Supplementary Figure 1

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Supplementary Figure 1

Supplementary Figure 1: Flow chart of the data collection from the Dutch Pathology Register

Pathology reports were collected from the Dutch Pathology Register (PALGA) from January 2017 till June 2019. Reports were retrieved matching the following search criteria: gastrointestinal stromal tumor AND KIT OR PDGFRA OR molecular biology OR therapy decision test. Reports that were collected based on the search criteria were manually curated based on the presence of mutation analysis.

Dutch Pathology Database

From January 2017 to June 2019

1977 pathology reports of 986 cases

Present in report:

Gastrointestinal stromal tumor AND

KIT OR PDGFRA OR molecular biology OR therapy decision test

Molecular analysis:

545 cases

No molecular analysis:

396 cases 941 GIST cases

No gastrointestinal stromal tumor:

45 cases

Uncoupled pathology reports Initial diagnosis not in 2017 or 2018

171 cases Linked with NCR

Initial diagnosis in 2017 or 2018 374 cases

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Supplementary Figure 2

0.0 0.5 1.0 1.5 2.0 2.5 3.0

0.0 0.2 0.4 0.6 0.8 1.0

Time from initial diagnosis (years)

Overall survival (%)

KIT mutation, n= 58 , events= 13 No mutation, n= 3 , events= 2 PDGFRA mutation, n= 5 , events= 5 Unknown mutation status, n= 15 , events= 7

Metastatic disease

0.0 0.5 1.0 1.5 2.0 2.5 3.0

0.0 0.2 0.4 0.6 0.8 1.0

High risk

P < 0.001

P = 0.001

Supplementary Figure 2: Overall survival of GIST cases based on mutation status

Overall survival (OS) of GIST cases based on the mutation status. Analyses were performed per disease stage. OS rates were determined using Cox regression and compared using the Wald test. Overal p-values are reported within each graph.

In case of significance, each individual group was compared to the remaing patients. Imatinib therapy (yes/no) was included as covariate in these models. Signficant p-values for these individual groups are shown.

0.0 0.5 1.0 1.5 2.0 2.5 3.0

0.0 0.2 0.4 0.6 0.8 1.0

Low risk

0.0 0.5 1.0 1.5 2.0 2.5 3.0

0.0 0.2 0.4 0.6 0.8 1.0

Intermediate risk

P < 0.001 P = 0.920

P = 1.000 P = 0.621

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Supplementary Figure 3

Supplementary Figure 3: Molecular diagnostic analyses of GIST cases.

(a) Mutational landscape of GIST cases. Each column represents a tumor sample. Each row represents a gene. Tumor samples were sorted on the type of KIT/PDGFRA mutation. Reported (likely) pathogenic mutations, variants of unknown significance and (likely) benign variants are depicted in the figure. A colored bar represents a variant (see legend), a white bar represents no alteration, and a grey bar represents not analyzed (i.e. not present in NGS panel or single gene analysis of KIT/PDGFRA). (b) Reported frequencies of KIT and PDGFRA mutations per pathology department. The number of tests per bar are displayed behind each bar. Frequencies per pathology departments were compared the respective frequencies of the remaining pathology departments using the Fisher’s Exact test. * p<0.05

a

KIT exon 9 KIT exon 11 KIT exon 13-17 KIT unspecified KIT VUS

PDGFRA p.D842V PDGFRA other mutation PDGFRA VUS

No mutation

Insufficient quantity/quality

0 20 40 60 80 100

O N M L K J I H G F E D C B A Total

Frequency (%)

Pathology departments

3 4 9 10 10 14 36 26 46 59 62 64 78 79 87 587

O N M L K J

3 4 9 10 10 14

* *

Insufficient quality Insufficient quantity Not analyzed No mutation

KIT exon 11 + additional mutation KIT exon 9

KIT exon 11 KIT exon 13-17

PDGFRA p.D842V PDGFRA exon 18 other PDGFRA exon 14 PDGFRA exon 12

Unspecified mutation Variant of unknown significance (Likely) pathogenic mutation(s) (Likely) benign variant

TP53 TERT SMO SMAD4 RB1 RNF43 PTEN PIK3CA MUTYH MPL MDM2 KDR GNAQ FGFR1 EZH2 CDKN2A ATM APC SDHA NF1 BRAF PDGFRA KIT