Rachel Pearlman1, Wendy L Frankel2, Benjamin J Swanson2,3, Dan Jones2, Weiqiang Zhao2, Ahmet Yilmaz2, Kristin Miller2, Jason Bacher2, Christopher Bigley1,4, Lori Nelsen1, Paul J Goodfellow5, Richard M Goldberg6,7, Electra Paskett1, Peter G Shields1, Jo L Freudenheim8, Peter P Stanich9, Ilene Lattimer1, Mark Arnold10, Thomas W Prior2,11, Mitchell Haut12, Matthew F Kalady10,13, Brandie Heald13, Ian Paquette14, David J Draper15, Joanna M Brell16,17, Sameer Mahesh18, Kisa Weeman19, Shyamal Bastola20, Jeffrey Zangmeister21, Aruna Gowda22, Filix Kencana23, Albert Malcolm24, Yinong Liu25, Sharon Cole26, Charles Bane27, Chaoyang Li28, Esther Rehmus29, Colin C Pritchard30, Brian H Shirts30, Angela Jacobson30, Shelly A Cummings31, Albert de la Chapelle32, Heather Hampel1. 1. Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH. 2. Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH. 3. Department of Pathology and Microbiology, The University of Nebraska Medical Center, Omaha, NE. 4. Vikor Scientific, Charleston, SC. 5. Department of Obstetrics and Gynecology, The Ohio State University Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH. 6. Department of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH. 7. Department of Medicine, West Virginia University, Morgantown, WV. 8. Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY. 9. Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH. 10. Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH. 11. Department of Pathology, Case Western Reserve University, Cleveland, OH. 12. Mercy Medical Center, Canton, OH. 13. Sanford R. Weiss Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH. 14. Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH. 15. TriHealth Cancer Institute, Good Samaritan Hospital, Cincinnati, OH. 16. Department of Medicine, MetroHealth Cancer Center, Cleveland, OH. 17. Department of Medicine, Case Western Reserve University, Cleveland, OH. 18. Department of Internal Medicine, Summa Cancer Institute, Summa Akron City Hospital, Akron, OH. 19. Department of Hematology/Oncology, Aultman Hospital, Canton, OH. 20. Department of Oncology and Hematology, Genesis HealthCare System, Zanesville, OH. 21. The Mark H. Zangmeister Cancer Center, Columbus, OH. 22. Department of Hematology/Oncology, Licking Memorial Hospital, Newark, OH. 23. Division of Medical Oncology, Springfield Regional Medical Center, Springfield, OH. 24. Atrium Medical Center, Middletown, OH. 25. Southern Ohio Medical Center, Portsmouth, OH. 26. Blanchard Valley Medical Center, Findlay, OH. 27. Good Samaritan Hospital, Dayton, OH. 28. Grady Memorial Hospital, Delaware, OH. 29. Akron General Medical Center, Akron, OH. 30. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA. 31. Myriad Genetics Inc, Salt Lake City, UT. 32. Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.
Abstract
Hereditary cancer syndromes infer high cancer risks and require intensive surveillance. Identification of high-risk individuals among patients with colorectal cancer (CRC) needs improvement. METHODS: Three thousand three hundred ten unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016. Universal Tumor screening (UTS) for mismatch repair (MMR) deficiency was performed for all, and pathogenic germline variants (PGVs) were identified using multigene panel testing (MGPT) in those who met at least one inclusion criterion: MMR deficiency, diagnosed < 50 years, multiple primary tumors (CRC or endometrial cancer), or with a first-degree relative with CRC or endometrial cancer. RESULTS: Five hundred twenty-five patients (15.9%) had MMR deficiency. Two hundred thirty-four of 3,310 (7.1%; 16% of the 1,462 who received MGPT) had 248 PGVs in cancer susceptibility genes. One hundred forty-two (4.3%) had a PGV in an MMR gene, and 101 (3.1%) had a PGV in a non-MMR gene. Ten with Lynch syndrome (LS) also had a non-MMR PGV and were included in both groups. Two (0.06%) had constitutional MLH1 hypermethylation. Of unexplained MMR-deficient patients, 88.4% (76 of 86) had double somatic MMR mutations. Testing for only MMR genes in MMR-deficient patients would have missed 18 non-MMR gene PGVs (7.3% of total PGVs identified). Had UTS been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) would have been missed, including 6.3% (9 of 144) of those with LS. These results have treatment implications as 5.3% (175 of 3,310) had PGVs in genes with therapeutic targets. CONCLUSION: UTS alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with LS. At a minimum, 7.1% of individuals with CRC have a PGV and pan-cancer MGPT should be considered for all patients with CRC.
Hereditary cancer syndromes infer high cancer risks and require intensive surveillance. Identification of high-risk individuals among patients with colorectal cancer (CRC) needs improvement. METHODS: Three thousand three hundred ten unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016. Universal Tumor screening (UTS) for mismatch repair (MMR) deficiency was performed for all, and pathogenic germline variants (PGVs) were identified using multigene panel testing (MGPT) in those who met at least one inclusion criterion: MMR deficiency, diagnosed < 50 years, multiple primary tumors (CRC or endometrial cancer), or with a first-degree relative with CRC or endometrial cancer. RESULTS: Five hundred twenty-five patients (15.9%) had MMR deficiency. Two hundred thirty-four of 3,310 (7.1%; 16% of the 1,462 who received MGPT) had 248 PGVs in cancer susceptibility genes. One hundred forty-two (4.3%) had a PGV in an MMR gene, and 101 (3.1%) had a PGV in a non-MMR gene. Ten with Lynch syndrome (LS) also had a non-MMR PGV and were included in both groups. Two (0.06%) had constitutional MLH1 hypermethylation. Of unexplained MMR-deficient patients, 88.4% (76 of 86) had double somatic MMR mutations. Testing for only MMR genes in MMR-deficient patients would have missed 18 non-MMR gene PGVs (7.3% of total PGVs identified). Had UTS been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) would have been missed, including 6.3% (9 of 144) of those with LS. These results have treatment implications as 5.3% (175 of 3,310) had PGVs in genes with therapeutic targets. CONCLUSION: UTS alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with LS. At a minimum, 7.1% of individuals with CRC have a PGV and pan-cancer MGPT should be considered for all patients with CRC.
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