CEDAR/Cancer Specific Rules

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Cancer Specific Curation Rules

For cancer curation, follow all regular IEDB curations rules with the following rule additions. Note that these rules are still in process and are not yet comprehensive.

Neoepitopes

Neoepitope Definition

Multiple types of genetic changes occur in cancers leading to expression of new sequences. Use these guidelines to determine if a structure should be curated as a neoepitope.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2553210/ Identification of BING-4 Cancer Antigen Translated From an Alternative Open Reading Frame of a Gene in the Extended MHC Class II Region Using Lymphocytes From a Patient With a Durable Complete Regression Following Immunotherapy


  • When a peptide results from a tumor-specific mutation that disrupts the open reading frame of a protein through an insertion or a deletion (indel) of nucleotides into its coding region, curate this as a neoepitope (not SRC).  This includes peptides that overlap with the indel and those that are encoded downstream of the mutation.

Note: When in doubt (when it is not clear how the mutation arose) and if you are curating a cancer paper, curate it as a neoepitope.


  • If the epitope is derived from a tandem duplication of a natural peptide without any mutation, it is considered a neoepitope if the junction region is recognized.

Example: https://pubmed.ncbi.nlm.nih.gov/17119119/ A Neoepitope Generated by an FLT3 Internal Tandem Duplication (FLT3-ITD) Is Recognized by Leukemia-Reactive Autologous CD8+ T Cells Here the junction region is within the epitope, so these are curated as neoepitopes:

Neo junction ex.jpg

  • If the epitope is derived from fused gene products and spans the breakpoint, it is considered a neoepitope.

Example: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831673/ Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQs) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients.


Neoepitope Object Type


  • Neoepitopes with 100% blast match - Curate as peptide, no natural source
  • Neoepitopes without blast match - Curate as peptide, no natural source

Use the Epitope Related Object (ERO) fields to link the neoepitope to the wild type. Enter as much detail as the authors provide. If they give a peptide sequence, or it is easily deduced, always enter the wild type peptide as the ERO. If no peptide is available, the wild type protein may be used. In the worst case scenario, the ERO may be an organism.

ERO Issues

  • If authors claim a single specific mutation in the neoepitope, but all blast hits have multiple mutations or are 100% hits, then use the reference proteome peptide sequence as the ERO.

(PMID: 30880120)

  • When the ERO that is given by the author is a completely different peptide, with no homology to the neoepitope, use it anyway.

(PMID:30256815) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157866/ Neo ERO ex3.jpg


  • If authors do not provide the wild type sequence and the neoepitope has only 100% blast hits in Reference Proteome = where is the mutation at?

(PMID: 30880120)


FYGKTILWF is neoepitope Reference proteome gives Q9H993 ARMT1_HUMAN Protein-glutamate O-methyltransferase OS=Homo sapiens OX=9606 GN=ARMT1 PE=1 SV=1 FYGKTIPWF = the wild type peptide ignore authors positions (most are wrong)

Neo ERO ex.jpg


  • If authors claim a single specific mutation in the neoepitope, but that position is not mutated in the reference proteome = which sequence to use as the epitope related object? (PMID: 30880120)

RYPRYLYKL, for which they say aa 1 is mutated, but they do not say what aa position 1 should be Ref proetome: A0A087X1B3_HUMAN Transmembrane protein 178B OS=Homo sapiens OX=9606 GN=TMEM178B RYPRYLYGL Use ref proteome seq, ignore authors positions

Neo ERO ex2.jpg

Healthy Host

Curate assays where healthy controls are tested for recognition of neoepitopes and/or wild type sequences

Cancer Host

Do not curate cancer as the disease state for an infectious disease epitope unless that infection leads to cancer. For example, with an HTLV epitope, cervical cancer is a relevant in vivo process because HTLV infection is associated with cervical cancer. With an influenza epitope, melanoma is not a relevant in vivo process. With an influenza epitope, exposure to influenza virus or vaccine are the only relevant in vivo processes. The in vivo processes curated must always be relevant to the assay antigen.

Animal Models of Cancer

  • Cancer in mice can be caused by injecting tumor cells that grow and mimic a natural cancer
  • Specific strains of mice spontaneously develop cancer by a certain age (TRAMP mice)

Both cases to be curated as animal model of cancer


If new animal model of cancer arises, use ‘animal model of cancer’ and request new child term


Important Note: If the immunogen does not cause disease, do not fill in disease state in that process. For example, if a diseased human is injected with an epitope vaccine, that vaccine did not cause the disease, therefore do not enter a disease in the in vivo process describing the vaccination step. In this case, in vivo process 1 will be "Occurrence of cancer" with no immunogen and in vivo process 2 will be "Therapeutic Vaccination" with the vaccine as the immunogen.


Vaccination

Vaccination is a subtype of Administration in vivo

It is to be used for vaccination with author described "vaccines", even when this was not administered in relation to the experiment being performed. Use Vaccination whenever the authors refer to the immunogen as a "vaccine" and it is not clear if it was administered prior to or after disease development.

Prophylactic vaccination is to be used when the vaccine is administered prior to disease development.

Therapeutic vaccination is to be used when the vaccine is administered after disease development.

Important Note: do not bulk these two vaccination types in cancer papers. In all other categories, they may be bulked under whichever protocol gave the best result.

Tissues

Always capture the specific tissue that the tumor was derived from when describing effector cells, antigen presenting cells, immunogens, and antigens when they are derived from a tumor.

Generic “tumor” will not be added to the tissue types

If it is not known, Unknown/Other can be used

Cells

Always try to be as specific as possible when cancer cells are used as effector cells, antigen presenting cells, immunogens, and antigens.

Tumor Infiltrating Lymphocyte (TIL) is on the cell list

Make term requests when new cancer cells lines are encountered


Negative Monoclonal Responses

Always curate monoclonal negative data when it is deemed interesting, otherwise, it is not curatable. Lack of cross-reactivity to wild type qualifies as interesting. Curate wild type peptides as a negative assay antigen under the neoepitope if they are NOT recognized by a neoepitope monoclonal receptor. The wild type peptide is not curated as an epitope unless it is positive.

Treatments

Treatments that that are unrelated to the epitope (e.g., vaccination with unrelated peptide or protein) are not curated as the immunogen. The immunogen must relate to the antigen being recognized. Treatments should be described in the Immunization Comments Field whenever they affect the recognition of the epitope and/or antigen.