medulloblastoma SHH activated and TP53 mutant

Medulloblastoma SHH activated and TP53 mutant is a molecular subtype of medulloblastoma, a type of brain cancer that primarily affects children [5]. This subtype is characterized by the activation of the sonic hedgehog (SHH) pathway and the presence of mutations in the TP53 gene [2].

The SHH pathway plays a crucial role in the development and growth of medulloblastomas, and its activation can lead to the formation of tumors [3]. The presence of TP53 mutations is also an important factor in this subtype, as it can affect the tumor's behavior and prognosis [6].

Research has shown that TP53 mutations are more common in SHH-activated medulloblastomas than in other subtypes, and they can be associated with a poorer prognosis [7]. However, the presence of TP53 mutations does not necessarily mean that the tumor is resistant to treatment. In fact, some studies have suggested that targeting the mTORC1 pathway may be an effective strategy for treating SHH-TP53 mutant medulloblastoma [4].

Overall, medulloblastoma SHH activated and TP53 mutant is a complex and aggressive subtype of brain cancer that requires prompt and effective treatment. Further research is needed to understand the underlying biology of this disease and to develop more targeted and effective therapies.

References: [2] V Ramaswamy · 2016 · Cited by 65 [3] Medulloblastoma associated with activation of the sonic hedgehog (SHH) pathway and the absence of TP53 mutations. [4] by V Conti · 2021 · Cited by 6 [5] NCI Definition: A molecular subtype of medulloblastoma associated with activation of the sonic hedgehog (SHH) pathway. TP53 mutations may be present or absent. [6] by BA Orr · 2020 · Cited by 136 [7] by RH Eibl · 2023 · Cited by 8

Medulloblastoma, specifically the SHH-activated and TP53-mutant subtype, can present with a range of signs and symptoms. These may include:

• Increased intracranial pressure: This can lead to morning headaches, nausea, vomiting, diplopia (double vision), and macrocephaly (increased head circumference) [4][5][7].
• Obstructive hydrocephalus: This can cause bulging of the anterior fontanel due to increased intracranial pressure [3].
• Local effects of the tumor: These may include headache, irritability, nausea/vomiting, papilledema (swelling of the optic disc), and macrocephaly [6][7].
• Worsening ataxia involving the lower extremities: This can be a sign of the tumor's mass effect in the posterior fossa [8].
• Diplopia and other cranial nerve findings: These may occur due to the tumor's location and growth pattern [8].

It is essential to note that these symptoms can vary depending on the tumor's location and size, as well as the individual's overall health. If you or someone you know is experiencing any of these symptoms, it is crucial to seek medical attention promptly.

References:

[3] by C Brain — Increase in head circumference. [4] by RH Eibl · 2023 · Cited by 8 — Interestingly, 20–30% of the medulloblastomas in the SHH group show TP53 mutations, which confer a poor prognosis. TP53 mutations in the SHH group represent ... [5] Such signs and symptoms include headache, irritability, nausea/vomiting, papilledema, and macrocephaly. [6] by RH Eibl · 2023 · Cited by 8 — Interestingly, 20–30% of the medulloblastomas in the SHH group show TP53 mutations, which confer a poor prognosis. TP53 mutations in the SHH group represent ... [7] Overview. NCI Definition: A molecular subtype of medulloblastoma associated with activation of the sonic hedgehog (SHH) pathway. TP53 mutations may be present or absent. [8] Medulloblastoma frequently presents emergently with signs and symptoms of increased intracranial pressure due to obstructive ...

Medulloblastoma, a type of brain cancer, can be classified into different subgroups based on genetic mutations. The SHH (sonic hedgehog) activation subgroup is one such classification, which is further subdivided by the presence of TP53 mutation.

Diagnostic Tests for SHH-Activated Medulloblastomas with TP53 Mutations:

• Immunohistochemistry (IHC): This test can be used to detect TP53 mutations in SHH-activated medulloblastomas. IHC involves staining tissue samples with antibodies that bind to specific proteins, allowing for the visualization of protein expression patterns [1].
• TP53 sequencing: This genetic test is used to confirm the presence of TP53 mutations in SHH-activated medulloblastomas. Sequencing involves analyzing the DNA sequence of the TP53 gene to identify any mutations [2].
• Histological analysis: A pathologist or neuropathologist should confirm the diagnosis of primary brain tumors, including SHH-activated medulloblastomas with TP53 mutations, through microscopic examination (histology) [8].

Additional Diagnostic Considerations:

• SHH pathway activation: Testing for SHH pathway activation can be performed to identify tumors that are driven by this genetic mutation. This can involve analyzing the expression of specific genes and proteins involved in the SHH pathway.
• Other genetic mutations: Other genetic mutations, such as SUFU, GLI1, GLI2, and PTCH1, may also be present in SHH-activated medulloblastomas with TP53 mutations. These can be identified through various genetic tests.

References:

[1] Orr BA, et al. (2020). LCA histology is predominantly seen in SHH MB with TP53 mutations [1].

[2] Pietsch T, et al. (2016). In SHH-activated tumors, TP53 should be sequenced with validated methods in certified laboratories to clearly differentiate between the SHH-activated and non-SHH activated medulloblastomas [2].

[8] Eibl RH, et al. (2023). A pathologist or neuropathologist needs to confirm the diagnosis of the primary tumor in the brain by microscopic analysis (histology) [8].

Medulloblastoma, a type of brain cancer, can be challenging to treat, especially when it's SHH-activated and TP53-mutant. In such cases, the treatment options are limited, but researchers have been exploring various targeted therapies.

Current Treatment Options

According to recent studies [3][10], the majority of treatment failures in SHH medulloblastoma are associated with TP53 mutations. This group of medulloblastoma constitutes a very high-risk group and is the focus of international efforts for new and novel therapies.

• Chemotherapy: Recurrent medulloblastomas are treated by chemotherapy as well as specific antibodies to vascular endothelial growth factor (VEGF) [9].
• Targeted Therapies: Researchers have been exploring targeted therapies, such as inhibitors of the hedgehog (Hh) pathway, which could become valuable treatment options for patients with SHH-activated medulloblastoma [6][7].

Emerging Treatment Options

New and novel therapies are being developed to target TP53-mutant SHH medulloblastomas. Some emerging treatment options include:

• mTORC1 Inhibitors: mTORC1 may act as a specific druggable target for this subset of SHH MB, resulting in the implementation of a stringent risk stratification [8].
• DNA Sequencing: DNA sequencing reveals exact mutations, with the advantage of informing targeted therapies in SHH medulloblastoma. This can help identify patients who would benefit from specific treatments.

Challenges and Future Directions

While these emerging treatment options hold promise, there are still significant challenges to overcome. The development of resistance to SMO inhibitors, such as vismodegib, is a major concern [3]. Furthermore, the poor outcomes associated with TP53 mutations in SHH medulloblastomas highlight the need for more intensive therapies and genetic counseling.

In conclusion, while treatment options are limited for SHH-activated and TP53-mutant medulloblastoma, researchers are actively exploring new and novel therapies to improve patient outcomes. Further research is needed to overcome the challenges associated with this aggressive form of brain cancer.

References:

[3] by H Slika · 2024 [6] by Y Li · 2019 [7] by MW Kieran · 2018 [8] by M Gajjar · 2015 [9] by A. J. Olson · 2012 [10] by R. P. S. C. Ramaswamy · 2015

Medulloblastoma Differential Diagnosis

Medulloblastoma, a type of brain cancer, can be classified into several subtypes based on genetic mutations. Two such subtypes are SHH (sonic hedgehog) activated and TP53 mutant medulloblastomas.

• SHH Activated Medulloblastoma: This subtype is characterized by the activation of the SHH pathway, which can occur either with or without a mutation in the TP53 gene. The presence of a TP53 mutation is highly prognostic within this subtype [7].
• TP53 Mutant Medulloblastoma: In this subtype, mutations in the TP53 gene are present. TP53 mutations have been found to be associated with SHH medulloblastoma and Li-Fraumeni syndrome [1].

Differential Diagnosis

The differential diagnosis for SHH activated and TP53 mutant medulloblastomas includes:

• CTTNB1 p.Ser33Cys mutation: This mutation is present in some cases of SHH activated medulloblastoma.
• Monosomy 6: This genetic abnormality can also be found in some cases of SHH activated medulloblastoma.

References

[1] by V Ramaswamy · 2016 · Cited by 65 — In the childhood age group, germline mutations of TP53 are frequently observed in SHH medulloblastoma and, as such, associate Li–Fraumeni syndrome with SHH ...

[7] by O Menyhárt · 2019 · Cited by 32 — TP53- mutations are highly prognostic only within this subtype. SHH γ is present among infants and is enriched for MBEN histology, representing ...