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BACKGOUND: Hereditary cancer predisposition syndromes are believed to be responsible for approximately 5-10% of all diagnosed cancer cases. In the past, single genes analysis of certain high risk genes was used for the determination of the genetic cause of cancer heritability in certain families. The selection of genes was mainly based on the family history of the individuals analyzed and included only highly associated genes (e.g. the BRCA1 and BRCA2 genes for families with breast cancer history. Nowadays though, the application of Next Generation Sequencing (NGS) technology has facilitated multigene panel analysis and is widely used in clinical practice, for the identification of individuals with cancer predisposition gene mutations. AIM: The aim of this study was to investigate the extent and nature of mutations in 36 genes implicated in hereditary cancer predisposition in individuals referred for testing in our lab. MATERIALS & METHODS: In total, 1197 individuals were referred for testing in our lab in the past four years from Greece, Romania and Turkey. The analysis of genes involved in hereditary cancer predisposition was performed using two NGS approaches. The first 451 individuals were analyzed using an amplicon based sequencing method (26 gene panel), while the following 746 individuals were analyzed using a capture based method (33 gene panel). Genomic DNA was enriched for targeted regions of 36 genes involved in hereditary predisposition to cancer included in both versions of the panel (APC, BMPR1A, BRCA1, BRCA2, CDH1, CDK4, CDKN2A, EPCAM, MEN1, MLH1, MSH2, MSH6, MUTYH, PALB2, PMS2, PTEN, RET, SMAD4, STK11, TP53, VHL, ATM, BRIP1, CHEK2, NBN, RAD51C, RAD51D, BARD1, BLM, CHEK1, ABRAXAS1 (FAM175A), MRE11 (MRE11A), NF1, RAD50, RAD51B, XRCC2). Sequencing was carried out using the Illumina NGS technology. Reads were aligned to the reference sequence (GRCh37), and sequence changes were identified and interpreted in the context of a single clinically relevant transcript. The presence of large genomic rearrangements was investigated by computational analysis of NGS results and the use of MLPA for 13 genes. All clinically significant observations were confirmed by orthogonal technologies. RESULTS: In total, a pathogenic mutation was identified in 259 of the 1197 individuals (21.6%) analyzed while a VUS was identified in 35.7% of the cases. Clinically significant mutations were identified in 29 of the genes analyzed. Concerning the mutation distribution among individuals with positive findings, 44.7% of them were located in BRCA1/2 genes whereas 20.9%, 19.9%, and 14.5% in high, moderate and low risk genes respectively. In addition to BRCA1 and BRCA2 genes other highly mutated genes were CHEK2 (10.6%), PALB2 (7.1%), MUTYH (7.1%) and ATM (4.3%). Of note is that 25 of the 259 positive individuals (9.7%) carried clinically significant mutations in two different genes and 5.8% had a large genomic rearrangement (LGR). CONCLUSIONS: Our results support the clinical significance of analysis of a panel of genes involved in hereditary cancer predisposition. In our cohort, analysis of this panel allowed for the identification of 8.3% additional pathogenic variants in moderate/low risk genes, enabling personalized management of these individuals. Citation Format: Tsoulos N, Tsaousis GN, Papadopoulou E, Agiannitopoulos K, Pepe G, Kambouri S, Apessos A, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, Tansan S, Tekinel M, Yalcin S, Nasioulas G. Analysis of hereditary cancer syndromes by using a panel of genes: Novel and multiple pathogenic mutations [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-03-07.

Background: State health insurance authorities in Greece do not reimburse genetic testing for cancer predisposition. The Hellenic Society of Medical Oncology has launched and carries out a national program covering genetic testing for BRCA1/2 mutations detection, with the financial support of pharmaceutical industry. Aim: This analysis evaluates how, during this program, access to genetic testing transformed the oncologists' therapeutic approach toward their ovarian cancer patients and how the results impacted treatment decisions concerning PARP inhibitors. Adoption of testing by healthy relatives and timing of testing in the disease continuum were also evaluated. Methods: Adult patients with high-grade epithelial ovarian carcinoma, irrespectively of family history or age at diagnosis were eligible for this program. Genetic counseling was recommended before testing, and both were offered at no financial cost. First degree family members of pathogenic mutation carriers were also offered free counseling and testing. Results: From March 2015 through January 2018, 708 patients were enrolled and tested. One hundred and forty seven (20.7%) mutation carriers were identified, 102 (14.4%) in BRCA1 and 45 (6.3%) in BRCA2 gene. Testing was more often pursued at initial diagnosis (61%) than at recurrence (39%), as recorded for 409 patients with available relevant information. During the 1st year of the program, average monthly tests performed were 25.1, while during the 3rd year this number increased to 34.3 tests per month. Among patients who tested positive for deleterious BRCA1/2 mutations, relapse was reported in 58 patients, 94.8% of which (n= 55) received treatment with the PARP inhibitor olaparib as per its indication. Family members of 21 patients (14.3%), out of the 147 who tested positive, received genetic counseling and testing for the mutation identified in the context of the program. Conclusion: Free access to genetic testing for BRCA1/2 for ovarian cancer patients and genetic consultation facilitates testing uptake, affects common clinical practice & has major impact on patients and their families. Still, diffusion of genetic information and broader testing of family members require further efforts by the oncological community.

In rectal cancer management, accurate staging by magnetic resonance imaging, neo-adjuvant treatment with the use of radiotherapy, and total mesorectal excision have resulted in remarkable improvement in the oncological outcomes. However, there is substantial discrepancy in the therapeutic approach and failure to adhere to international guidelines among different Greek-Cypriot hospitals. The present guidelines aim to aid the multidisciplinary management of rectal cancer, considering both the local special characteristics of our healthcare system and the international relevant agreements (ESMO, EURECCA). Following background discussion and online communication sessions for feedback among the members of an executive team, a consensus rectal cancer management was obtained. Statements were subjected to the Delphi methodology voting system on two rounds to achieve further consensus by invited multidisciplinary international experts on colorectal cancer. Statements were considered of high, moderate or low consensus if they were voted by ≥80%, 60-80%, or