub= GADD45B, top DElncRNA RP11-87P3.1, P=1.7x10-113). Conclusion: HGSOC-dysregulated lncRNA expression revealed tissue-specific differences that highlight unique biological pathways in precursor epithelia and the ovarian microenvironment that contribute to HGSOC pathogenesis. Our results provide additional evidence to support previously nominated risk genes. Integration with eQTL and GWAS are underway to further elucidate novel HGSOC susceptibility genes. Citation Format: Brett M. Reid, Ann Chen, Zhihua Chen, Florian A. Karreth, Peter Kanetsky, Jennifer B. Permuth, Ozlen Saglam, Jamie Teer, Xiaoqing Yu, Simon Gayther, Ellen Goode, Paul Pharoah, Thomas A. Sellers, Kate Lawrenson. Patterns of dysregulated coding and noncoding gene expression in high-grade serous ovarian carcinomas [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 6065.

689 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer typically discovered at incurable stages. The PRECEDE Consortium was established to accelerate early detection by using a large-scale, collaborative, innovative model, predicated on standardized collection of demographic, clinical, and imaging data from high-risk individuals (HRI). Here we report the initial pancreas imaging findings in Cohort 1, representing HRI with familial pancreatic cancer (FPC) or pathogenic germline variants (PGV) in PDAC susceptibility genes with a 1 st or 2 nd degree relative with PDAC. Methods: The PRECEDE Consortium (NCT04970056) began enrollment in 5/2020. HRI enrolled prospectively at centers worldwide into one of 7 cohorts based on personal and/or family history of PDAC and PGV status. PRECEDE’s planned enrollment is 10,000 patients. Data sharing is required to join PRECEDE, facilitated by a standardized data collection system and central database (PRECEDELink). Imaging (MRI/MRCP and EUS) is performed using standardized image acquisition and reporting templates. Imaging and clinical sequencing data are stored and analyzed in the PRECEDE data cloud. Results: By 9/16/2022, 26 sites enrolled 3156 patients in 7 cohorts, with 1716 in Cohort 1. Cohort 1 was 60% female, 80% white; 48% met FPC criteria, and 52% were PGV carriers. Within Cohort 1, 658 FPC and 965 PGV (1353 total, 79%) underwent imaging (68% MRI; 32% EUS). Overall, 573/1353 (42%) had pancreas abnormalities: 320/573 (49%) FPC, and 253/573 (36%) PGV (OR [95% CI] 1.65 [1.32–2.06], P < 0.001). Cysts were the most common abnormality, present in 549/1353 (41%) and accounting for 310/320 (97%) FPC and 239/253 (94%) PGV HRI abnormalities. Of 549 HRI with cysts, 262 (48%) had 1 cyst, including 137/310 (44%) FPC and 125/239 (52%) PGV HRI (OR 1.43 [1.07–1.92], P = .012) The remaining 287/549 (52%) had ≥2 cysts, including 173/310 (56%) FPC and 114/239 (48%) PGV HRI (OR 1.98 [1.49–2.64], P < 0.001). Worrisome features occurred in 83/1353 (6.1%) including: 14 (1%) cyst > 2 cm, 7 (0.5%) cyst ≥3 cm, 35 (2.6%) main pancreatic duct (MPD) diameter ≥5 mm; 2 (0.15%) duct strictures; and 25 (1.8%) solid masses. Solid masses included 1 (0.07%) PDAC, 9 (0.7%) neuroendocrine tumors, and 15 (1.1%) benign lesions (e.g. lipoma, splenule). Conclusions: Pancreatic abnormalities are common in a cohort of 1353 HRI enrolled in PRECEDE; 6.1% of HRI had findings with worrisome features and clinical implications. Multiple cysts were significantly more common in FPC HRI (OR 1.98); worrisome findings did not differ between FPC and PGV groups. The longitudinal study of this growing HRI cohort with standardized imaging and matched comprehensive epidemiological, clinical, and laboratory data, along with germline testing, will provide critical information and understanding of PDAC risk, and augment existing clinical decision-making models governing surveillance and treatment.

e16239 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with lack of effective early detection strategies. There is an incomplete understanding of who is at risk for PDAC development and the contribution of heritability to that risk. Further, efforts at biomarker development for detection of early stage disease have been hampered by small sample sizes, lack of coordination, and inadequate access to high quality clinical data and biospecimens in relevant clinical populations. The PRECEDE Consortium was established to serve as a collaborative international network of PDAC clinical and research centers to accelerate early detection advances by standardizing collection of clinical data and biospecimens from patients at increased risk for PDAC. The consortium goal is to increase the overall survival rate for PDAC to 50% in 10 years by enabling transformative biomarker-driven discoveries in early detection of high-risk premalignant lesions and early stage cancers. Methods: The PRECEDE Consortium (NCT04970056; precedestudy.org) launched in 2019 and began enrollment in May, 2020. Data and biospecimen sharing are required for centers to join the consortium, which is facilitated through use of standardized data and biospecimen collection, and a centralized database (PRECEDELink) managed by a data coordinating center (Arbor Research). Imaging and clinical sequencing data will be stored and analyzed via a PRECEDE solution in the Amazon Web Services cloud. Participants age 18-90 are enrolled into one of seven cohorts based on personal and/or family history of PDAC and carrier status of pathogenic germline variants (PGV) in cancer predisposition genes (CPG). Three-generation pedigrees are collected at enrolment from participants, and standardized clinical germline testing is offered. Blood sample collection for DNA, plasma, and serum is completed at enrollment, and repeated annually for individuals meeting guidelines for annual surveillance. Results: To date, 24 clinical sites have enrolled 2187 participants, with a target of 10,000 participants enrolled from100 sites over the next 5 years. Among enrolled patients, 55% meet criteria for annual surveillance by MRI or endoscopic ultrasound. Demographics of the cohort to date: 56% female; 73% white; 35% CPG PGV carriers; 32% meet criteria for familial pancreatic cancer. Conclusions: The PRECEDE Consortium study is a large international, longitudinal, prospective cohort study designed to accelerate the pace and scale of early diagnosis. Planned projects will address modifiers of risk, penetrance of disease, creating comprehensive risk models for clinical decision-making, and development and validation of biomarker assays. The PRECEDE Consortium provides a unique, innovative platform to bring together key stakeholders (academia, patients, public and private sector) to effect progress.