Ido Laish1,2, Eitan Friedman3,2, Gili Levi-Reznick4, Inbal Kedar5, Lior Katz6, Zohar Levi7,2, Naama Halpern8,2, Shani Parnasa9, Aasem Abu-Shatya10, Elizabeth Half11, Yael Goldberg12,13. 1. Gastroenterology Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel. 2. Sackler School 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, Tel Hashomer, Israel. 4. Genetic Institute, Rambam Health Care Campus, Haifa, Israel. 5. Recanati Genetic Institute, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., 4941492, Petach Tikva, Israel. 6. Department of Gastroenterology and Hepatology, Hadassah Medical Center, Jerusalem, Israel. 7. Gastroenterology Institute, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel. 8. Department of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel. 9. Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. 10. Department of Internal Medicine, Carmel Medical Center, Haifa, Israel. 11. Gastroenterology Institute, Rambam Health Care Campus, Haifa, Israel. 12. Recanati Genetic Institute, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., 4941492, Petach Tikva, Israel. yaelgo43@gmail.com. 13. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. yaelgo43@gmail.com.
Abstract
BACKGROUND: Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes. METHODS: Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed. RESULTS: Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1-2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36-76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines. CONCLUSIONS: This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies.
BACKGROUND: Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes. METHODS: Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed. RESULTS: Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1-2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36-76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines. CONCLUSIONS: This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies.
Authors: R Moslehi; W Chu; B Karlan; D Fishman; H Risch; A Fields; D Smotkin; Y Ben-David; J Rosenblatt; D Russo; P Schwartz; N Tung; E Warner; B Rosen; J Friedman; J S Brunet; S A Narod Journal: Am J Hum Genet Date: 2000-03-16 Impact factor: 11.025
Authors: W D Foulkes; I Thiffault; S B Gruber; M Horwitz; N Hamel; C Lee; J Shia; A Markowitz; A Figer; E Friedman; D Farber; C M T Greenwood; J D Bonner; K Nafa; T Walsh; V Marcus; L Tomsho; J Gebert; F A Macrae; C L Gaff; B Bressac-De Paillerets; P K Gregersen; J N Weitzel; P H Gordon; E MacNamara; M-C King; H Hampel; A De La Chapelle; J Boyd; K Offit; G Rennert; G Chong; N A Ellis Journal: Am J Hum Genet Date: 2002-11-26 Impact factor: 11.025
Authors: E Warner; W Foulkes; P Goodwin; W Meschino; J Blondal; C Paterson; H Ozcelik; P Goss; D Allingham-Hawkins; N Hamel; L Di Prospero; V Contiga; C Serruya; M Klein; R Moslehi; J Honeyford; A Liede; G Glendon; J S Brunet; S Narod Journal: J Natl Cancer Inst Date: 1999-07-21 Impact factor: 13.506
Authors: Pål Møller; Toni T Seppälä; Inge Bernstein; Elke Holinski-Feder; Paulo Sala; D Gareth Evans; Annika Lindblom; Finlay Macrae; Ignacio Blanco; Rolf H Sijmons; Jacqueline Jeffries; Hans F A Vasen; John Burn; Sigve Nakken; Eivind Hovig; Einar Andreas Rødland; Kukatharmini Tharmaratnam; Wouter H de Vos Tot Nederveen Cappel; James Hill; Juul T Wijnen; Mark A Jenkins; Kate Green; Fiona Lalloo; Lone Sunde; Miriam Mints; Lucio Bertario; Marta Pineda; Matilde Navarro; Monika Morak; Laura Renkonen-Sinisalo; Mev Dominguez Valentin; Ian M Frayling; John-Paul Plazzer; Kirsi Pylvanainen; Maurizio Genuardi; Jukka-Pekka Mecklin; Gabriela Moeslein; Julian R Sampson; Gabriel Capella Journal: Gut Date: 2017-07-28 Impact factor: 23.059
Authors: Karoline B Kuchenbaecker; John L Hopper; Daniel R Barnes; Kelly-Anne Phillips; Thea M Mooij; Marie-José Roos-Blom; Sarah Jervis; Flora E van Leeuwen; Roger L Milne; Nadine Andrieu; David E Goldgar; Mary Beth Terry; Matti A Rookus; Douglas F Easton; Antonis C Antoniou; Lesley McGuffog; D Gareth Evans; Daniel Barrowdale; Debra Frost; Julian Adlard; Kai-Ren Ong; Louise Izatt; Marc Tischkowitz; Ros Eeles; Rosemarie Davidson; Shirley Hodgson; Steve Ellis; Catherine Nogues; Christine Lasset; Dominique Stoppa-Lyonnet; Jean-Pierre Fricker; Laurence Faivre; Pascaline Berthet; Maartje J Hooning; Lizet E van der Kolk; Carolien M Kets; Muriel A Adank; Esther M John; Wendy K Chung; Irene L Andrulis; Melissa Southey; Mary B Daly; Saundra S Buys; Ana Osorio; Christoph Engel; Karin Kast; Rita K Schmutzler; Trinidad Caldes; Anna Jakubowska; Jacques Simard; Michael L Friedlander; Sue-Anne McLachlan; Eva Machackova; Lenka Foretova; Yen Y Tan; Christian F Singer; Edith Olah; Anne-Marie Gerdes; Brita Arver; Håkan Olsson Journal: JAMA Date: 2017-06-20 Impact factor: 56.272