Multiplex high-throughput gene mutation analysis in acute myeloid leukemia

Dunlap, Jennifer; Beadling, Carol; Warrick, Andrea; Neff, Tanaya; Fleming, William H.; Loriaux, Marc; Heinrich, Michael C.; Kovacsovics, Tibor; Kelemen, Katalin; Leeborg, Nicky; Gatter, Ken; Braziel, Rita M.; Press, Richard D.; Corless, Christopher L.; Fan, Guang

doi:10.1016/j.humpath.2012.03.002

Cited by 17 publications

(11 citation statements)

References 24 publications

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“…The AML cells of the brother and sister in family 1 acquired different pathogenic RUNX1 and SETBP1 mutations, both of which were present at high VAFs (Table 2 and Supplemental Table 5). The AML clone of patient 1B also acquired mutations in BRAF (p.N581Y), and KRAS (p.T58I) -the latter is a recurrent mutation in sporadic AML (13)(14)(15)(16) Tables 2 and 3). In contrast to family 1, this variant was not detected in either parent, despite the fact that previous RFLP analysis by Southern blot demonstrated loss of the paternal chromosome 7 homolog in both siblings (Supplemental Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes

Wong¹,

Bryant²,

Lamprecht³

et al. 2018

JCI Insight

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Germline SAMD9 and SAMD9L mutations cause a spectrum of multisystem disorders that carry a markedly increased risk of developing myeloid malignancies with somatic monosomy 7. Here, we describe 16 siblings, the majority of which were phenotypically normal, from 5 families diagnosed with myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270) who primarily had onset of hematologic abnormalities during the first decade of life. Molecular analyses uncovered germline SAMD9L (n = 4) or SAMD9 (n = 1) mutations in these families. Affected individuals had a highly variable clinical course that ranged from mild and transient dyspoietic changes in the bone marrow to a rapid progression of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with monosomy 7. Expression of these gain-of-function SAMD9 and SAMD9L mutations reduces cell cycle progression, and deep sequencing demonstrated selective pressure favoring the outgrowth of clones that have either lost the mutant allele or acquired revertant mutations. The myeloid malignancies of affected siblings acquired cooperating mutations in genes that are also altered in sporadic cases of AML characterized by monosomy 7. These data have implications for understanding how SAMD9 and SAMD9L mutations contribute to myeloid transformation and for recognizing, counseling, and treating affected families.

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Section: Resultsmentioning

confidence: 99%

Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes

Wong¹,

Bryant²,

Lamprecht³

et al. 2018

JCI Insight

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“…Multiplex mutation analysis was performed on the Mass Array system (Sequenom, San Diego, CA, USA) using a panel that screens for 647 mutations across 53 genes, exactly as previously described [10]. A PIK3CA H1047R mutation identified by this approach was confirmed by Sanger sequencing.…”

Section: Methodsmentioning

confidence: 99%

MDM2Amplification andPI3KCAMutation in a Case of Sclerosing Rhabdomyosarcoma

Kikuchi

Wettach

Ryan

et al. 2013

Sarcoma

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A rare sclerosing variant of rhabdomyosarcoma characterized by prominent hyalinization and pseudovascular pattern has recently been described as a subtype biologically distinct from embryonal, alveolar, and pleomorphic forms. We present cytogenetic and molecular findings as well as experimental studies of an unusual case of sclerosing rhabdomyosarcoma. The primary lesion arose within the plantar subcutaneous tissue of the left foot of an otherwise healthy 23-year-old male who eventually developed pulmonary nodules despite systemic chemotherapy. Two genetic abnormalities identified in surgical and/or autopsy samples of the tumor were introduced into 10T1/2 murine fibroblasts to determine whether these genetic changes cooperatively facilitated transformation and growth. Cytogenetic analysis revealed a complex abnormal hyperdiploid clone, and MDM2 gene amplification was confirmed by fluorescence in situ hybridization. Cancer gene mutation screening using a combination of multiplexed PCR and mass spectroscopy revealed a PIK3CA exon 20 H1047R mutation in the primary tumor, lung metastasis, and liver metastasis. However, this mutation was not cooperative with MDM2 overexpression in experimental assays for transformation or growth. Nevertheless, MDM2 and PIK3CA are genes worthy of further investigation in patients with sclerosing rhabdomyosarcoma and might be considered in the enrollment of these patients into clinical trials of targeted therapeutics.

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“…Currently, studies on the immunology and cytogenetic features of FLT3-ITD mutation-positive AML are scarce (22,23). Among the 14 cases of AML with t(11; 12) (p15; q13) reported, including the present case, 21% (3 cases) demonstrated an FLT3-ITD mutation.…”

Section: Discussionmentioning

confidence: 61%

Acute monocytic leukaemia with t(11; 12) (p15; q13) chromosomal changes: A case report and literature review

Hong

et al. 2015

Oncology Letters

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Abstract. Acute myeloid leukaemia (AML) is a type of heterogeneous disease derived from haematopoietic stem cells. Cytogenetic characterisation is essential for diagnosis and prognosis stratification. Here, we present the case of a 43-year-old female diagnosed with leukaemia, who demonstrated a rare chromosomal change of t(11; 12) (p15; q13) along with a positive FLT3-ITD mutation. The patient had a white blood cell count of 76.41x10 9 /l. Bone marrow morphology revealed that monoblasts accounted for 25.5% of cells, and premonocytes accounted for 49.0%. This patient strongly responded to idarubicin and Ara-c (cytarabine) chemotherapy, which rapidly eliminated the leukaemia cell clones. However, the proliferation rate of the leukaemia cells was high during the intermission of chemotherapy. Subsequently, following two courses of chemotherapy, full haematological remission could not be attained. AML patients with t(11; 12) (p15; q13) combined with FLT3-ITD mutations are expected to have a short life expectancy; however, early haematopoietic stem cell transplantation therapy may improve the treatment outcome for these patients.

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Multiplex high-throughput gene mutation analysis in acute myeloid leukemia

Cited by 17 publications

References 24 publications

Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes

Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes

MDM2Amplification andPI3KCAMutation in a Case of Sclerosing Rhabdomyosarcoma

Acute monocytic leukaemia with t(11; 12) (p15; q13) chromosomal changes: A case report and literature review

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