Emergence of secondary acute leukemia in a patient treated for osteosarcoma: implications of germline TP53 mutations

Panizo, Carlos; Patiño, Ana; Calasanz, Marı́a José; Rifón, J.; Sierrasesúmaga, Luis; Rocha, Eduardo

doi:10.1002/(sici)1096-911x(199803)30:3<165::aid-mpo7>3.0.co;2-f

Cited by 19 publications

(3 citation statements)

References 32 publications

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“…Germ-line mutations in tumor-suppressor genes or genetic variation in drug metabolism are examples of host risk factors. Germ-line mutations in the NF-1 and p53 tumorsuppressor genes have been observed in alkylating agentassociated leukemias with chromosome 5 and 7 monosomies (9)(10)(11)(12). Similar host risk factors for leukemias induced by DNA topoisomerase II inhibitors currently are unknown.…”

supporting

confidence: 46%

Association of CYP 3 A 4 genotype with treatment-related leukemia

Felix

Walker

Lange

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

289

153

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Epipodophyllotoxins are associated with leukemias characterized by translocations of the MLL gene at chromosome band 11q23 and other translocations. Cytochrome P450 (CYP) 3A metabolizes epipodophyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyllotoxin catechol and quinone metabolites, which could damage DNA. There is a polymorphism in the 5 promoter region of the CYP3A4 gene (CYP3A4-V) that might alter the metabolism of anticancer drugs. We examined 99 de novo and 30 treatmentrelated leukemias with a conformation-sensitive gel electrophoresis assay for the presence of the CYP3A4-V. In all treatmentrelated cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99 de novo (19%) and 1 of 30 treatment-related (3%) leukemias carried the CYP3A4-V (P ‫؍‬ 0.026; Fisher's Exact Test, FET). Nine of 42 de novo leukemias with MLL gene translocations (21%), and 0 of 22 treatment-related leukemias with MLL gene translocations carried the CYP3A4-V (P ‫؍‬ 0.016, FET). This relationship remained significant when 19 treatment-related leukemias with MLL gene translocations that followed epipodophyllotoxin exposure were compared with the same 42 de novo cases (P ‫؍‬ 0.026, FET). These data suggest that individuals with CYP3A4-W genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism by CYP3A4 may contribute to the secondary cancer risk. The CYP3A4-W genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.Second cancers are uncommon events occurring at a frequency of about 7% in survivors of primary malignant neoplasms (1). Although leukemias comprise a small fraction of second cancers (2), leukemias are the major second cancers that result from chemotherapy (3-6). There are two major forms of treatmentrelated leukemia, those with chromosome 5 and 7 monosomies induced by alkylating agents, and those with MLL gene translocations and other translocations related to DNA topoisomerase II inhibitors (7). Because only a minority of patients develop leukemia after chemotherapy, it has been suggested that differences in drug interactions with the host may be predisposing factors (8). Germ-line mutations in tumor-suppressor genes or genetic variation in drug metabolism are examples of host risk factors. Germ-line mutations in the NF-1 and p53 tumorsuppressor genes have been observed in alkylating agentassociated leukemias with chromosome 5 and 7 monosomies (9-12). Similar host risk factors for leukemias induced by DNA topoisomerase II inhibitors currently are unknown.We explored genetic variation in drug metabolism as a potential host risk factor. Distinct phase I and phase II pathways of drug metabolism comprise a protective mechanism against environmental toxins (13-15). Phase I metabolism by cytochrome P450 (CYP) enzymes converts many ...

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supporting

confidence: 46%

Association of CYP 3 A 4 genotype with treatment-related leukemia

Felix

Walker

Lange

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

289

153

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“…Recent efforts have concentrated on elucidating genetic factors that modulate susceptibility to t-AML. Indeed, germ-line mutations in the tumor suppressor gene p53 have been associated with increased susceptibility to t-AML (12,13), as has polymorphic variation in the NAD(P)H:quinone oxidoreductase gene (14,15) and the cytochrome P450 3A4 gene (16).…”

mentioning

confidence: 99%

Polymorphism in glutathione S -transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

Allan

Wild

Rollinson

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

236

139

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Glutathione S -transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1 . Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11–2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39–5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43–13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50–2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.

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“…[6–9] Presence of p53 mutation (Li Frumani syndrome) in OS patients increases the incidence of nontherapy-related synchronous or metachronous SMNs. [17] Our patient had no family history of malignancy. The occurrence of sAML in OS is a rare complication.…”

Section: Discussionmentioning

confidence: 99%

Secondary acute myeloid leukemia after successful treatment for osteosarcoma

Mittal

Ramaswamy

Pandita

et al. 2010

Indian J Med Paediatr Oncol

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Secondary acute myeloid leukemia (sAML) is a rare complication following chemotherapy for osteogenic sarcoma. However, the exact offending drug is difficult to prove as there is no consistent data. It usually develops 2 years after completion of therapy. We report a case of sAML that developed within 8 months of completing the treatment. The patient was treated with cisplatin, doxorubicin and high-dose methotreaxate followed by surgery (amputation). Eight months after completion of therapy, while on follow-up, he presented with leukocytosis and thrombocytopenia and confirmed to have AML.

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Emergence of secondary acute leukemia in a patient treated for osteosarcoma: implications of germline TP53 mutations

Cited by 19 publications

References 32 publications

Association of CYP 3 A 4 genotype with treatment-related leukemia

Association of CYP 3 A 4 genotype with treatment-related leukemia

Polymorphism in glutathione S -transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

Secondary acute myeloid leukemia after successful treatment for osteosarcoma

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