Rinat Bernstein-Molho1,2, Eitan Friedman3,2, Inbal Kedar4, Yael Laitman3, Tanir M Allweis5,6, Einav Nili Gal-Yam7, Hagit Baris Feldman8, Albert Grinshpun9, Naama Halpern1,2, Shulamit Hartmajer10, Luna Kadouri9, Lior H Katz11, Bella Kaufman1,2, Ido Laish2,12, Keren Levanon1,2, Shira Litz Philipsborn10, Mark Ludman10, Gal Moran13, Tamar Peretz14, Eyal Reinstein2,10, Gili Reznick Levi15, Tamar Safra2,16, Shiri Shkedi17, Chana Vinkler18, Zohar Levy2,19, Yael Goldberg20. 1. Breast Cancer Center, Oncology Institute, Chaim Sheba Medical Center, 52621, Tel-Hashomer, Israel. 2. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 3. Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621, Tel-Hashomer, Israel. 4. Rabin Medical Center, Recanati Genetics Institute, Beilinson Hospital, Petach Tikva, Israel. 5. Breast Health Center & Dept of Surgery, Kaplan Medical Center, Rehovot, Israel. 6. Hebrew University Medical School, Jerusalem, Israel. 7. The Talpiot Medical Leadership Program, Institute of Oncology, Sheba Medical Center, Tel-Hashomer, Israel. 8. The Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 9. Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. 10. Medical Genetics Institute, Meir Medical Center, Kfar-Saba, Israel. 11. Department of Gastroenterology and Hepatology, Hadassah Medical Center, Jerusalem, Israel. 12. Gastroenterology Institute, Chaim Sheba Medical Center, Tel Hasomer, Israel. 13. Maccabi Health Services, Rehovot, Israel. 14. Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 15. The Genetics Institute, Rambam Health Care Campus, Haifa, Israel. 16. Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 17. Department of Genetics and Metabolic Diseases, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel. 18. Institute of Medical Genetics, Wolfson Medical Center, 58100, Holon, Israel. 19. Division of Gastroenterology, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel. 20. Rabin Medical Center, Recanati Genetics Institute, Beilinson Hospital, Petach Tikva, Israel. yaelgo43@gmail.com.
Abstract
BACKGROUND: Carriers of pathogenic variants (PVs) in moderate-high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear. METHODS: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018. RESULTS: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals. CONCLUSIONS: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.
BACKGROUND: Carriers of pathogenic variants (PVs) in moderate-high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear. METHODS: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018. RESULTS: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancerpatients, 6% of breast or ovarian cancerpatients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals. CONCLUSIONS: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.
Entities:
Keywords:
Cancer predisposition; Clinical utility; Inherited cancer syndromes; Low-penetrance variants; Multi-gene panel testing; Recurrent mutations