With mortality rates of liver cancer doubling in the last 20 years, this disease is on the rise and has become the fifth most common cancer in men and the seventh most common cancer in women. Hepatocellular carcinoma (HCC) represents approximately 90% of all primary liver cancers and is a major global health concern. Patients with HCC can be managed curatively with surgical resection or with liver transplantation, if they are diagnosed at an early stage. Unfortunately, most patients with HCC present with advanced stages of the disease and have underlying liver dysfunction, which allows only 15% of patients to be eligible for curative treatment. Several different treatment modalities are available, including locoregional therapy radiofrequency ablation, microwave ablation, percutaneous ethanol injection, trans-arterial chemoembolization, transarterial radio-embolization, cryoablation, radiation therapy, stereotactic radiotherapy, systemic chemotherapy, molecularly targeted therapies, and immunotherapy. Immunotherapy has recently become a promising method for inhibiting HCC tumor progression, recurrence, and metastasis. The term "Immunotherapy" is a catch-all, encompassing a wide range of applications and targets, including HCC vaccines, adoptive cell therapy, immune checkpoint inhibitors, and use of oncolytic viruses to treat HCC. Immunotherapy in HCC is a relatively safe option for treating patients with advanced disease in the USA who are either unable to receive or failed sorafenib/lenvatinib therapy and thus may offer an additional survival benefit for these patients. The purpose of this review is to elaborate on some of the most recent advancements in immunotherapy.

PURPOSENext Generation Sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC), which is on the rise in many parts of the developing World including, Iran. Little is known about its genetic hallmarks in these populations.AIMTo identify variants in 15 CRC-associated genes in patients of Iranian descent.RESULTSThere were 51 validated variants distributed on 12 genes: 22% MSH3 (n = 11/51), 10% MSH6 (n = 5/51), 8% AMER1 (n = 4/51), 20% APC (n = 10/51), 2% BRAF (n = 1/51), 2% KRAS (n = 1/51), 12% PIK3CA (n = 6/51), 8% TGFβR2A (n = 4/51), 2% SMAD4 (n = 1/51), 4% SOX9 (n = 2/51), 6% TCF7L2 (n = 3/51), and 6% TP53 (n = 3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%).MATERIALS AND METHODSCRC specimens from 63 Shirazi patients were used to establish the variant' profile on an Ion Torrent platform by targeted exome sequencing. To rule-out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established.CONCLUSIONThese results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies.

Background Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. African Americans are disproportionately affected by CRC. Our hypothesis is that driver genes with known and novel mutations have an impact on CRC outcome in this population. Therefore, we investigated the variants’ profiles in a panel of 15 CRC genes. Patients & Methods Colorectal specimens (n=140) were analyzed by targeted exome sequencing using an Ion Torrent platform. Detected variants were validated in 36 samples by Illumina sequencing. The novel status of the validated variants was determined by comparison to publicly available databases. Annotated using ANNOVAR and in-silico functional analysis of these variants were performed to determine likely pathogenic variants. Results Overall, 121 known and novel variants were validated: APC (27%), AMER1 (3%) , ARID1 (7%), MSH3 (12%), MSH6 (10%), BRAF (4%), KRAS (6%), FBXW7 (4%), PIK3CA (6%), SMAD4 (5%), SOX9 (2%), TCF7L2 (2%), TGFBR2 (5%), TP53 (7%). From these validated variants, 12% were novel in 8 genes (AMER1, APC, ARID1A, BRAF, MSH6, PIK3CA, SMAD4, and TCF7L2 ). Of the validated variants, 23% were non-synonymous, 14% were stopgains, 24% were synonymous and 39% were intronic variants. Conclusion We here report the specifics of variants’ profiles of African Americans with colorectal lesions. Validated variants showed that Tumor Suppressor Genes (TSGs) APC and ARID1 and DNA Mismatch repair (MMR) genes MSH3 and MSH6 are the genes with the highest numbers of validated variants. Oncogenes KRAS and PIK3CA are also altered and likely participate in the increased proliferative potential of the mutated colonic epithelial cells in this population.

PurposeAfrican Americans have a higher incidence and mortality from colorectal cancer. This disparity might be due, in part, to the type of mutations in driver genes. In this study, we examined alterations specific to APC, MSH3, and MSH6 genes using targeted exome sequencing to determine distinctive variants in the course of neoplastic transformation.Experimental DesignA total of 140 African American colon samples (30 normal, 21 adenomas, 33 advanced adenomas and 56 cancers) were used as our discovery set on an Ion Torrent platform. A 36 samples subset was resequenced on an Illumina platform for variants’ validation. Bioinformatics analyses were performed and novel validated variants are reported.ResultsTwo novel MSH6 variants were validated and mapped to the MutS-V region near the MSH2 binding site. For MSH3, 4 known variants were validated and were located in exon 10 (3 non-synonymous) and exon 18 (1 synonymous). As for APC, 20 variants were validated with 4 novel variants: 3 stopgain and 1 non-synonymous. These variants mapped prior to and on the Armadillo repeats region, to the 15-amino acid repeat region, and to the 20-amino acid repeats region, respectively.ConclusionWe defined novel variants that target DNA mismatch repair and APC genes in African Americans with colorectal lesions. A greater frequency of variants in genes encoding DNA mismatch repair functions and APC likely plays major roles in colorectal cancer initiation and higher incidence of the disease in African Americans.

Background and Aim Next generation sequencing (NGS) has quickly the tool of choice for genome and exome data generation. The multitude of sequencing platforms as well as the variabilities within each platform need to be assessed. In this paper we used two platforms (ION TORRENT AND ILLUMINA) to assess single nucleotides variants in colorectal cancer (CRC) specimens. Methods CRC specimens (n = 13) collected from 6 CRC (cancer and matched normal) patients were used to establish the mutational profile using ION TORRENT AND ILLUMINA sequencing platforms. We analyzed a set of samples from Formalin Fixed Paraffin Embedded and FF (FF) samples on both platforms to assess the effect of sample nature (FFPE vs. FF) on sequencing outcome and to evaluate the similarity/differences of SNVs across the two platforms. In addition, duplicates of FF samples were sequenced on each platform to assess variability within platform. Results The comparison of FF replicates to each other gave a concordance of 77% (± 15.3%) in Ion Torrent and 70% (± 3.7%) in Illumina. FFPE vs. FF replicates gave a concordance of 40% (± 32%) in Ion Torrent and 49% (± 19%) in Illumina. For the cross platform concordance were FFPE compared to FF (Average of 75% (± 9.8%) for FFPE samples and 67% (± 32%) for FF and 70% (± 26.8%) overall average). Conclusion Our data show a significant variability within and across platforms. Also the number of detected variants depend on the nature of the specimen; FF vs. FFPE. Validation of NGS discovered mutations is a must to rule-out false positive mutants. This validation might either be performed through a second NGS platform or through Sanger sequencing.

Background: There is limited data on the safety of endoscopic retrograde cholangiopancreatography (ERCP) in patients with Inflammatory Bowel Diseases (IBD). Aim: The aim of this study is to assess safety and efficacy of the ERCP in IBD patients who underwent ERCP for a variety of reasons in a national inpatient data base. Method: The National Inpatient Sample (NIS) is the largest all-payer inpatient database consisting of approximately 20% of all inpatient admissions to nonfederal hospitals in the United States. Data from the years 2009 to 2014 were collected. Patients older than 18 years with a diagnosis of IBD who had undergone ERCP (nZ1519) were included. Case-control 2:1 matching was done based on gender, age, race and Charlson Comorbidity Index (CCI) for IBD patients. Complications and mortality were evaluated for IBD patients against case-controls. Results were adjusted via logistic regression analyses to obtain adjusted odds ratios (aOR) for different outcomes. IBM Statistical Package for the Social Sciences (SPSS) version 25 was used for statistical analysis. Results: Between 2009 and 2014 there were 1519 patients with IBD aged older than 18 years who had undergone an ERCP. Baseline patient demographics are presented in Table 1. Age, sex, CCI, and race were all matched without statistically significant differences between cases and controls. We used the binary logistic regression models for mortality and post ERCP complications. We found significant differences between IBD and non-IBD patients for post-ERCP pancreatitis (aOR 13.38, 95% CI 1.45-1.24) and post-ERCP Infection (aOR 1.21, CI 1.01-1.45). However, there was no significant differences between IBD and non-IBD patients for post-ERCP mortality (aOR 1.29, 95% CI 0.73-2.71), post-ERCP cholecystitis (aOR 2.11, 95% CI 0.76-5.84), post-ERCP perforation (aOR 4.01, 95% CI 0.36-44.27), or post-ERCP bleeding (aOR 0.72, 95% CI 0.28-1.83). Conclusion: IBD appears an independent risk factor for post-ERCP pancreatitis and post-ERCP infection. However, limitation of the study is that NIS is an administrative database which predisposes to errors from coding inaccuracies as well as obscurement of temporal relationships between outcomes and diseases. More prospective research would be useful to confirm our findings.

PURPOSE: Next-generation sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC) which is on the rise in many parts of the developing World including in the Middle East. Little is known about its genetic hallmarks in these populations. AIM: To identify variants in 15 CRC-associated genes in patients of Iranian descent. METHODS: CRC specimens from 63 patients were used to establish the variants’ profile on an Ion Torrent platform by targeted exome sequencing. To rule out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established. RESULTS: There were 51 validated variants distributed on 12 genes: 22% MSH3 (n=11/51), 10% MSH6 (n=5/51), 8% AMER1 (n=4/51), 20% APC (n=10/51), 2% BRAF (n=1/51), 2% KRAS (n=1/51), 12% PIK3CA (n=6/51), 8% TGFβR2A (n=4/51), 2% SMAD4 (n=1/51), 4% SOX9 (n=2/51), 6% TCF7L2 (n=3/51), and 6% TP53 (n=3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%). MSH3 variants were more frequent and predominantly homozygous in the analyzed population. CONCLUSION: These results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. This is especially true for MSH3 variants that were very frequent and predominantly homozygous as these will associate with the EMAST phenotype that has prognostic implications. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies. Citation Format: Pooneh Mokarram, Sudhir Varma, Hamed Azimi, Hasti Olumi, Ali reza Safarpour, Michael Nickerson, Hassan Brim, Hassan Ashktorab. Targeted sequencing reveals distinct and rare pathogenic variants in Caucasians with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4384. doi:10.1158/1538-7445.AM2017-4384

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