My ctDNA summary attached. Low intermediate TMU. And, a list of Variants of Uncertain Clinical Significance (VoUCS) but no other smoking guns. My PROMISE COLOR germ line results were ‘clean’. Here are most of the VoUCS. The major VoUCS gene/protein is SETD2 F341Y (5.4%). Google has SETD2 as a DNA repair protein (cancer suppressor). The mutation, converting phenylalanine to tyrosine, basically adding a hydroxyl, seems kinda minor but my biology diploma is 50 years old (I moved to chemistry and materials for my career but stayed interested in molecular biology - a dilettante).
Any comments to help me understand the genetics of my disease would be appreciated.
ARID2 c.638-12_643delins
(Splice Site Indel) (0.1%)
ARID2 G1369fs (0.4%)
BRCC3 K31fs (0.3%)
IDH2 P368P (0.2%)
NOTCH1 P2484S (0.2%)
KMT2D M3777fs (0.1%)
NOTCH3 G843D (0.7%)
MET S1044R (0.1%)
PREX1 T308A (0.3%)
SETD2 F341Y (5.4%)
SMARCA4 P354S (0.3%)
Written by
kreg001
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Thanks for sharing this detailed information. It sounds like you’ve done your homework on your ctDNA and germline results. I’ll help unpack this from a molecular biology and clinical perspective to the best of my ability.
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SETD2 F341Y (5.4%)
SETD2 encodes a protein critical for histone H3 lysine 36 trimethylation (H3K36me3), a marker linked to DNA damage repair, transcriptional regulation, and genomic stability.
The F341Y mutation substitutes phenylalanine (a hydrophobic residue) with tyrosine (which is hydrophilic due to a hydroxyl group). While the change might seem minor chemically, its impact depends on its location and role in the protein. Structural alterations in critical regions of SETD2 could impair its function, potentially reducing H3K36me3 levels, contributing to genomic instability, and impairing DNA repair pathways.
SETD2 mutations are associated with various cancers, including renal cell carcinoma and advanced prostate cancer, particularly when DNA repair is impaired. However, the functional impact of F341Y specifically may require further study or functional assays to confirm its significance.
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Variants of Uncertain Clinical Significance (VUS)
Here’s a breakdown of other notable VUS genes and their potential relevance:
1. ARID2
Tumor suppressor involved in chromatin remodeling.
c.638-12_643delins (splice site) and G1369fs (frameshift) may result in partial loss of function. ARID2 mutations have been linked to cancers with disrupted chromatin remodeling, though these specific variants would require functional validation.
2. BRCC3 K31fs
BRCC3 is involved in DNA double-strand break repair through homologous recombination.
Frameshift mutations typically result in truncated or dysfunctional proteins, possibly impairing repair mechanisms.
3. IDH2 P368P
A synonymous variant (no change in protein sequence). Likely benign unless it alters splicing or regulatory mechanisms.
4. NOTCH1 P2484S and NOTCH3 G843D
NOTCH signaling is critical for cell differentiation and tissue homeostasis.
Mutations could potentially dysregulate signaling, contributing to tumorigenesis. Functional studies are usually required to assess impact.
5. KMT2D M3777fs
KMT2D is a histone methyltransferase essential for transcriptional regulation.
Frameshift mutations likely lead to truncated proteins with loss of function, which can contribute to epigenetic dysregulation in cancer.
6. MET S1044R
MET encodes a receptor tyrosine kinase involved in growth signaling.
The S1044R mutation, though rare, could alter downstream signaling, potentially contributing to oncogenesis.
7. PREX1 T308A
PREX1 regulates RAC1 signaling pathways, impacting cell migration and invasion.
Functional significance of T308A is unclear but could impact cancer progression pathways.
8. SMARCA4 P354S
SMARCA4 is part of the SWI/SNF chromatin remodeling complex, frequently mutated in cancers.
While P354S may not directly truncate the protein, even subtle changes in function can have oncogenic potential in the right context.
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Your Genetic Landscape
The clean germline results suggest no inherited predisposition but doesn’t preclude somatic changes driving your disease.
The VoUCS list includes alterations in DNA repair (SETD2, BRCC3, KMT2D), chromatin remodeling (ARID2, SMARCA4), and signaling (MET, NOTCH). While no single mutation stands out as a smoking gun, the accumulation of these mutations might contribute synergistically to tumor development or progression.
SETD2’s relatively high allelic frequency (5.4%) suggests clonal selection, possibly indicating its relevance to tumor biology in your case.
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Next Steps and Considerations
1. Functional Validation:
If possible, seek studies or trials evaluating the functional impact of these mutations, particularly SETD2 F341Y.
Ask about next-generation sequencing (NGS) panels that assess broader pathways for actionable targets.
2. Targeted Therapies:
SETD2 mutations and chromatin remodeling defects may sensitize tumors to PARP inhibitors or DNA-damaging agents.
MET mutations might also render tumors responsive to MET inhibitors, though this depends on activation state and downstream signaling.
3. Clinical Trials:
Consider exploring trials focused on advanced prostate cancer with DNA repair defects or epigenetic dysregulation.
4. Expert Input:
Engage with a molecular tumor board or consult with specialists in cancer genomics for a nuanced interpretation and therapeutic strategy.
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Your understanding of these molecular changes is impressive for a "dilettante," and it’s clear you’re taking a proactive approach. While SETD2 F341Y stands out, the broader context of your ctDNA results reinforces the importance of a holistic and expert-guided strategy.
Your biology diploma is 50 years old. Mine is a formal Native American high school pictograph located on the wall of a Adirondack Mountain in upstate New York.
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Never delay seeking advice or dialling emergency services because of something that you have read on HealthUnlocked.
Expectations on docetaxel
PSA going up
Latest PSA! Undetectable 
Prostate recurrence 
