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Background Colorectal cancer (CRC) keeps an upward incidence and rejuvenation trend in Kazakhstan, as well as worldwide, which is the motive for revising traditional risk factors and searching for cause-effective relationships at the genome level. Genetic nature of early-onset CRC is still unclear. The aim of this study was to determine the spectrum of cancer-related gene mutations among early-onset CRC patients. Methods The study included 125 CRC patients aged between 17 and 50 from Kazakhstan. DNAs were extracted from blood using the GeneJET Purification Kit. Next-generation sequencing (NGS) was done on the MiSeq using the TruSightCancer Kit. NGS data were analyzed by the MiSeq Reporter and Variant Studio. SIFT and PolyPhen-2 were used to predict potential pathogenic effects of missense variants on protein structure and function. Results We were able to detect 24 pathogenic/likely pathogenic mutations in 20 (16%) cases, out of which 8 were novel. Out of all mutations, five were detected in the APC gene, three in FANCI, three in BRCA2, two in BRCA1, two in MLH1, and one mutation each, in MSH6, MUTYH, BLM, NBN, ATM, BMPR1A, CHEK2, AIP, and DICER1 genes. The analysis of mutation type has revealed 10 frameshift mutations, 5 missense mutations, 5 stop-gain mutations, 1 in-frame deletion, and 3 mutations involving uncorrected splicing. All mutations were in the heterozygous state. Most of the mutations were not available in the 1000G, ESP6500 and ExAC databases. 5% were available in the dbSNP database, 29.1% in the COSMIC, and 38.4% in the ClinVar and/or LOVD. Pathogenic mutations in high penetrance CRC genes were higher in patients with family history of cancer (FHC) (21.1%, P = 0.0002) and in patients with primary multiple tumors (20.0 %, P = 0.0004) compared with patients without/unknown FHC (3.1%). Conclusions Molecular genetic study of CRC in young patients using NGS allows to identify CRC cases with syndromic and sporadic nature, to stratify the level of risk for a particular patient and his/her relatives, to influence on the diagnostic and therapeutic approaches and clinical examinations. The findings from this study show the diagnostic value of the detected pathogenic mutations in key CRC genes from the Kazakhstan population as promising biomarkers for CRC diagnosis in young people. Legal entity responsible for the study Institute of General Genetics and Cytology. Funding Ministry of Healthcare of the Republic of Kazakhstan. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background The utility of next generation sequencing (NGS) is rapidly evolving within our medical practice with various applications. The 100K Genomes Project was established to sequence 100 000 genomes from NHS patients with cancer or rare diseases, and to date actionable findings have been found for approximately 50% of cancer cases. Data from the 100K Genomes Project were reviewed at Guy's Hospital Molecular Tumour Board (MTB). Methods Whole genome sequencing (WGS) was performed for the 100K Genomes Project and Genomics England using an Illumina platform. Results Between December 2016 and August 2018, 66 patients with colorectal cancer (CRC) were treated with surgery at GSTT. Median age was 68.5 (52-95). Majority were left sided (69%) vs right sided (30%) adenocarcinomas. TNM status was 1.5% / 47% / 37.9% / 13.6% for stage I/II/III/IV respectively. Analyses were performed in FFPE (35.8%) and frozen tissue (64.2%). Median estimated tumour purity was 53.5% (20-100%). Median tumour mutational burden (TMB) was 5.92 (2.94-173.26). Mutational signatures 6, 10 and 15 were found for 8 patients and were associated with high TMB. A total of 557 Domain 1 (actionable) variants (range 1-68) were identified for this cohort. After review in the MTB, at least one clinically relevant actionable variant was identified for 59.7% of the patients; KRAS 37.3%, NRAS 6%, BRAF 11.9%, TP53 70.1%, PIK3CA 35.8%, ATM 17.9%, RICTOR 14.9%, APC and PTEN 11.9% each and mTOR 8.6%. Somatic BRCA1 and BRCA2 variants were found in 7.6% and 12.1% respectively. Further validation was recommended for 9 patients (13.4%). DPYD alterations were identified in 11.9%, but none of the clinically relevant DPYD mutations related to 5FU toxicity were discovered for 2 of the patients that were tested. 9.4% were identified with potentially pathogenic germline variants (7.6% with RAD51D, RAD51C, MUTYH, MSH6 and PMS2 class 4 & 5 variants) and referral to Clinical Genetics was recommended. Conclusions GSTT MTB identified actionable mutations in more than half patients in the CRC cohort, out of whom 14% had alterations that made them eligible for clinical trials. Over 9% had potentially pathogenic germline variants. Our data from this small cohort resemble data in the literature from other MTBs. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Mismatch repair deficiency (dMMR) / microsatellite instability-high (MSI-H) in cells lead to neoplastic development and progression, an important feature in Lynch syndrome. dMMR/MSI-H is a positive predictive marker for immune checkpoint inhibitors. Nivolumab is a PD-1 inhibitor, approved in the US for pts with dMMR/MSI-H colorectal cancers. Other than colorectal cancers, a subset of rare cancers also share this characteristic. Methods This is a phase 2, open-label, single arm study designed to investigate the efficacy and safety of nivolumab monotherapy in patients with advanced rare tumors with dMMR/MSI-H. This study is conducted as part of the MASTER KEY Project, which is a basket/umbrella trial including a registry study for rare cancers (UMIN000027552). dMMR was identified by a negative immunohistochemical staining of one of the following: MLH1, MSH2, MSH6, PMS2. Rare cancer was defined as annual incidence < 6 / 100,000 population. Other main inclusion criteria were: age ≥ 16, ECOG-PS of 0-1, unresectable lesion and have completed standard treatment, adequate organ function. Patients will receive intravenous nivolumab monotherapy of 240 mg every 2 weeks until disease progression, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, or death. Primary endpoint is response rate (central assessment), and secondary endpoints include progression free survival, overall survival, stable disease rate and toxicity. The trial will utilize a Bayesian hierarchical model enrolling 5 to 15 patients depending on the ongoing results as an adaptive design. Participating sites are National Cancer Center and Kyoto University Hospital, and will be expanding shortly. Clinical Trial Information JMA-IIA00344 [ABSTRACT FROM AUTHOR]

Gastroesophageal cancers, eg cancers of the stomach and esophagus, are a leading cause of cancer related death worldwide. Recent evidence suggests that these cancers are complex and heterogeneous diseases with emerging subtypes shown to influence response to treatment and survival. Immunotherapy is an advancing field and immune checkpoint inhibitors have become standard treatment options in numerous tumor types and is emerging therapy in gastroesophageal malignancies. Several immune checkpoint inhibitors have been examined in gastric and esophageal cancers, both as single agents and in combination with cytotoxic therapy. Tumors with deficiency in mismatch repair have demonstrated considerable activity with single agent immunotherapy. These tumors, typically characterized by loss or inactivation of DNA repair proteins MLH1, MSH2, MSH6, and PMS2, accumulate hundreds to thousands of mutations in the microsatellite regions of DNA during replication, mutations that would normally be repaired if the mismatch repair system were intact. These tumors are noted to have high lymphocytic infiltrates, and are primed for an anti-tumor immune response by host immunity, with high single agent immunotherapy activity of ∼50% response rates. However across several studies, particularly without patient selection or by selection based on PD-L1 expression alone, the response rates to anti-PD-1 or anti-PD-L1 therapy in gastric and esophageal cancer is marginal, ranging from 5-15%. The most compelling and transformative aspect of immunotherapy is that the few patients who do respond have durable responses, often greater than 1 year, generally with minimal side effects. Our challenge is to better select patients who will benefit from single agent immunotherapy. We will discuss the emerging data examining immunotherapy in upper gastrointestinal malignancies across first, second, and third line studies and the development of biomarkers to improve patient selection. [ABSTRACT FROM AUTHOR]