Máté Manczinger
@matemanc.bsky.social
Group leader of the Systems Immunology Research Group at HUN-REN Biological Research Centre, Szeged, Hungary
9/ Takeaway: Protein-level mutation patterns provide a complementary lens to DNA mutational signatures—linking mutagenesis + repair defects to peptide properties, immune contexture, and therapy response.
February 3, 2026 at 12:51 PM
9/ Takeaway: Protein-level mutation patterns provide a complementary lens to DNA mutational signatures—linking mutagenesis + repair defects to peptide properties, immune contexture, and therapy response.
8/ But there’s nuance inside AAS4:
Among AAS4-driven tumors, specific HLA variants are enriched in immune-hot cases.
So antigen presentation genetics may modulate whether an AAS4 tumor ends up “cold” vs “hot.”
Among AAS4-driven tumors, specific HLA variants are enriched in immune-hot cases.
So antigen presentation genetics may modulate whether an AAS4 tumor ends up “cold” vs “hot.”
February 3, 2026 at 12:50 PM
8/ But there’s nuance inside AAS4:
Among AAS4-driven tumors, specific HLA variants are enriched in immune-hot cases.
So antigen presentation genetics may modulate whether an AAS4 tumor ends up “cold” vs “hot.”
Among AAS4-driven tumors, specific HLA variants are enriched in immune-hot cases.
So antigen presentation genetics may modulate whether an AAS4 tumor ends up “cold” vs “hot.”
7/ One signature stood out clinically: AAS4.
AAS4 is associated with predominantly immune-cold tumors, poor prognosis, and limited response to immune checkpoint blockade.
AAS4 is associated with predominantly immune-cold tumors, poor prognosis, and limited response to immune checkpoint blockade.
February 3, 2026 at 12:50 PM
7/ One signature stood out clinically: AAS4.
AAS4 is associated with predominantly immune-cold tumors, poor prognosis, and limited response to immune checkpoint blockade.
AAS4 is associated with predominantly immune-cold tumors, poor prognosis, and limited response to immune checkpoint blockade.
6/ That biophysical bias matters for immunology.
By shaping the properties of mutated peptides, AASs can influence neopeptide immunogenicity → and, downstream, the tumor immune microenvironment.
By shaping the properties of mutated peptides, AASs can influence neopeptide immunogenicity → and, downstream, the tumor immune microenvironment.
February 3, 2026 at 12:50 PM
6/ That biophysical bias matters for immunology.
By shaping the properties of mutated peptides, AASs can influence neopeptide immunogenicity → and, downstream, the tumor immune microenvironment.
By shaping the properties of mutated peptides, AASs can influence neopeptide immunogenicity → and, downstream, the tumor immune microenvironment.
5/ Next: not all amino acid substitutions are equal.
Different AASs preferentially generate amino acids with distinct biophysical properties (think charge, polarity, size).
Different AASs preferentially generate amino acids with distinct biophysical properties (think charge, polarity, size).
February 3, 2026 at 12:50 PM
5/ Next: not all amino acid substitutions are equal.
Different AASs preferentially generate amino acids with distinct biophysical properties (think charge, polarity, size).
Different AASs preferentially generate amino acids with distinct biophysical properties (think charge, polarity, size).
4/ Why does that matter?
Because it suggests the protein-level consequence can converge even when the DNA-level cause differs.
Because it suggests the protein-level consequence can converge even when the DNA-level cause differs.
February 3, 2026 at 12:49 PM
4/ Why does that matter?
Because it suggests the protein-level consequence can converge even when the DNA-level cause differs.
Because it suggests the protein-level consequence can converge even when the DNA-level cause differs.
3/ Importantly, these AASs aren’t a 1:1 readout of any single DNA mutational process.
The same AAS can be produced by multiple, largely unrelated exogenous + endogenous mutagenic processes.
The same AAS can be produced by multiple, largely unrelated exogenous + endogenous mutagenic processes.
February 3, 2026 at 12:49 PM
3/ Importantly, these AASs aren’t a 1:1 readout of any single DNA mutational process.
The same AAS can be produced by multiple, largely unrelated exogenous + endogenous mutagenic processes.
The same AAS can be produced by multiple, largely unrelated exogenous + endogenous mutagenic processes.
2/ ~82% of tumor samples are dominated by a single AAS.
So despite massive heterogeneity, most cancers have one main “protein-mutation style.”
So despite massive heterogeneity, most cancers have one main “protein-mutation style.”
February 3, 2026 at 12:49 PM
2/ ~82% of tumor samples are dominated by a single AAS.
So despite massive heterogeneity, most cancers have one main “protein-mutation style.”
So despite massive heterogeneity, most cancers have one main “protein-mutation style.”
1/ Cancer mutations look chaotic—different tumors, different genes, different DNA changes.
But at the protein level, we found surprising order.
Introducing amino acid substitution signatures (AASs): 5 recurrent patterns that repeatedly show up across cancers.
But at the protein level, we found surprising order.
Introducing amino acid substitution signatures (AASs): 5 recurrent patterns that repeatedly show up across cancers.
February 3, 2026 at 12:49 PM
1/ Cancer mutations look chaotic—different tumors, different genes, different DNA changes.
But at the protein level, we found surprising order.
Introducing amino acid substitution signatures (AASs): 5 recurrent patterns that repeatedly show up across cancers.
But at the protein level, we found surprising order.
Introducing amino acid substitution signatures (AASs): 5 recurrent patterns that repeatedly show up across cancers.