Med Oncol (2015) 32:371 DOI 10.1007/s12032-014-0371-3
LETTER TO THE EDITOR
BRCA2-associated therapy-related acute myeloid leukemia Armin Rashidi • Ina Amarillo • Stephen I. Fisher
Received: 31 October 2014 / Accepted: 13 November 2014 / Published online: 27 November 2014 Ó Springer Science+Business Media New York 2014
A 56-year-old female was with petechiae. She had a history of hormone receptor-positive ductal carcinoma in situ of the left breast 11 years before this presentation, treated with bilateral mastectomy and oophorectomy due to a deleterious germline heterozygous BRCA2 mutation (1282insT). Several members of her family from the paternal side were affected by breast or endometrial cancer. Ten years later, she had a left axillary recurrence, treated with three cycles of neoadjuvant FEC-T (fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel), left axillary lymph node dissection (with involvement of all 13 lymph nodes), and adjuvant radiation and anastrozole. Her blood counts upon presentation were WBC 13.1 9 109/L, Hb 9.6 g/dL, and platelets 77 9 109/L. The smear showed 43 % myeloid blasts. A bone marrow specimen was hypercellular (80 %) and demonstrated mild trilineage dysplasia; 7 % eosinophils; and 52 % myelomonocytic blasts expressing CD13, CD33, CD34, CD117, HLA-DR, myeloperoxidase (subset) by flow, and aNBE (subset) by enzyme cytochemistry, and negative for additional T cell, B-cell, and monocytic markers. Her karyotype was 46,XX,inv(16)(p13.1q22), and molecular studies did not show a KIT D816 mutation or a TP53 mutation by fluorescence in situ hybridization (FISH). A. Rashidi (&) Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO 63110, USA e-mail: [email protected] I. Amarillo Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA S. I. Fisher Pathology Sciences Medical Group/Sentara Laboratory Services, Norfolk, VA, USA
A diagnosis of BRCA2-associated therapy-related acute myeloid leukemia (t-AML)-M4Eo with inv(16)(p13.1q22) was established. She achieved a complete remission with standard induction chemotherapy, but developed catastrophic intracranial bleeding due to severe thrombocytopenia following the first consolidation and died. BRCA2-associated t-AML has been reported only once before [1]. By participating in error-free repair of doublestrand DNA damage, BRCA1 and BRCA2 have an important role in maintaining genomic integrity, especially in rapidly dividing cells [2]. In BRCA-deficient cells, the alternate, error-prone, double-strand DNA break repair mechanisms predominate, leading to genomic instability [3]. Accordingly, BRCA1 loss results in augmented mutation accumulation after exposure to genotoxic damage and has been suggested to be a pathogenetic mechanism in t-AML [4]. Mutations in the so-called guardian of the genome, TP53, are found in up to one-third of cases of t-AML [5]. Contrary to previous belief, there is now evidence that TP53-mutated hematopoietic clones are already present before, rather than caused by cytotoxic therapy [6, 7]. These somatic mutations occur randomly during normal hematopoiesis. TP53-mutated cells have a selective survival advantage over their unmutated counterparts when exposed to chemotherapy or radiation. This is because unmutated cells that develop irreparable DNA damage as a result of genotoxic insult go in cell cycle arrest or undergo apoptosis, whereas TP53-mutated cells continue to survive, proliferate, and accumulate more mutations, one of which may eventually be an AML-driving mutation and cause t-AML. By definition, germline BRCA mutations are present before exposure to cytotoxic therapy. Therefore, they are not able per se to provide any selective advantage for a
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Fig. 1 Schematic diagram demonstrating the sequence of events leading to t-AML. Top (no BRCA mutation): Genotoxic insult results, by causing irreparable DNA damage (red circles), in death of both breast cancer cells and hematopoietic stem and progenitor cells (HSPCs) without a checkpoint (e.g., TP53) mutation. TP53 causes cell cycle arrest or apoptosis of the HSPC that have wild-type TP53. HSPCs with mutated TP53, on the other hand, survive and continue to proliferate despite irreparable DNA damage, pass through the bottleneck created by genotoxic insult, accumulate more mutations (dark circles), and develop AML. Bottom (BRCA mutation): BRCA
mutations are germ line and present in both breast cancer cells and HSPCs before exposure to cytotoxic therapy. With genotoxic insult, BRCA-mutated cells develop more irreparable DNA damage (red circles) to their unstable genome compared to BRCA-unmutated cells (top). HSPCs with TP53 mutation are unable to undergo cell cycle arrest or apoptosis; they pass through the bottleneck created by chemotherapy or radiation and develop additional mutations (dark circles) leading to AML. AML cells in these patients (bottom) are predicted to have a higher mutation load compared to patients without a BRCA mutation (top)
subset of hematopoietic stem cells during cytotoxic therapy. Furthermore, while irreparable DNA damage in otherwise normal BRCA-deficient cells leads to cell growth arrest or apoptosis by the activity of checkpoint genes such as TP53, BRCA-deficient cells with loss-offunction checkpoint mutations are prone to neoplastic transformation [8]. Accordingly, TP53 mutations are more frequent in BRCA-mutated cases of breast cancer [9]. Our patient represents a unique scenario of a germline cancersusceptibility mutation (BRCA2) associated with t-AML, possibly via cooperation with a loss-of-function somatic checkpoint mutation that was likely present before exposure to cytotoxic insult. BRCA-deficient hematopoietic
cells attempt to repair the genetic damage by error-prone mechanisms, thereby causing genomic instability. However, once the accumulation of faulty repair products becomes irreparable, only TP53 (or other checkpoint gene)-mutated cells survive while others either develop cell cycle arrest or undergo apoptosis. The surviving cells may then procure and accrue additional mutations, including driver mutation(s), resulting in AML. FISH for TP53 is unable to detect point mutations, which may be identifiable by higher-resolution methods such as next-generation sequencing or polymerase chain reaction. We are not sure whether this was the case in our patient because we did not have the consent to do additional testing.
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Hall et al. [10] reported three patients with a BRCA2 mutation and early-stage breast cancer, who developed acute promyelocytic leukemia several years later. Two of these patients received no cytotoxic treatment for breast cancer, and one was treated with surgery and local radiation. These cases demonstrated the possibility that the genetic instability due to deleterious BRCA2 mutations may contribute to the occurrence of AML even in the absence of prior cytotoxic treatment. Although due to its presence in all cells a sole BRCA2 deficiency does not conceptually alter the bottleneck created by cytotoxic therapy, its concurrence with a checkpoint gene mutation can result in cells with a larger number of irreparable damages that, owing to checkpoint gene mutation, enjoy a survival advantage and pass selectively through the bottleneck (Fig. 1). We predict that BRCA-mutated patients with t-AML have a higher mutation load in their AML clone than those without a BRCA mutation. This prediction is amenable to empiric testing. Acknowledgments We thank Sandra Crocker and the Cytogenomics Lab at Washington University for performing FISH studies. Conflict of interest
None.
References 1. Schulz E, Valentin A, Ulz P, Beham-Schmid C, Lind K, Rupp V, et al. Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms. J Med Genet. 2012;49:422–8.
Page 3 of 3 371 2. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171–82. 3. Tutt A, Bertwistle D, Valentine J, Gabriel A, Swift S, Ross G, et al. Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J. 2001;20:4704–16. 4. Scardocci A, Guidi F, D’Alo’ F, Gumiero D, Fabiani E, Diruscio A, et al. Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acutemyeloid leukaemia. Br J Cancer. 2006;95:1108–13. 5. Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol. 2001;19:1405–13. 6. Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS, et al. The role of TP53 mutations in the origin and evolution of therapy-related AML. Nature. 2014 (in press). 7. Schulz E, Kashofer K, Heitzer E, Mhatre KN, Speicher MR, Hoefler G, et al. Preexisting TP53 mutation in therapy-related acute myeloid leukemia. Ann Hematol. 2014. doi:10.1007/ s00277-014-2191-0. 8. Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet. 2001;29:418–25. 9. Greenblatt MS, Chappuis PO, Bond JP, Hamel N, Foulkes WD. TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distribution. Cancer Res. 2001;61:4092–7. 10. Hall MJ, Li L, Wiernik PH, Olopade OI. BRCA2 mutation and the risk of hematologic malignancy. Leuk Lymphoma. 2006;47: 765–7.
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LETTER TO THE EDITOR
BRCA2-associated therapy-related acute myeloid leukemia Armin Rashidi • Ina Amarillo • Stephen I. Fisher
Received: 31 October 2014 / Accepted: 13 November 2014 / Published online: 27 November 2014 Ó Springer Science+Business Media New York 2014
A 56-year-old female was with petechiae. She had a history of hormone receptor-positive ductal carcinoma in situ of the left breast 11 years before this presentation, treated with bilateral mastectomy and oophorectomy due to a deleterious germline heterozygous BRCA2 mutation (1282insT). Several members of her family from the paternal side were affected by breast or endometrial cancer. Ten years later, she had a left axillary recurrence, treated with three cycles of neoadjuvant FEC-T (fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel), left axillary lymph node dissection (with involvement of all 13 lymph nodes), and adjuvant radiation and anastrozole. Her blood counts upon presentation were WBC 13.1 9 109/L, Hb 9.6 g/dL, and platelets 77 9 109/L. The smear showed 43 % myeloid blasts. A bone marrow specimen was hypercellular (80 %) and demonstrated mild trilineage dysplasia; 7 % eosinophils; and 52 % myelomonocytic blasts expressing CD13, CD33, CD34, CD117, HLA-DR, myeloperoxidase (subset) by flow, and aNBE (subset) by enzyme cytochemistry, and negative for additional T cell, B-cell, and monocytic markers. Her karyotype was 46,XX,inv(16)(p13.1q22), and molecular studies did not show a KIT D816 mutation or a TP53 mutation by fluorescence in situ hybridization (FISH). A. Rashidi (&) Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO 63110, USA e-mail: [email protected] I. Amarillo Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA S. I. Fisher Pathology Sciences Medical Group/Sentara Laboratory Services, Norfolk, VA, USA
A diagnosis of BRCA2-associated therapy-related acute myeloid leukemia (t-AML)-M4Eo with inv(16)(p13.1q22) was established. She achieved a complete remission with standard induction chemotherapy, but developed catastrophic intracranial bleeding due to severe thrombocytopenia following the first consolidation and died. BRCA2-associated t-AML has been reported only once before [1]. By participating in error-free repair of doublestrand DNA damage, BRCA1 and BRCA2 have an important role in maintaining genomic integrity, especially in rapidly dividing cells [2]. In BRCA-deficient cells, the alternate, error-prone, double-strand DNA break repair mechanisms predominate, leading to genomic instability [3]. Accordingly, BRCA1 loss results in augmented mutation accumulation after exposure to genotoxic damage and has been suggested to be a pathogenetic mechanism in t-AML [4]. Mutations in the so-called guardian of the genome, TP53, are found in up to one-third of cases of t-AML [5]. Contrary to previous belief, there is now evidence that TP53-mutated hematopoietic clones are already present before, rather than caused by cytotoxic therapy [6, 7]. These somatic mutations occur randomly during normal hematopoiesis. TP53-mutated cells have a selective survival advantage over their unmutated counterparts when exposed to chemotherapy or radiation. This is because unmutated cells that develop irreparable DNA damage as a result of genotoxic insult go in cell cycle arrest or undergo apoptosis, whereas TP53-mutated cells continue to survive, proliferate, and accumulate more mutations, one of which may eventually be an AML-driving mutation and cause t-AML. By definition, germline BRCA mutations are present before exposure to cytotoxic therapy. Therefore, they are not able per se to provide any selective advantage for a
123
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Fig. 1 Schematic diagram demonstrating the sequence of events leading to t-AML. Top (no BRCA mutation): Genotoxic insult results, by causing irreparable DNA damage (red circles), in death of both breast cancer cells and hematopoietic stem and progenitor cells (HSPCs) without a checkpoint (e.g., TP53) mutation. TP53 causes cell cycle arrest or apoptosis of the HSPC that have wild-type TP53. HSPCs with mutated TP53, on the other hand, survive and continue to proliferate despite irreparable DNA damage, pass through the bottleneck created by genotoxic insult, accumulate more mutations (dark circles), and develop AML. Bottom (BRCA mutation): BRCA
mutations are germ line and present in both breast cancer cells and HSPCs before exposure to cytotoxic therapy. With genotoxic insult, BRCA-mutated cells develop more irreparable DNA damage (red circles) to their unstable genome compared to BRCA-unmutated cells (top). HSPCs with TP53 mutation are unable to undergo cell cycle arrest or apoptosis; they pass through the bottleneck created by chemotherapy or radiation and develop additional mutations (dark circles) leading to AML. AML cells in these patients (bottom) are predicted to have a higher mutation load compared to patients without a BRCA mutation (top)
subset of hematopoietic stem cells during cytotoxic therapy. Furthermore, while irreparable DNA damage in otherwise normal BRCA-deficient cells leads to cell growth arrest or apoptosis by the activity of checkpoint genes such as TP53, BRCA-deficient cells with loss-offunction checkpoint mutations are prone to neoplastic transformation [8]. Accordingly, TP53 mutations are more frequent in BRCA-mutated cases of breast cancer [9]. Our patient represents a unique scenario of a germline cancersusceptibility mutation (BRCA2) associated with t-AML, possibly via cooperation with a loss-of-function somatic checkpoint mutation that was likely present before exposure to cytotoxic insult. BRCA-deficient hematopoietic
cells attempt to repair the genetic damage by error-prone mechanisms, thereby causing genomic instability. However, once the accumulation of faulty repair products becomes irreparable, only TP53 (or other checkpoint gene)-mutated cells survive while others either develop cell cycle arrest or undergo apoptosis. The surviving cells may then procure and accrue additional mutations, including driver mutation(s), resulting in AML. FISH for TP53 is unable to detect point mutations, which may be identifiable by higher-resolution methods such as next-generation sequencing or polymerase chain reaction. We are not sure whether this was the case in our patient because we did not have the consent to do additional testing.
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Med Oncol (2015) 32:371
Hall et al. [10] reported three patients with a BRCA2 mutation and early-stage breast cancer, who developed acute promyelocytic leukemia several years later. Two of these patients received no cytotoxic treatment for breast cancer, and one was treated with surgery and local radiation. These cases demonstrated the possibility that the genetic instability due to deleterious BRCA2 mutations may contribute to the occurrence of AML even in the absence of prior cytotoxic treatment. Although due to its presence in all cells a sole BRCA2 deficiency does not conceptually alter the bottleneck created by cytotoxic therapy, its concurrence with a checkpoint gene mutation can result in cells with a larger number of irreparable damages that, owing to checkpoint gene mutation, enjoy a survival advantage and pass selectively through the bottleneck (Fig. 1). We predict that BRCA-mutated patients with t-AML have a higher mutation load in their AML clone than those without a BRCA mutation. This prediction is amenable to empiric testing. Acknowledgments We thank Sandra Crocker and the Cytogenomics Lab at Washington University for performing FISH studies. Conflict of interest
None.
References 1. Schulz E, Valentin A, Ulz P, Beham-Schmid C, Lind K, Rupp V, et al. Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms. J Med Genet. 2012;49:422–8.
Page 3 of 3 371 2. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171–82. 3. Tutt A, Bertwistle D, Valentine J, Gabriel A, Swift S, Ross G, et al. Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J. 2001;20:4704–16. 4. Scardocci A, Guidi F, D’Alo’ F, Gumiero D, Fabiani E, Diruscio A, et al. Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acutemyeloid leukaemia. Br J Cancer. 2006;95:1108–13. 5. Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol. 2001;19:1405–13. 6. Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS, et al. The role of TP53 mutations in the origin and evolution of therapy-related AML. Nature. 2014 (in press). 7. Schulz E, Kashofer K, Heitzer E, Mhatre KN, Speicher MR, Hoefler G, et al. Preexisting TP53 mutation in therapy-related acute myeloid leukemia. Ann Hematol. 2014. doi:10.1007/ s00277-014-2191-0. 8. Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet. 2001;29:418–25. 9. Greenblatt MS, Chappuis PO, Bond JP, Hamel N, Foulkes WD. TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distribution. Cancer Res. 2001;61:4092–7. 10. Hall MJ, Li L, Wiernik PH, Olopade OI. BRCA2 mutation and the risk of hematologic malignancy. Leuk Lymphoma. 2006;47: 765–7.
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