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The PLAG1 gene was first discovered in 1997 while scientists were studying benign salivary gland tumors. [1]
- PLAG1 is considered an oncofetal gene. It is normally active during fetal development to promote growth in organs like the brain, lungs, and liver.
- After birth, it becomes largely dormant in healthy adult cells.
- When it is dysregulated, it can drive benign growths all the way to aggressive cancers.
PLAG1 fusion
Rearrangement between two chromosomes causes two genes to fuse together.
In some tumors, PLAG1 gets improperly reactivated and overexpressed.
- This overexpression can be caused by a fusion when a piece of a chromosome breaks off and reattaches to another location.
- There have been many different genes found to fuse with PLAG1 across tumor types.
Genes that have been reported to fuse with PLAG1 across tumor types
Uterine sarcomas
Uterine leiomyoma (Fibroid)
Lipoblastoma
CNS embryonal tumors
Pleomorphic adenoma (PA) / Carcinoma ex PA
Apocrine mixed tumor / breast pleomorphic adenoma
Myoepithelial Carcinoma
Some of these fusions place PLAG1 next to a highly expressed gene.
- As a result, PLAG1 is under the control of a strong, always-on regulatory element from another gene.
- This leads to a constant production of the PLAG1 protein in tumor cells.
- In turn, this activates growth-promoting genes downstream, such as insulin-like growth factor 2 (IGF2), driving uncontrolled cell proliferation.
Consequence of PLAG1 overexpression
PLAG1 is a transcription factor that causes expression of downstream genes, such as IGF2.
PLAG1-driven tumors are a diverse group with a common molecular feature: the aberrant overexpression of PLAG1, often caused by chromosomal rearrangements.
These tumors can show remarkably different clinical behaviors, even though they share the same underlying mechanism.
Below is a list of tumors that have been found to have some PLAG1-driven subsets.
Uterine leiomyosarcoma (LMS) is a malignant smooth muscle tumor. A specific, rare subtype called myxoid LMS is associated with PLAG1 gene fusions. The fusion partner varies (PBX1, PUM1, CHCHD7, C15orf29, CD44, MYOCD, FRMD6, PTK2, TRPS1 and RAD51B), but all show aberrant PLAG1 overexpression. Some researchers advocated for the diagnostic term "PLAG1-rearranged uterine sarcoma" to classify them as a distinct molecular entity to differentiate them from other uterine sarcomas, such as low-grade endometrial stromal sarcoma or undifferentiated sarcoma. [1][2][3]
Uterine leiomyomas (fibroids) are benign smooth muscle tumors. While most are driven by other mutations, a distinct subgroup is defined by PLAG1 overexpression caused by chromosomal rearrangements with fusion partners such as RBPMS, ACTG2, RNF19A, and RBPJ. This type shares a similar gene expression profile with HMGA2-driven fibroids. Both types seem to have a shared oncogenic program that activates the PLAG1-IGF2 pathway, whether it is through fusion or HMGA2. [4][5][6]
Soft tissue myoepithelial tumors are rare tumors that are both histologically and molecularly similar to pleomorphic adenomas. PLAG1 plays a significant role in these tumors, although not all cases have a detectable gene rearrangement. This suggests alternative mechanisms driving PLAG1 overexpression in these tumors. [9][10]
Pediatric lipoblastomas are benign tumors of fat tissue. ~70% of them have chromosomal fusions (e.g., with COL1A2 or HAS2) that overactivate PLAG1 in adipocyte precursors. [11]
Other tumors: PLAG1 overexpression have also been identified in a subset of hepatoblastoma (a childhood liver tumor), ~20% of acute myeloid leukemia cases with CBFB-MYH11 fusion, a calcifying spindle cell neoplasm with a SOX10-PLAG1 fusion, and rare adult soft tissue tumors resembling lipoblastoma in locations like the vulva. [12][13]
Normal Function
The PLAG1 gene was first discovered in 1997 while scientists were studying benign salivary gland tumors. [1]
- PLAG1 is considered an oncofetal gene. It is normally active during fetal development to promote growth in organs like the brain, lungs, and liver.
- After birth, it becomes largely dormant in healthy adult cells.
- When it is dysregulated, it can drive benign growths all the way to aggressive cancers.
Role in Cancer
PLAG1 fusion
Rearrangement between two chromosomes causes two genes to fuse together.
In some tumors, PLAG1 gets improperly reactivated and overexpressed.
- This overexpression can be caused by a fusion when a piece of a chromosome breaks off and reattaches to another location.
- There have been many different genes found to fuse with PLAG1 across tumor types.
Genes that have been reported to fuse with PLAG1 across tumor types
Uterine sarcomas
Uterine leiomyoma (Fibroid)
Lipoblastoma
CNS embryonal tumors
Pleomorphic adenoma (PA) / Carcinoma ex PA
Apocrine mixed tumor / breast pleomorphic adenoma
Myoepithelial Carcinoma
Some of these fusions place PLAG1 next to a highly expressed gene.
- As a result, PLAG1 is under the control of a strong, always-on regulatory element from another gene.
- This leads to a constant production of the PLAG1 protein in tumor cells.
- In turn, this activates growth-promoting genes downstream, such as insulin-like growth factor 2 (IGF2), driving uncontrolled cell proliferation.
Consequence of PLAG1 overexpression
PLAG1 is a transcription factor that causes expression of downstream genes, such as IGF2.
PLAG1 in Diverse Tumors
PLAG1-driven tumors are a diverse group with a common molecular feature: the aberrant overexpression of PLAG1, often caused by chromosomal rearrangements.
These tumors can show remarkably different clinical behaviors, even though they share the same underlying mechanism.
Below is a list of tumors that have been found to have some PLAG1-driven subsets.
Uterine leiomyosarcoma (LMS) is a malignant smooth muscle tumor. A specific, rare subtype called myxoid LMS is associated with PLAG1 gene fusions. The fusion partner varies (PBX1, PUM1, CHCHD7, C15orf29, CD44, MYOCD, FRMD6, PTK2, TRPS1 and RAD51B), but all show aberrant PLAG1 overexpression. Some researchers advocated for the diagnostic term "PLAG1-rearranged uterine sarcoma" to classify them as a distinct molecular entity to differentiate them from other uterine sarcomas, such as low-grade endometrial stromal sarcoma or undifferentiated sarcoma. [1][2][3]
Uterine leiomyomas (fibroids) are benign smooth muscle tumors. While most are driven by other mutations, a distinct subgroup is defined by PLAG1 overexpression caused by chromosomal rearrangements with fusion partners such as RBPMS, ACTG2, RNF19A, and RBPJ. This type shares a similar gene expression profile with HMGA2-driven fibroids. Both types seem to have a shared oncogenic program that activates the PLAG1-IGF2 pathway, whether it is through fusion or HMGA2. [4][5][6]
Soft tissue myoepithelial tumors are rare tumors that are both histologically and molecularly similar to pleomorphic adenomas. PLAG1 plays a significant role in these tumors, although not all cases have a detectable gene rearrangement. This suggests alternative mechanisms driving PLAG1 overexpression in these tumors. [9][10]
Pediatric lipoblastomas are benign tumors of fat tissue. ~70% of them have chromosomal fusions (e.g., with COL1A2 or HAS2) that overactivate PLAG1 in adipocyte precursors. [11]
Other tumors: PLAG1 overexpression have also been identified in a subset of hepatoblastoma (a childhood liver tumor), ~20% of acute myeloid leukemia cases with CBFB-MYH11 fusion, a calcifying spindle cell neoplasm with a SOX10-PLAG1 fusion, and rare adult soft tissue tumors resembling lipoblastoma in locations like the vulva. [12][13]
