Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: SRSF2 Gene Mutation in Patients With t-MDS/AML

Summary: -  To detect SRSF2 gene mutation by polymerase chain reaction (PCR) in the two types of t-MDS/AML which recognized in the WHO classification.
  -  Association between SRSF2 gene mutation and the presence of other cytogenetic abnormalities in the two types of t-MDS/AML which recognized in the WHO classification, e.g. (Loss of chromosome 7 or del(7q), del(5q), isochromosome 17q, recurrent balanced chromosomal translocations involving chromosomal segments 11q23 (KMT2A, previously called MLL) or 21q22.1 (RUNX1), and PML-RARA).
  -  Relationship between SRSF2 gene mutation and cumulative dose, dose intensity, time of exposure and prognostic criteria (disease free survival, overall survival and disease course).

Detailed description: Therapy-related myeloid neoplasms (t-MNs) are a group of hematologic diseases that arise after chemotherapy and/or radiation therapy for a previous cancer or rarely autoimmune diseases.
  The revised 2016 World Heath Organization (WHO) classification defines t-MN as a subgroup of acute myeloid leukemia (AML) comprising myelodysplastic syndrome (t-MDS), acute myeloid leukemia (t-AML), and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN) .
  Two forms of t-MN have been recognized. Alkylating agent/radiation-related t-MN usually appears 4 to 7 years, which is frequently associated with unbalanced chromosomal abnormalities involving chromosomes 5 and/or 7, as well mutations or loss of TP53 ( tumor protein 53).
  In contrast, a combination of different topoisomerase II inhibitor-related t-MNs is associated with a high incidence of recurrent balanced translocations involving chromosomal segments 11q23 (KMT2A), 21q22 (RUNX1), and PML-RARA [1].
  T-MNs are characterized by a subset of molecular mutations including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, STAG2, and TP53.
  RNA splicing is a process that produces mature mRNAs by excising introns and splicing exons from pre-messenger RNA. The spliceosome mutations induce an abnormally spliced mRNA species and compromising hematopoiesis.
  One of the potential candidate genes involved in the RNA splicing pathway is serine and arginine rich splicing factor 2 (SRSF2). SRSF2, located on chromosome 17q25.1, and plays a role in preventing exon skipping, confirming the accuracy of splicing and regulating alternative pre-mRNA splicing. Many studies have already reported the potential prognostic value of SRSF2 mutations, which have an adverse prognostic impact on survival and disease progression.
  Somatic mutations recently identified in patients with de novo AML and MDS, such as those of epigenetic regulators, spliceosome machinery and SETBP1, are rare, with the exception of SRSF2.
  TP53 mutations have been associated to the occurrence of cytogenetic abnormalities and poor response to chemotherapy that are typical of t-MN.
  On the other hand, several studies have shown that the presence of isochromosome 17q i(17q) abnormality is associated with wild-type TP53 and mutations in SETBP1 and SRSF2.
  Also, somatic loss of one copy of the long arm of chromosome 7 del(7q) is associated with unfavorable prognosis and can co-occur with the SRSF2 mutation in patients with MDS and AML.

Eligibility: Inclusion Criteria:
  -  Patients with myelodysplastic syndromes (MDS), who fulfill the WHO criteria.
  -  Patients with acute myeloid leukemia (AML), who fulfill the WHO criteria.
  -  Patients must start therapy (cytotoxic agents and/or ionizing radiotherapy) before beginning of the study, with a documented history of a benign or malignant condition for which they had received therapy prior to the diagnosis of MDS or AML.
  Exclusion Criteria:
  -  Patients not fulfill the WHO criteria for diagnosis of MDS and AML.

Relevance to patient case: not relevant