Kara N Maxwell1,2, Brandon M Wenz3, Abha Kulkarni3, Bradley Wubbenhorst3, Kurt D'Andrea3, Benita Weathers3, Noah Goodman1, Joseph Vijai4, Jenna Lilyquist5,6, Steven N Hart5,6, Thomas P Slavin7,8, Kasmintan A Schrader9, Vignesh Ravichandran4, Tinu Thomas4, Chunling Hu5,6, Mark E Robson10, Paolo Peterlongo11, Bernardo Bonanni12, James M Ford13, Judy E Garber14, Susan L Neuhausen8, Payal D Shah1,2, Angela R Bradbury1,2, Angela M DeMichele1,2, Kenneth Offit4,10, Jeffrey N Weitzel7,8, Fergus J Couch5,6, Susan M Domchek1,2, Katherine L Nathanson2,3. 1. Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 2. Basser Center for BRCA and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 3. Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 4. Clinical Genetics Research Laboratory, Department of Medicine and Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY. 5. Health Sciences Research, Mayo Clinic, Rochester, MN. 6. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. 7. Department of Medical Oncology, Division of Clinical Cancer Genetics, City of Hope, Duarte, CA. 8. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA. 9. Department of Molecular Oncology, BC Cancer, and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. 10. Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. 11. IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy. 12. Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy. 13. Division of Oncology, Stanford University School of Medicine, Palo Alto, CA. 14. Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA.
Abstract
PURPOSE: Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown. PATIENTS AND METHODS: We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]). RESULTS: Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [P = .02] and 7.1% v 4.2% [P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non-breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC. CONCLUSION: Mutation rates are at least 7% in all patients with BRCA1/2 mutation-negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.
PURPOSE:Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown. PATIENTS AND METHODS: We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]). RESULTS: Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [P = .02] and 7.1% v 4.2% [P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non-breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC. CONCLUSION: Mutation rates are at least 7% in all patients with BRCA1/2 mutation-negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.
Authors: Kara N Maxwell; Steven N Hart; Joseph Vijai; Kasmintan A Schrader; Thomas P Slavin; Tinu Thomas; Bradley Wubbenhorst; Vignesh Ravichandran; Raymond M Moore; Chunling Hu; Lucia Guidugli; Brandon Wenz; Susan M Domchek; Mark E Robson; Csilla Szabo; Susan L Neuhausen; Jeffrey N Weitzel; Kenneth Offit; Fergus J Couch; Katherine L Nathanson Journal: Am J Hum Genet Date: 2016-05-05 Impact factor: 11.025
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