Consider adding a tumor predisposing syndrome grouping term

[allenbaron]

There are a number of tumor predisposing syndromes, some cancerous, others benign. These are often represented in the syndrome branch but not the 'disease of cellular proliferation' branch, where clinicians might expect to find them as well. Consider adding a grouping term that can be placed in the 'disease of cellular proliferation' branch.

Orphanet has something like this 'Inherited cancer-predisposing syndrome' (ORDO:140162) but I'm not sure the name is appropriate since it includes both benign and malignant tumors.

Example malignant predisposing syndrome:

• 'rhabdoid tumor predisposition syndrome' (DOID:0070617)

Example benign predisposing syndromes:

• neurofibromatosis 1 (DOID:0111253) --> might be beneficial to review this classification as well... parent term, neurofibromatosis (DOID:8712) is undefined and could be a candidate for obsoletion
• schwannomatosis (DOID:3204)

It seems like this would be great to do in conjunction with CIViC.

[lschriml]

defining: Tumor predisposition syndromes are genetic mutations that increase the risk of developing cancer --> This sounds like a risk factor. I would start to tackle this, by considering if an axiom could be utilized to annotated these types of disease terms. As they are both benign and malignant types, it would be difficult to add a parent term to map all terms to.

--> Looking at relations: https://www.ebi.ac.uk/ols4/ontologies/ro/properties/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FRO_0004005?lang=en RO term: "has major susceptibility factor" some 'sequence variant" -- is a good fit

[allenbaron]

Addressing logical relationships

These diseases ARE basically risk factors for developing tumors. I don't know exactly what proportion of people with these mutations get tumors but my initial impression was that the proportion in most of these cases is very high, which makes me think of them more in terms of penetrance than as susceptibilities.

At least for variants in one gene that of RTPS the gene review states[^1]:

Penetrance of SMARCB1-related RTPS may be extremely high (>90% by age 5 years)

That's way higher than I would normally associate with a susceptibility which is why I think it makes sense for them to be added as their own syndromes (they also often result in multiple tumors, possibly of different types, which makes them unique from the tumors themselves). Although I understand the words in that relation, I don't really understand what it means... especially without a definition for has major susceptibility factor. Is that still an appropriate relation for mutations that cause disease with such high penetrance? Looking at it on OLS I see that it has an inverse relationship with is causal susceptibility factor for (RO:0004015) which is defined as:

Relates a gene to condition, such that a mutation in this gene predisposes to the development of a condition and that is necessary but not sufficient to develop the condition[modified from orphanet].

This suggests that has major susceptibility factor should be a relationship between a disease and a gene. These predisposing syndromes have such a relationship (gene to the syndrome) but as you noted they are unusual intermediate diseases, in that the true relationship is really between the gene and the tumors it predisposes to. Using RTPS as an example, technically, I think we'd add ('has major susceptibility factor' some SMARCB1) or ('has major susceptibility factor' some SMARCA4) to 'rhabdoid cancer' (DOID:3672) instead of RTPS (DOID:0070617). It seems to me we may need a new relation that is somewhat the opposite of disease has feature linking the syndrome to the tumors... or maybe disease has feature is the right relation here because the tumors are features of the syndrome?

I propose that for each predisposing syndrome we add a disease has feature logical axiom for each predisposing syndrome. Using RTPS as an example it would get the axiom 'disease has feature' some 'rhabdoid cancer'.

Addressing classification

We could create a new sub-branch term that is a sibling of the 'benign neoplasm' and cancer terms, since this includes both benign and malignant tumors, called 'tumor predisposing syndrome'. Alternatively, we could create two new terms under those two terms. I'm not in favor of that latter proposal since the syndromes aren't the tumors themselves but I do favor them appearing in the 'disease of cellular proliferation' branch.

What our your (or CIViC's, or the clinician's) thoughts on classifying these syndromes in the 'disease of cellular proliferation' branch?

[^1]: Nemes K, Bens S, Bourdeaut F, et al. Rhabdoid Tumor Predisposition Syndrome. 2017 Dec 7 [Updated 2022 May 12]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK469816/

[lschriml]

For me, it comes down to the definitions of the parent classes. As you noted, these are not cancers or benign neoplasms. I think they are correctly listed under Syndrome, as they defined by a set of 'features' - in OMIM, that is a set if symptoms/phenotypes. I think of 'Tumor predisposition syndrome' -- caused by a specific gene mutation -- having this disease increases the risk of also having a specific cancer

In order to connect the 'predisposition syndrome' with the disease that occurs subsequently, we can use: RO term, disease_has_feature defined as: A relationship between a disease and some feature of that disease, where the feature is either a phenotype or an isolated disease.

disease: cancer feature of that disease: another disease (e.g., predisposition syndrome)

--> add axioms to the cancer terms, to define this relationship