Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0004135 (
ATM
)
13,001
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including
IDH1
,
IDH2
,
HUWE1
,
KLHL6
, and
PTPN11
Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more driver gene abnormalities are associated with worse outcomes, as are identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in
FGFR3
,
DIS3
, and
PRKD2
; t(11;14) with mutations in
CCND1
and
IRF4
; t(14;16) with mutations in
MAF
,
BRAF
,
DIS3
, and
ATM
; and hyperdiploidy with gain 11q, mutations in
FAM46C
, and
MYC
rearrangements. These associations indicate that the genomic landscape of myeloma is predetermined by the primary events upon which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens.
...
PMID:Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. 3026 86
Sequencing studies have been used to determine a spectrum of multiple myeloma (MM) mutations. Mutation of certain genes, including
KRAS, NRAS, TP53, FAM46C,
DIS3
and
BRAF
, have a high recurrence rate and may play important roles in the pathogenesis, progression and prognosis of MM. Mutations in
DIS3
, which encodes a highly conserved RNA exonuclease, lead to loss of function. The expression of
FAM46C
is highly correlated with the expression of ribosomal protein, but the exact function of
FAM46C
mutation is unclear. There are mutants of
IRF4
, which is considered an MM survival factor. Mutations in the gene coding for the DNA damage-binding protein (
DDB1
) may affect interactions with
CUL4A
, which is part of the cereblon (
CRBN
) ubiquitin ligase complex.
IRF4
is part of the complex, which binds to DNA. These findings might explain the resistance to immunomodulatory.
TP53
deletion or mutation is often present in B-cell malignancies and is associated with low response rates. Myeloma pathogenic mutations in
ATM
have been found in adult lymphatic tumors.
XBP1
and
PSMB5
mutations may be related to bortezomib resistance. Multiple gene mutations (
KRAS, NRAS
and
BRAF
) involved in the same pathway were found a single patient. Identification of driver gene mutations has brought great hope to the field of individualized, targeted medicine for MM.
...
PMID:Progress in the identification of gene mutations involved in multiple myeloma. 3121 29
