Abstract P3-08-11: Contribution of germline mutations in cancer predisposition genes to tumor etiology in women diagnosed with invasive breast cancer before 40 years
Authors: Ellsworth RE , Rummel SK , Shriver CD 
Published: March 2017

Abstract
Background: Although breast cancer in young women (YW) accounts for &lt;10% of diagnoses annually, tumors in young patients have more aggressive characteristics and higher mortality rates. The cost of breast cancer, including treatment costs, physical and psychosocial effects, and lost productivity, is higher in YW than older patients. Improved understanding of etiology of breast cancer in YW is critical to developing effective prevention strategies.
Methods: All patients diagnosed before 40 years were identified. Family history was classified as average (No first or second degree relatives with breast or ovarian cancer or 1 second degree relative with breast cancer diagnosed &gt;50 years), moderate (1 first degree relative with breast cancer, 2 first or second degree relatives with breast cancer diagnosed &gt;50 years or 1 first or second degree relative with ovarian cancer) or strong (&gt;1 first or second degree relative with bilateral breast cancer, breast and ovarian cancer or male breast cancer, &gt;2 first or second degree relatives with breast cancer before age 50, breast and ovarian cancer in different relatives, ovarian cancer at any age or &gt;3 first or second degree relatives with breast cancer at any age). Genomic DNA was isolated from blood samples and targeted sequencing was performed using the TruSight Cancer panel (Illumina). Pathogenic mutations were identified using VariantStudio.
Results: Seven percent (132/1950) of patients enrolled in the CBCP were diagnosed &lt;40 years. Of these, 7% had a strong family history). TruSight sequencing was completed for 63 women for whom genomic DNA was available: five patients had pathogenic BRCA2 mutations (1813dupA, 5849del4, 999del5, Q2491X, Y3098X), all ER+ tumors, and seven patients had BRCA1 mutations (187delAG, 448insA, 943ins10, E84X, Q1313X, E1535X) all in triple negative breast cancers (TNBC). A pathogenic CHEK2 I157T was detected in an African American woman with TNBC. Variants of unknown significant were also detected in APC, ATM, BRCA1, BRCA2, CHEK2, CDH1, ERCC4, FANCA and PMS2 and heterozygote mutations detected in autosomal recessive genes BLM and RECQL4.
Discussion: Pathogenic mutations were found in 21% of young women with breast cancer with an additional 22% harboring potentially pathogenic mutations. BRCA1 mutations were associated with triple negative breast tumors in individuals with moderate to strong family history and BRCA2 mutations were associated with ER+ tumors in young women without strong family histories. These data demonstrate that although genetic predisposition may account for 21-43% of tumors, &gt;50% of tumors in young women are not attributable to genetic causes, and identification of those non-genetic factors is critical to reduce the burden of breast cancer in this population.
Citation Format: Ellsworth RE, Rummel SK, Shriver CD. Contribution of germline mutations in cancer predisposition genes to tumor etiology in women diagnosed with invasive breast cancer before 40 years [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-08-11.