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Genes Chromosomes Cancer. 2018 Jan;57(1):19-27. doi: 10.1002/gcc.22503. Epub 2017 Sep 30.

Breast cancer risk and germline genomic profiling of women with neurofibromatosis type 1 who developed breast cancer.

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Department of Individualized Cancer Management, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Department of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Cardiology Genetics, GeneDx, Gaithersburg, Maryland.
Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, Michigan.
Pathology and Laboratory Medicine, Henry Ford Hospital, Detroit, Michigan.
The Johns Hopkins Comprehensive Neurofibromatosis Center, Brain cancer program, Johns Hopkins Hospital and Health System Cancer, Baltimore, Maryland.
Department of Pediatrics and Neurology, Gilbert Family Neurofibromatosis Institute, Children's National Health System, George Washington University, Washington, District of Columbia.
Department of Genetics, The University of Alabama at Birmingham, Birmingham, Alabama.
Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan.


NF1 mutations predispose to neurofibromatosis type 1 (NF1) and women with NF1 have a moderately elevated risk for breast cancer, especially under age 50. Germline genomic analysis may better define the risk so screening and prevention can be applied to the individuals who benefit the most. Survey conducted in several neurofibromatosis clinics in the United States has demonstrated a 17.2% lifetime risk of breast cancer in women affected with NF1. Cumulated risk to age 50 is estimated to be 9.27%. For genomic profiling, fourteen women with NF1 and a history of breast cancer were recruited and underwent whole exome sequencing (WES), targeted genomic DNA based and RNA-based analysis of the NF1 gene. Deleterious NF1 pathogenic variants were identified in each woman. Frameshift mutations because of deletion/duplication/complex rearrangement were found in 50% (7/14) of the cases, nonsense mutations in 21% (3/14), in-frame splice mutations in 21% (3/14), and one case of missense mutation (7%, 1/14). No deleterious mutation was found in the following high/moderate-penetrance breast cancer genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDH1, CHEK2, FANCC, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, TP53, and STK11. Twenty-five rare or common variants in cancer related genes were discovered and may have contributed to the breast cancers in these individuals. Breast cancer predisposition modifiers in women with NF1 may involve a great variety of molecular and cellular functions.

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