ASXL1

Primary Author(s)*

Kay Weng Choy MBBS

Synonyms

ASXL Transcriptional Regulator 1, Additional Sex Combs Like Transcriptional Regulator 1, Additional Sex Combs-Like 1 (Drosophila), KIAA0978, BOPS, MDS

Genomic Location

Cytoband: 20q11.21

Genomic Coordinates:

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chr20:32,358,330-32,439,319 (GRCh38/hg38)

chr20:30,946,147-31,027,122 (GRCh37/hg19)

Cancer Category/Type

Haematological malignancies, particularly myeloid neoplasms, e.g., chronic myelomonocytic leukemia, acute myeloid leukemia

Colorectal cancer

Gene Overview

ASXL1 is essential for the activation and repression of homeotic loci (genes that regulate the development of anatomical structures) [1]. It interacts with polycomb and super sex combs (proteins involved in epigenetic regulation of chromatin) [1]. Given the location of ASXL1 in the chromosome band 20q11, the association of this chromosome region with amplification in tumors and the increasing evidence for the involvement of chromatin proteins in cancer, expression of ASXL1 in a variety of cell lines derived from human tumors has been examined closely [1,2]. It is expressed at higher levels in several cancer cell lines such as in myeloid neoplasms and colorectal cancer [1,3].

ASXL1 contains an N-terminal ASX homology domain, ASXH, and a C-terminal plant homeodomain, PHD [4]. The gene encodes a member of the polycomb family of the chromatic binding proteins and is involved in epigenetic regulation of gene expression via its PHD finger (figure 1) [1]. The PHD finger interacts with the polycomb group repressive complex protein (PRC1 and PRC2) and other transcription activators and repressors to regulate chromatin [1].

ASXL1 mutations in myeloid neoplasms are associated with a truncation in exon 12 (NM_015338.5), adjacent to the PHD finger [5,6]. In vitro studies in leukemic cells demonstrate that there is a loss of ASXL1 protein expression when ASXL1 mutations are seen in myeloid neoplasms [7]. The most common ASXL1 mutation associated with myeloid neoplasms is c.1934_1935insG (NM_015338.5) (p.G646Wfs*12), reportedly accounting for more than 50% of cases [1]. It is suggested that the mutation is responsible for a truncated ASXL1 protein that lacks the PHD finger, rather than the loss of the entire ASXL1 protein [1].

AXSL1 mutations in myeloid neoplasms

ASXL1 mutations have been found in almost all types of myeloid malignancies, including MDS, AML and MPN [1].

ASXL1 mutations are more likely to be seen in secondary AML as opposed to de novo AML [8]; it has been proposed that ASXL1 mutations are implicated in dysplastic changes and ineffective hematopoiesis, without contributing directly to the acute leukemic transformation [8]. It is reported that ASXL1 mutations were detected more frequently in patients with secondary AML after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) as opposed to patients with primary AML or therapy-related AML [9]. A higher frequency of ASXL1 mutations has been observed in patients with essential thrombocytopenia (ET) who also had CALR mutations, compared with patients with JAK2 mutations (instead of CALR mutations); ASXL1 mutations correlated with lower median hemoglobin levels [10].

A study of 41 MDS patients who had progressed to either higher grade MDS or AML found a high frequency of concomitant ASXL1 and RUNX1 mutations [11]. In the pre-progression samples, all patients with RUNX1 mutations also had ASXL1 mutations; this was in contrast with patients without RUNX1 mutations where only approximately a third had ASXL1 mutations [11].

In patients with newly diagnosed AML, the presence of ASXL1 mutations have been found to be associated with older age and male gender [9,12]. In immunophenotypic analysis, ASXL1 mutated cases are found to have a stronger expression of CD13, CD34, CD133, and HLA-DR and a weaker expression of CD33, suggesting a more immature immunophenotype in ASXL1 mutated patients compared to ASXL1-wild type patients [9].

Compared to all other AML types, ASXL1 mutations are more frequently found in AML-MRC (myelodysplasia-related changes) [1]; the 2-year overall survival is worse in patients with AML-MRC with ASXL1 mutation, compared to those without the mutation [13].

Prognostic implications in myeloid neoplasms

Patients with ASXL1 mutations diagnosed with AML/MDS have a higher mortality rate compared with patients with AML/MDS without ASXL1 mutations [1]. The presence of ASXL1 mutations is associated with worse prognostic risk [14,15]. There is a higher leukemic transformation rate in ASXL1 mutated patients compared with ASXL1 wild type [16].

In patients with chronic myelomonocytic leukemia (CMML), ASXL1 frameshift and nonsense mutations are associated with a significantly lower overall survival [17]. In contrast, missense ASXL1 mutations do not appear to affect survival in CMML patients [1]. In patients with MDS, ASXL1 frameshift mutations are associated with worse overall survival whereas heterozygous point mutations are not [17].

In patients with primary myelofibrosis (PMF), there is significantly higher mortality in patients with ASXL1 mutations compared to ASXL1 wild type; ASXL1 mutations are associated with lower leukemia-free survival [18].

In de novo AML, patients with ASXL1 mutations had a significantly lower rate of complete remission after standard high-intensity chemotherapy; the median overall survival is significantly lower [12].

Therapeutic implications in myeloid neoplasms

In patients with CMML treated with hypomethylating agents, there is a shorter overall survival in subjects with ASXL1 mutations compared to ASXL1 wild type [19].

In cytogenetically normal AML patients receiving cytarabine-daunorubicin, there is a lower complete remission (CR) rate in patients with ASXL1 mutations compared to wild-type [20]. Among patients who achieve CR, those with ASXL1 mutations have shorter disease-free survival than ASXL1-wild type patients [20].

Stem cell transplantation is recommended in patients with PMF with presence of mutational status CALR-/ASXL+, as the mutational status is associated with a worse prognosis [21].

Colorectal cancer

ASXL1 is frequently mutated in colorectal cancer cell lines with microsatellite instability (MSI) [22]. The G8 mononucleotide repeat at nucleotide position c.1927 to c.1934 of the ASXL1 gene is susceptible to the deletion or insertion of a G nucleotide as a result of MSI [22]. The deletion of c.1934G (c.1934delG) causes a frameshift and the insertion of G between c.1934 and c.1935 (c.1934_1935insG) causes a frameshift [22]. The c.1934_1935insG ASXL1 mutation is reported to be resistant to nonsense-mediated decay in CRC with MSI and consequently is predicted to be expressed as a C-terminally truncated protein [22].

Common Alteration Types

The majority of ASXL1 mutations are nonsense or frameshift variants causing truncation of downstream of the ASXH domain with consequent loss of the PHD domain [1]. Some of the common variants reported in the Catalogue of Somatic Mutations in Cancer database (COSMIC) (accessed 6th August 2018) are c.2444T>C (NM_015338.5) (p.L815P) (n=97) (all AML), c.2077C>T (NM_015338.5) (p.R693*) (majority hematological malignancies), c.1934_1935insG (NM_015338.5) (p.G646Wfs*12) (majority hematological malignancies).

Copy Number Loss	Copy Number Gain	LOH	Loss-of-Function Mutation	Gain-of-Function Mutation	Translocation/Fusion

Internal Pages

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EXAMPLE Germline Cancer Predisposition Genes

External Links

Put your text here - Include as applicable links to: 1) Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2) COSMIC, 3) CIViC, 4) St. Jude ProteinPaint, 5) Precision Medicine Knnowledgebase (Weill Cornell), 6) Cancer Index, 7) OncoKB, 8) My Cancer Genome, 9) UniProt, 10) Pfam, 11) GeneCards, 12) GeneReviews, and 13) Any gene-specific databases.

EXAMPLES

TP53 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

TP53 by COSMIC - sequence information, expression, catalogue of mutations

TP53 by CIViC - general knowledge and evidence-based variant specific information

TP53 by IARC - TP53 database with reference sequences and mutational landscape

TP53 by St. Jude ProteinPaint mutational landscape and matched expression data.

TP53 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

TP53 by Cancer Index - gene, pathway, publication information matched to cancer type

TP53 by OncoKB - mutational landscape, mutation effect, variant classification

TP53 by My Cancer Genome - brief gene overview

TP53 by UniProt - protein and molecular structure and function

TP53 by Pfam - gene and protein structure and function information

TP53 by GeneCards - general gene information and summaries

GeneReviews - information on Li Fraumeni Syndrome

References

EXAMPLE Book

1. Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.

EXAMPLE Journal Article

1. Li Y, et al., (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.

Notes

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