We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.
African Americans have a disproportionate burden of aggressive young-onset breast cancer. Genomic testing for inherited predisposition to breast cancer is increasingly common in clinical practice, but comprehensive mutation profiles remain unknown for most minority populations. We evaluated 289 patients who self-identified as African American with primary invasive breast cancer and with personal or family cancer history or tumor characteristics associated with high genetic risk for all classes of germline mutations in known breast cancer susceptibility genes using a validated targeted capture and multiplex sequencing approach. Sixty-eight damaging germline mutations were identified in 65 (22 %, 95 % CI 18–28 %) of the 289 subjects. Proportions of patients with unequivocally damaging mutations in a breast cancer gene were 26 % (47/180; 95 % confident interval [CI] 20–33 %) of those with breast cancer diagnosis before age 45; 25 % (26/103; 95 % CI 17–35 %) of those with triple-negative breast cancer (TNBC); 29 % (45/156; 95 % CI 22–37 %) of those with a first or second degree relative with breast cancer before age 60 or with ovarian cancer; and 57 % (4/7; 95 % CI 18–90 %) of those with both breast and ovarian cancer. Of patients with mutations, 80 % (52/65) carried mutations in BRCA1 and BRCA2 genes and 20 % (13/65) carried mutations in PALB2, CHEK2, BARD1, ATM, PTEN, or TP53. The mutational allelic spectrum was highly heterogeneous, with 57 different mutations in 65 patients. Of patients meeting selection criteria other than family history (i.e., with young age at diagnosis or TNBC), 48 % (64/133) had very limited information about the history of cancer in previous generations of their families. Mutations in BRCA1 and BRCA2 or another breast cancer gene occur in one in four African American breast cancer patients with early onset disease, family history of breast or ovarian cancer, or TNBC. Each of these criteria defines patients who would benefit from genomic testing and novel therapies targeting DNA repair pathways.
Background Risk factors for therapy-related leukemia (TRL) development, an often lethal late complication of cytotoxic therapy, remain poorly understood and may differ for survivors of different malignancies. Breast cancer (BC) survivors now account for the majority of TRL cases, making study of TRL risk factors in this population a priority. Methods Patients with TRL following cytotoxic therapy for a primary BC were identified from The University of Chicago TRL registry. Those with an available germline DNA sample were screened with a comprehensive gene panel covering known inherited BC susceptibility genes. Clinical and TRL characteristics of all subjects and those with identified germline mutations are described. Results Nineteen (22%) of 88 BC survivors with TRL had an additional primary cancer and 40 (57%) of the 70 with available family history had a close relative with breast, ovarian, or pancreatic cancer. Of the 47 subjects with available DNA, 10 (21%) were found to carry a deleterious inherited mutation in: BRCA1 (n=3, 6%), BRCA2 (n=2, 4%), TP53 (n=3, 6%), CHEK2 (n=1, 2%), and PALB2 (n=1, 2%). Conclusions BC survivors with TRL have personal and family histories suggestive of inherited cancer susceptibility and frequently carry germline mutations in BC susceptibility genes. These data support the role of these genes in TRL risk and suggest that long term follow-up studies of women with germline mutations treated for BC and functional studies of the effects of heterozygous mutations in these genes on bone marrow function following cytotoxic exposures are warranted.
• Brca1 deficiency causes Fanconi anemia-like cytopenias, mitomycin C hypersensitivity, and spontaneous bone marrow failure.• Brca1 is critical for the maintenance of normal hematopoietic progenitor function and genomic stability in the bone marrow.BRCA1 is critical for maintenance of genomic stability and interacts directly with several proteins that regulate hematopoietic stem cell function and are part of the Fanconi anemia (FA) double-strand break DNA repair pathway. The effects of complete BRCA1 deficiency on bone marrow (BM) function are unknown. To test the hypothesis that Brca1 is essential in hematopoiesis, we developed a conditional mouse model with Mx1-Cre-mediated Brca1 deletion. Mice lacking Brca1 in the BM have baseline cytopenias and develop spontaneous bone marrow failure or diverse hematologic malignancies by 6 months of age. Brca1 2/2 BM cells have a reduced capacity to form hematopoietic colonies in vitro and to reconstitute hematopoiesis in irradiated recipients, consistent with a hematopoietic progenitor functional defect. Brca1 2/2 BM cells also show FA-like hypersensitivity to the DNA crosslinking agent mitomycin C, and karyotypes feature genomic instability. Taken together, our results show that loss of Brca1 in murine BM causes hematopoietic defects similar to those seen in people with FA, which provides strong evidence that Brca1 is critical for normal hematopoiesis and that Brca1 is a bona fide FA-like gene. (Blood. 2016;127(3):310-313) IntroductionFanconi anemia (FA) is an inherited bone marrow failure (BMF) syndrome characterized by hypersensitivity to DNA crosslinking agents, congenital anomalies, BMF, and an increased risk of developing leukemia and solid tumors. 1 FA is caused by mutations in one of 17 genes that make up the FA DNA repair pathway. 2-4 BRCA1 binds directly to several FA proteins, all of which are essential for normal hematopoiesis, but the effects of BRCA1 deficiency on hematopoiesis are unknown. Several lines of evidence suggest that BRCA1 may also be an important regulator of hematopoiesis. First, BRCA1 is highly expressed in hematopoietic tissues, 5,6 whereas its expression is lost in myeloid leukemias. 7,8 Second, overexpression of Brca1 in the bone marrow (BM) disrupts stem cell quiescence and differentiation. 9 Finally, the first person ever reported to have biallelic BRCA1 mutations experienced unusually severe myelosuppression after exposure to the DNA crosslinking agent carboplatin, 10 which provides direct evidence that BRCA1 is important in human hematopoiesis.To test whether BRCA1 has a critical role in hematopoiesis, we created a conditional Mx1-Cre-induced Brca1 deficiency mouse model. We demonstrated that mice with homozygous deficiency of Brca1 in the BM have FA-like cytopenias, DNA crosslinking agent hypersensitivity, and susceptibility to BMF and hematologic malignancies (HMs). Furthermore, Brca1 2/2 cells have a hematopoietic precursor functional defect characterized by a reduced capacity to form hematopoietic colonies in vitro and to reconstitut...
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