Updated analysis: chordoma subtyping

[jharenza]

What analysis module should be updated and why?

We should add the "poorly differentiating" subtype

What changes need to be made? Please provide enough detail for another participant to make the update.

We have a data table of SMARCB1 copy number information and RNA expression, but this should be reviewed by a pathologist or chordoma expert for final determination of the poorly differentiating subtype. I was also reading that IHC can inform/distinguish this, so if possible, they should also review histology imaging for confirmation.

What input data should be used? Which data were used in the version being updated?

This table and histology images available on KidsFirst.

When do you expect the revised analysis will be completed?

?

Who will complete the updated analysis?

? D3b to pull IHC images and coordinate with a disease expert.

cc @yuankunzhu @allisonheath

[jharenza]

CC @stefankies for coordination

[jaclyn-taroni]

I'm going to label this as blocked because this is external to analyses contained within the repository.

[jharenza]

I will coordinate with pathology to get these reviewed.

[jharenza]

After my some pathology report translations by Laura Scolaro, my pathology report review, CN inspection, and discussion with pathologist, Mariarita Santi, I have the following to report:

Kids_First_Participant_ID	Kids_First_Biospecimen_ID_RNA	Kids_First_Biospecimen_ID_DNA	pathology_diagnosis	sample_id	tumor_descriptor	focal_SMARCB1_status	SMARCB1_expression	Path report inspection	Poorly differentiated? Comments
PT_F1086Z0A	BS_P4D8Y3S8	BS_BWZTMWTM	Chordoma	7316-1101	Initial CNS Tumor	loss	7.1	INI1 negative; poorlydifferentiated per pathology report	yes
PT_HFQNKP5X	BS_YB07VF1X	BS_9GN1QA3Q	Chordoma	7316-2935	Progressive	neutral	14.29	poorly differentiated per pathology report; INI1 negative	yes
PT_HFQNKP5X	BS_EJ9JKM1C	BS_6F49F7WH	Chordoma	7316-3295	Recurrence	loss	3.89	INI1 retained in 50% of cells	likely yes with immunostain being wrong - repeat immunostain
PT_WTMSD2WB	BS_67PX06P3	BS_JTBM5TSE	Chordoma	7316-3632	Initial CNS Tumor	loss	15.68	INI1 not mutated	no - tumor is ploidy 4 and loss with chr22 CN of 3
PT_HFQNKP5X	BS_DBDXCXT5	BS_5B6XZ7YP	Chordoma	7316-4062	Progressive	loss	18.66	poorly differentiated per autopsy report	yes
PT_HFQNKP5X	BS_GFM6EA61	BS_FBJ516WW	Chordoma	7316-921	Initial CNS Tumor	neutral	20.87	loss of INI1 immunostain; no deletion or duplication of SMARB1 or coding mutation	likely no with immunostain being wrong - repeat immunostain
PT_3WA7SBQ6	BS_0VRSD9V3	BS_HN8DE43A	Choroid plexus carcinoma	7316-2248	Initial CNS Tumor	neutral	113.08	no mention of INI1; recurrent tumor one year later (7316-3135) notes preserved INI1 nuclear staining	no (remove, not chordoma)
PT_41BCPB7R	BS_64HCD9K3	NA	Choroid plexus carcinoma	7316-406	Initial CNS Tumor	NA	33.73	INI1 positive	no (remove, not chordoma)
PT_7TRGHZBK	BS_W36RZSFA	BS_XEVMEYFS	Choroid plexus carcinoma	7316-431	Initial CNS Tumor	neutral	53.15	INI1 positive	no (remove, not chordoma)
PT_YZ8A8A36	BS_GSVCN2XC	BS_59FR1NC2	Choroid plexus carcinoma	7316-723	Initial CNS Tumor	neutral	43.79	INI1 normal	no (remove, not chordoma)

I am not certain we will have immunostains on the two samples in question, so we could make those To be classified for now to get this updated and merged.

[jharenza]

Forgot to add this CN image:

[kgaonkar6]

Just wanted to add a note from slack discussion, we will add the above subtypes to molecular-subtyoing-pathology once we have a 3rd type called dedifferentiated also identified and annotated for chordoma samples.

[jharenza]

Pasting here email correspondence from Mariarita Santi

Dear Jo Lynne,

Thank you for your enquire; however it is difficult to answer your questions without looking at the morphology:

These are some elements that I can give to you:

Classic chordoma/ conventional are defined from soft tissue tumor WHO classification 2020 as positive for S-100-,cytokeratin, EMA and brachyury and in majority of cases retained INI-1. Now there are reports of conventional chordoma with loss of INI-1 immunostain. Case 7316-921 is reported as chordoma with loss of INI-1 expression; however you mentioned that no alteration/mutation of INI-1/SMARCB1 were found. Probably the immunostain was wrongly interpreted, if you think that the genetic test you did was correct , here there is a discrepancy between immunostains and genetic result. You should run again on unstained section the INI-1 immunostain. In addition a test done from the contributor 7316-921 cytogenetic mentioned that no INI-1 mutation/abnormality is found. Putting everything together I would say that the immunostain was wrong, this is probably a chordoma, but I cannot be completely sure without looking at the morphology and correlating everything together.

Poorly differentiated chordoma are characterized by loss of INI-1/SMARCB1 loss; these are brachyury positive. Therefore yes 7316-3295 may be a poorly differentiated if you see deletion/mutation of SMACB1 gene. Again what does it mean loss of immunostains in 50% of the cells. It is impossible to judge without looking. Again you should repeat immunostains.

Remember there is a third category of dedifferentiated chordoma that is conventional chordoma plus sarcoma, with brachyury negative but no loss of INI-1

I think that for this chordoma study you should request unstained FFPE from each contributor and repeat the immunostains here in the core lab if there is no correlation between immunostains and genetic finding

I have another curiosity, what you mean when you write focal SMARCB1 gene loss? Mosaic situation

Thanks

I hope this help

mariarita

[jharenza]

@kgaonkar6 I realized that the two samples in question were from one patient for which we have 4 samples, so going back through the timeline of the tumor, I added the most likely subtypes and this is ready for a PR:

Kids_First_Biospecimen_ID_RNA	Kids_First_Biospecimen_ID_DNA	pathology_diagnosis	sample_id	tumor_descriptor	focal_SMARCB1_status	SMARCB1_expression	Path report inspection	Poorly differentiated? Comments	molecular_subtype
BS_P4D8Y3S8	BS_BWZTMWTM	Chordoma	7316-1101	Initial CNS Tumor	loss	7.1	INI1 negative; poorlydifferentiated per pathology report	yes	CHDM, poorly differentiated
BS_YB07VF1X	BS_9GN1QA3Q	Chordoma	7316-2935	Progressive	neutral	14.29	poorly differentiated per pathology report; INI1 negative	yes	CHDM, poorly differentiated
BS_EJ9JKM1C	BS_6F49F7WH	Chordoma	7316-3295	Recurrence	loss	3.89	INI1 retained in 50% of cells; in areas, tumor is more solid and less differentiated than previous resection	likely yes with immunostain being wrong - repeat immunostain	CHDM, poorly differentiated
BS_DBDXCXT5	BS_5B6XZ7YP	Chordoma	7316-4062	Progressive	loss	18.66	poorly differentiated per autopsy report	yes	CHDM, poorly differentiated
BS_GFM6EA61	BS_FBJ516WW	Chordoma	7316-921	Initial CNS Tumor	neutral	20.87	loss of INI1 immunostain; no deletion or duplication of SMARB1 or coding mutation	likely no with immunostain being wrong - repeat immunostain	CHDM, conventional
BS_67PX06P3	BS_JTBM5TSE	Chordoma	7316-3632	Initial CNS Tumor	loss	15.68	morphological and immunohistochemistry results ( AE1/AE3 +, Cam5.2+, EMA+,S100+, INI-1 not mutated) consistent with chordoma.	no - tumor is ploidy 4 and loss with chr22 CN of 3	CHDM, conventional
BS_0VRSD9V3	BS_HN8DE43A	Choroid plexus carcinoma	7316-2248	Initial CNS Tumor	neutral	113.08	no mention of INI1; recurrent tumor one year later (7316-3135) notes preserved INI1 nuclear staining	no (remove, not chordoma)
BS_64HCD9K3	NA	Choroid plexus carcinoma	7316-406	Initial CNS Tumor	NA	33.73	INI1 positive	no (remove, not chordoma)
BS_W36RZSFA	BS_XEVMEYFS	Choroid plexus carcinoma	7316-431	Initial CNS Tumor	neutral	53.15	INI1 positive	no (remove, not chordoma)
BS_GSVCN2XC	BS_59FR1NC2	Choroid plexus carcinoma	7316-723	Initial CNS Tumor	neutral	43.79	INI1 normal	no (remove, not chordoma)

[kgaonkar6]

cool, adding a PR for this

[kgaonkar6]

Are there integrated_diagnosis terms attached with each of the subtypes below? sample_id	molecular_subtype
7316-1101	CHDM, poorly differentiated
7316-2935	CHDM, poorly differentiated
7316-3295	CHDM, poorly differentiated
7316-4062	CHDM, poorly differentiated
7316-921	CHDM, conventional
7316-3632	CHDM, conventional

[jharenza]

closed with #951