Rashid, Asif

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 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.

Abstract Context. —Primary esophageal melanoma (PEM) is a rare disease and is difficult to distinguish from other esophageal malignancies and from metastatic melanoma. Objective. —To develop diagnostic criteria for PEM, we compared the clinicopathologic features of 5 PEMs and 5 metastatic melanomas to esophagus. Design. —Ten cases of esophageal melanoma, including 4 surgically resected specimens, 2 autopsy cases, and 4 cases reported on mucosal biopsies, were reviewed. The histologic parameters used in this study were well-characterized features for cutaneous melanoma, including junctional component (in situ melanoma), radial growth phase, modified Breslow thickness, depth of invasion, lymphovascular invasion, satellitosis, predominant type of cytology, and regional lymph node metastasis. Clinical and follow-up information was obtained by reviewing patients' medical records. Results. —Previous history of cutaneous melanoma was present in all 5 cases of metastatic esophageal melanoma but was not present in the 5 patients with PEMs. In situ melanoma and/or radial growth phase were identified in all 5 PEMs but were not present in any of the metastatic cases. Among the 4 resected and 2 autopsy cases, melanocytosis and mixed epithelioid and spindle cell morphology was present in 2 (50%) of 4 PEMs but was not present in 2 (40%) of the metastatic melanomas. Melanin pigment was detectable in all cases. Patients with PEM had better survival than those who had metastatic melanoma to esophagus ( P = .03). Conclusions. —The presence of in situ melanoma, radial growth phase, melanocytosis, and mixed epithelioid and spindle cell morphology, in the context of no history of melanoma, distinguishes PEM from metastatic melanoma.

480 Background: Currently, there is a lack of imaging biomarkers of immunotherapy outcome in hepatocellular carcinoma (HCC). The study aim was to determine if HCC enhancement on MRI and stiffness change measured by magnetic resonance elastography (MRE) can predict immunotherapy response. Methods: This was a prospective, Institutional Review Board approved study of 38 patients with HCC treated with immune checkpoint blockade (ICB) therapy. All patients had liver MRI/MRE and HCC biopsy at baseline, and MRI/MRE with biopsy or resection after 6 weeks therapy. HCC stiffness (kPa) was measured on MRE elastograms (liver stiffness maps). HCC enhancement and change in stiffness were compared with treatment response to ICB in 1) non-surgical patients (pembrolizumab), and 2) surgical patients (nivolumab +/- ipilimumab). For non-surgical patients, treatment response was defined as overall survival >1 year. For surgical patients, treatment response was defined as <50% viable tumor at time of resection. Analysis was performed using descriptive statistics and Spearman correlation; p-value <0.05 was considered statistically significant. Results: Twenty-five patients were evaluable. Median age was 67 years (32, 78). Etiology of liver disease was NASH (n=8), HCV (n=8), HBV (n=2) and unknown (n=7). Treatment response occurred in 11/25 (44%) patients. Median HCC size and change in size were 4.7 cm (1.2, 14.0) and –0.32 cm, respectively. Median baseline HCC stiffness and change in stiffness were 5 kPa (2.2, 12.4) and –0.1 kPa (–2.2, 1.5), respectively. Median change in HCC size for responders and non-responders was –1.2 cm (–4.8, 0.4) and 0 cm (–1.5, 1.1), respectively (p = 0.02). Treatment response was associated with absence of portal venous phase capsular enhancement and increase in HCC stiffness, (p<0.001). Conclusions: Capsular enhancement and MRE stiffness change may be useful biomarkers of immune cell activated response to ICB therapy.

263 Background: DNA repair genomic alterations (GAs) have been identified in 12% of Intrahepatic cholangiocarcinoma (IHCCA), 26% of extrahepatic CCA (EHCCA) and 8% of gallbladder cancer (GBC) patients (pts) ( Cancer 2016;122:3838–3847). Recently, the Cancer Genome Atlas (TCGA) has described more than 20 mutated DNA repair genes, many of which were not previously represented in prior reports. DNA repair GAs including MSI are associated with higher tumor mutational burden (TMB). Our study aim is to identify variations in the frequency of DNA repair GAs in IHCCA, EHCCA, and GBC. Methods: Hybrid capture-based next-generation sequencing of 422 fixed formalin paraffin embedded (FFPE) tissue blocks of BTC including; 270 IHCCA, 60 EHCCA, and 92 GBC was performed. We included 20 DNA repair genes and classified them as "direct" DNA repair genes ( ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, RAD50, SLX4) and "caretaker" genes that induce genomic instability ( BAP1, CDK12, MLL3, TP53, BLM). We calculated TMB on 1.1 Mb of sequenced DNA in 205 tissue specimens [138 IHCCA, 23 EHCCA, and 44 GBC] and classified into three groups; high (TMB-H; ≥ 20 mut/Mb), intermediate (TMB-I; 6-19mut/Mb) and low (TMB-L; < 6mut/Mb). Results: A distinct pattern of DNA repair GAs in each tumor type was detected. (Table 1). DNA repair GAs were more commonly noted in both EHCCA and GB (63%) as compared with IHCAA (45.2%) (p= .002). Direct DNA repair GAs were highest within EHCCA (25%), while indirect DNA GAs were predominant in GBC (59.8%) (p= 0.04 and 0.001, respectively). The frequency of TMB-H and TMB-I differed significantly between BTC subtypes. Pts with EHCCA and GBC had significantly higher TMB-H and TMB-I versus IHCCA. Conclusions: The frequency of DNA repair GA’s is higher in EHCCA and GBC as compared with IHCCA. These results may have implications for clinical trials with DNA repair inhibitors and immune checkpoint blockers. [Table: see text]

PURPOSE: The current American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) fails to stratify patients adequately with respect to prognosis. PATIENTS AND METHODS: The ability of the currently proposed tumor (T) categories to effectively stratify the survival of 557 patients who underwent complete resection for HCC at four centers was examined. Independent predictors of survival were combined into a new staging system. RESULTS: Using the current AJCC T classification, patients with T1 and T2 tumors had similar 5-year survivals (P = .6). In addition, the survival of patients with multiple bilobar tumors (T4) matched that of T3 patients (P = .5). Independent predictors of death were major vascular invasion (P < .001), microvascular invasion (P = .001), severe fibrosis/cirrhosis of the host liver (P = .001), multiple tumors (P = .007), and tumor size greater than 5 cm (P = .01). Based on our results, a simplified stratification is proposed: (a) patients with a single tumor and no microvascular invasion, (b) patients with a single tumor and microvascular invasion or multiple tumors, none more than 5 cm, and (c) patients with either multiple tumors, any more than 5 cm, or tumor with major vascular invasion (P < .001). Severe fibrosis/cirrhosis had a negative impact on survival within all categories. The survival of patients with lymph node involvement matched that of patients with major vascular invasion (P = .3). CONCLUSION: The current AJCC staging system for HCC is unnecessarily complex. We propose a simplified model of stratification that is based on vascular invasion, tumor number, and tumor size and incorporates the effect of fibrosis on survival.