A prospective epidemiological study of new incident GISTs during two consecutive years in Rhône Alpes region: incidence and molecular distribution of GIST in a European region.

Abstract

Preliminary data indicate that the molecular epidemiology of localised gastrointestinal stromal tumour (GIST) may be different from that of advanced GIST. We sought to investigate the molecular epidemiology of sarcomas, including GIST, in the Rhone-Alpes region in France.
A prospective and exhaustive study in the Rhone-Alpes Region in France to assess the precise incidence of primary sarcomas with systematic centralised pathological review and molecular analysis was conducted for 2 consecutive years.
Among 760 patients with a confirmed diagnosis of sarcoma, 131 (17%) had a GIST. The majority of patients had gastric primaries (61%). Mutational analysis could be performed in 106 tumour samples (74%), and 71 (67%) had exon 11 mutations. PDGFRA mutations were found in 16% of cases, which is twice as high as previously reported for advanced GIST.
Data indicate that PDGFRA mutations in localised GIST may be twice as high as what was previously reported in patients with advanced disease. This finding may have important consequences for patients offered adjuvant imatinib, although most of these tumours are in the low-risk group.

Full text

Page 1

A prospective epidemiological study of new incident GISTs
during two consecutive years in Rho ˆne Alpes region: incidence
and molecular distribution of GIST in a European region
PA Cassier1, F Ducimetie `re2, A Lurkin2, D Ranche `re-Vince3, J-Y Scoazec4,5, P-P Bringuier4,5,
A-V Decouvelaere3, P Me ´eus6, D Cellier7, J-Y Blay1,5,8and I Ray-Coquard*,1,2
1Department of Medicine, Centre Le ´on Be ´rard, Lyon, France;2EA4129 ‘Sante ´, Individu, Socie ´te ´’ Centre Le ´on Be ´rard, Lyon, France;3Department of
Pathology, Centre Le ´on Be ´rard, Lyon, France;4Department of Pathology, Ho ˆpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France;5Universite ´ de
Lyon, Universite ´ Claude Bernard Lyon 1, Villeurbanne, France;6Department of Surgery, Centre Le ´on Be ´rard, Lyon, France;7Merck Serono, Lyon, France;
8INSERM U590, Centre Le ´on Be ´rard, Lyon, France
BACKGROUND: Preliminary data indicate that the molecular epidemiology of localised gastrointestinal stromal tumour (GIST) may be
different from that of advanced GIST. We sought to investigate the molecular epidemiology of sarcomas, including GIST, in the
Rhone-Alpes region in France.
PATIENTS AND METHODS: A prospective and exhaustive study in the Rhone-Alpes Region in France to assess the precise incidence of
primary sarcomas with systematic centralised pathological review and molecular analysis was conducted for 2 consecutive years.
RESULTS: Among 760 patients with a confirmed diagnosis of sarcoma, 131 (17%) had a GIST. The majority of patients had gastric
primaries (61%). Mutational analysis could be performed in 106 tumour samples (74%), and 71 (67%) had exon 11 mutations.
PDGFRA mutations were found in 16% of cases, which is twice as high as previously reported for advanced GIST.
CONCLUSION: Data indicate that PDGFRA mutations in localised GIST may be twice as high as what was previously reported in patients
with advanced disease. This finding may have important consequences for patients offered adjuvant imatinib, although most of these
tumours are in the low-risk group.
British Journal of Cancer (2010) 103, 165–170. doi:10.1038/sj.bjc.6605743
Published online 29 June 2010
& 2010 Cancer Research UK
www.bjcancer.com
Keywords: gastrointestinal stromal tumour (GIST); incidence; KIT; PDGFRA; kinase mutations
? ???????????????????????????????????????????????????
Gastrointestinal stromal tumours (GISTs) are rare tumours of
mesenchymal origin arising in the gastrointestinal tract. Incidence
data obtained from registries indicate an incidence of approxi-
mately 12–15 new cases per million inhabitants per year in
western countries (Goettsch et al, 2005; Nilsson et al, 2005);
however, there remain uncertainties because of variations in
diagnostic criteria before the NCI consensus reported in 2002
(Fletcher et al, 2002). Approximately 95% of GISTs stain positive
for CD117 (KIT) and 85% of cases harbour activating mutations in
the gene of one of two structurally related transmembrane
tyrosine-kinase receptors: KIT and PDGFRA (Hirota et al, 1998;
Heinrich et al, 2003a,b; Corless et al, 2005). These activating
mutations affect primarily the exons 9 and 11 of KIT, but may also
be found on exons 8, 13 and 17 of KIT and exons 12, 14 and 18 of
PDGFRA (Heinrich et al, 2003a, 2008; Debiec-Rychter et al, 2006).
The relative frequency of the different KIT and PDGFRA mutations
in patients with advanced GIST has been previously reported
(Heinrich et al, 2003a, 2008; Debiec-Rychter et al, 2006). The
frequency of KIT and PDGFRA mutations in localised GIST has
been reported in a single-institution study from Italy. Other
preliminary reports indicate that PDGFRA mutations may be
higher in localised than metastatic GIST, which may reflect their
more favourable prognosis. Two recent autopsy series have shown
that the incidence of GIST may be as high as 50% in stomach
specimens (Kawanowa et al, 2006; Agaimy et al, 2007); in one
of these series, canonical KIT or PDGFRA mutations were found
in 50% of assessable tumours (Agaimy et al, 2007). We sought
to assess the precise incidence of GIST and other sarcomas in
the Rhone-Alpes region in France. This report focuses exclusively
on GIST.
PATIENTS AND METHODS
A prospective and exhaustive study was conducted in the
Rhone-Alpes region in France to assess the precise incidence of
primary sarcomas and to assess conformity of management with
published guidelines. Rhone-Alpes represent 10% of the French
population (5958320 of 60825000 inhabitants) and 10% of the
French territory. All cases for which a diagnosis of sarcoma
was raised were systematically and centrally reviewed by experts
(DR and AVD) to confirm the diagnosis.
Received 4 January 2010; revised 10 May 2010; accepted 19 May 2010;
published online 29 June 2010
*Correspondence: Dr I Ray-Coquard; E-mail: ray@lyon.fnclcc.fr
British Journal of Cancer (2010) 103, 165–170
& 2010 Cancer Research UKAll rights reserved 0007– 0920/10
www.bjcancer.com
Clinical Studies

Page 2

Collection of data
All pathologists of the Rhone-Alpes region (n¼42) agreed to
participate in the study after a first meeting to inform them. They
had to prospectively notify their cases, and to address a paraffin-
embedded tumour sample for expert review. A financial support
was allocated for each notified case and each tumour bloc.
Duplications were checked in the database by a comparison of the
patient’s initials and the date of birth. If one patient was noted to
have several diagnostic materials (e.g., biopsy, surgery and
metastasis), or if tumour locations were multiple, the patient
could be included only once in the study.
All diagnosed patients with a first diagnosis of primary sarcoma,
between 1 March 2005 and 28 February 2006, and living in the
Rho ˆne-Alpes region (as testified by the ZIP code of patients’
address), were included in the study. All subtypes of sarcomas
were included: soft tissue, bone and visceral (GISTs and
gynaecological sarcomas) sarcomas. Exclusion criteria concerned
relapsed tumour, date of diagnosis not matched with the inclusion
period, patient living outside of the Rhone-Alpes region and no
definitive histology in favour of sarcoma after the review.
A validation series of all new cases diagnosed between 1 March
2006 and 28 February 2007 was also collected and analysed using
the same methodology.
Pathological review
All cases of suspicious sarcomas were reviewed by regional
sarcoma expert pathologists (JYS, DRV and AVD) and national
experts (JM Coindre and a panel of pathologists from French
Sarcoma group). New tissue sections were prepared from the
paraffin-embedded samples provided by the primary pathologist,
and immunohistochemical study was systematically performed
again by the expert reviewer (Lurkin et al, 2010). Diagnoses were
performed in accordance with the 2002 WHO classification.
Mutation analysis
After manual microdissection of tumour or normal tissue, DNA
was extracted from paraffin-embedded material, using the
MasterPure kit (Epicentre Biotechnologies, Le Parray en Yvelines,
France). Exons 9, 11, 13 and 17 of KIT and exons 12, 14 and 18 of
PDGFRA were amplified using the primers detailed in Table 1.
Except for exon 9 of KIT, mutation screening was performed by
dHPLC analysis with a WAVE system (Transgenomic, Montluc¸on,
France). Mutations were confirmed by sequencing with the same
primer as for PCR; PCR products were purified using Qiagen
MiniElute PCR (Qiagen, Courtaboeuf, France) purification columns
and then sequenced on both strands with the DYEnamic ET Dye
terminator kit (Amersham Bioscience, Orsay, France) and analysed
on a MegaBACE 1000 automatic sequencer (Amersham Bioscience).
For KIT exon 9, the six-nucleotide duplication was assessed using
high-resolution agarose gel electrophoresis (Resophor; Laboratoire
Eurobio, Les Ulis, France) of the 47bp (or 53bp) PCR product.
Statistical analysis
Data were described using percentages for qualitative variables and
median and range for numerical variables. All statistical analyses were
performed using the SPSS 12.0 package (SPSS Inc., Chicago, IL, USA).
RESULTS
Epidemiology of GIST
A total of 703 patients for whom a diagnosis of sarcoma was raised
were screened; 42 patients (6.1%) were diagnosed outside the study
period; 128 patients (18.5%) were found to have relapse (and not
primary sarcoma); 44 patients (6.4%) managed in the Rhone-Alpes
were found to live outside the predefined region; 33 patients
(4.8%) lived and were managed outside the Rhone-Alpes; and 68
patients (9.8%) did not have sarcoma after expert pathologic
review. In all, 376 patients (54.4%) conformed to the inclusion
criteria: confirmed diagnosis of sarcoma after expert review, initial
diagnosis between 1 March 2005 and 28 February 2006 (date of
biopsy if there was one/of surgery if no biopsy) and resident in
Rhone-Alpes region; 67 patients (17.8%) were diagnosed with
GIST. For the second year, the diagnosis of sarcoma was raised in
581 patients, of whom 369 patients had a confirmed diagnosis of
incident sarcoma, with 64 of them (16.7% of all sarcomas)
identified as incident cases with GIST. Overall, 745 of 1284 patients
had a confirmed diagnosis of sarcoma, of which 131 (18%) were
GISTs. The crude incidence of GIST was therefore 11.2 per million
inhabitant per year.
Patients’ characteristics
The main characteristics of the 131 patients with GIST are
described in Table 2. In brief, a majority of patients were female
(n¼75, 57%), median age was 66 (range 34–91) years and most
(61%) tumours originated from the stomach. In all, 117 patients
(89%) were diagnosed as having localised GIST, whereas 14
patients (11%) had metastatic disease at initial diagnosis, confined
to the abdominal cavity in all cases (liver metastases n¼9;
mesentery or peritoneum n¼8; and 2 patients had lymph node
metastases). Four tumours were diagnosed incidentally on surgical
specimens obtained for other reasons: two tumours were found in
oesophagectomy specimens (one performed after sulphuric acid
ingestion and one performed for squamous cell carcinoma), one
tumour was found on a gastrectomy specimen performed for
gastric adenocarcinoma and one patient had an incidental
diagnosis of GIST during cholecystectomy (the surgeon resected
a small gastric lesion). Risk stratification was performed according
to both the National Institute of Health (NIH) (Fletcher et al, 2002)
and the Armed Forces Institute of Pathology (AFIP) (Miettinen
and Lasota, 2006) criteria (Table 2).
Molecular data
Mutation analysis could be performed in 106 of 131 patients (81%),
55 of 67 patients (82%) in the first cohort and 51 of 64 patients
Table 1Primers used for PCR
ExonPrimer
KIT exon 9 forward
KIT exon 9 reverse
50-GATGTGGGCAAGACTTCTG-30
50-TTACCTTTAAATGCAAAGTTAA-30
KIT exon 11 forward
KIT exon 11 reverse
50-CCAGAGTGCTCTAATGACTG-30
50-ACTGTTATGTGTACCCAAAAAGG-30
KIT exon 13 forward
KIT exon 13 reverse
50-GCTTGACATCAGTTTGCCAGT-30
50-GGCAGCTTGGACACGGCTTTA-30
KIT exon 17 forward
KIT exon 17 reverse
50-TGAACATCATTCAAGGCGTATTGCTT-30
50-TTGAAACTAAAAATCCTTTGCAGGAC-30
PDGFRA exon 12 forward
PDGFRA exon 12 reverse
50-TCCAGTCACTGTGCTGCTTC-30
50-GCAAGGGAAAAGGGAGTCTT-30
PDGFRA exon 14 forward
PDGFRA exon 14 reverse
50-TGAGAACAGGAAGTTGGTAGCTCA-30
50-GATGGAGAGTGGAGGATTTAAGCC-30
PDGFRA exon 18 forward
PDGFRA exon 18 reverse
50-ACCATGGATCAGCCAGTCTT-30
50-TGAAGGAGGATGAGCCTGACC-30
Incidence and molecular partition of GIST
PA Cassier et al
166
British Journal of Cancer (2010) 103(2), 165–170
& 2010 Cancer Research UK
Clinical Studies

Page 3

(80%) in the second cohort (Table 2). In 16 cases, mutational
analysis could not be performed because of the fixative used, and in
the 9 remaining cases the sample size was not sufficient to retrieve
enough DNA for sequencing (microbiopsies or microGIST).
The majority of samples harboured KIT mutations (n¼71 of
106, 67%), and no KIT or PDGFRA mutations was found in 18
patients (17%). Seventeen tumours (16%) harboured PDGFRA
mutations, 15 tumours originated from the stomach (14 with
PDGFRA exon 18 and one PDGFRA exon 12), one from the
peritoneum (omentum, PDGFRA exon 18 mutation) and one from
the small bowel (PDGFRA exon 12 mutation). In addition, 10
patients (9%) had tumours with exon 9 mutations, 8 of which
originated from the small bowel (including the duodenum), one
from the rectum and one from the pelvis. The relative frequencies
of KIT exon 11, KIT exon 9 and PDGFRA mutations are described
in Table 3. When considering only patients with localised disease
for whom molecular data were available (n¼94), KIT exon 9, 11,
13 and 17 mutations were found in 9 (10%), 49 (52%), 3 (3%) and
1 (1%) patient, respectively, whereas PDGFRA mutations were
found in 14 (15%) patients (exon 18, n¼12 and exon 12, n¼2),
and 18 (19%) patients had KIT and PDGFRA wild-type tumours. Of
the 14 PDGFRA exon 18 mutations, 13 (93%) involved codon 842,
and 10 were D842V substitutions (11%). Molecular analysis could
be performed for only one of the four incidentally diagnosed GISTs
and showed a KIT exon 11 mutation. For the three other cases, the
amount of DNA was not sufficient to perform molecular analysis.
Correlation of mutation and risk stratification
The aim of this correlative analysis was to determine which patient
would be eligible for adjuvant imatinib, and it was therefore
conducted only for patients with localised disease. Furthermore,
both the NIH and the AFIP risk stratification were simplified into
two categories grouping very low and low-risk group on one side
and intermediate- and high-risk groups (i.e., those eligible for
adjuvant imatinib per EMEA approval) on the other. Results of
this correlative analysis are depicted in Table 4. As previously
described (Blackstein et al, 2010), approximately 15–20% of
patients from the high (intermediate and high) risk group in the
NIH classification were reallocated to the low (very low and low)
Table 2Patients’ characteristics
Year 2005 Year 2006Overall
CharacteristicsN¼67%Median RangeN¼64% MedianRangeN¼131% MedianRange
Age (years)66 34–916438–88 6634–91
Gender
Male
Female
25
42
37
63
31
33
48
52
56
75
43
57
Tumor location
Stomach
Small bowel
Rectum/pelvis
Peritoneum
Oesophagus
40
15
5
6
1
60
22
7
9
1
40
21
2
1
0
63
33
3
2
0
80
36
7
7
1
61
27
5
5
1
Tumor size (mm)a
503–290 554–45055 3–450
Mitose count/50 HPFa
p5
45 and p10
410
42
11
10
67
17
16
36
12
6
67
22
11
78
23
16
67
20
14
Disease status
Localised
NIH risk group
Very low
Low
Intermediate
High
NA
59 88589111789
7 12
24
37
24
3
47 11
31
41
28
6
9
14
22
14
2
17
19
14
4
29
33
24
7
26
35
24
5
AFIP risk group
Very low
Low
Intermediate
High
NA
7 12
39
19
20
10
4711
46
19
25
16
9
23
11
12
6
23
8
13
10
40
14
22
17
39
16
21
14
Metastatic8 1269 1411
Immunohistochemistryb
CD117 (KIT) positive
CD34 positive
63
58
97
88
62
51
98
81
125
109
95
83
Abbreviations: NA¼not available; HPF¼high power field; NIH¼National Institute of Health; AFIP¼Armed Forces Institute of Pathology.aTumour size and mitose count were
available for 63 patients in the 2005 cohort, whereas size was available for 61 and mitose count for 54 patients in the 2006 cohort.bImmunohistochemistry data were available
for CD117 in 65 patients, and for CD34 in 66 patients in the 2005 cohort, and they were available for both CD117 and CD34 in 63 patients in the 2006 cohort.
Incidence and molecular partition of GIST
PA Cassier et al
167
British Journal of Cancer (2010) 103(2), 165–170
& 2010 Cancer Research UK
Clinical Studies

Page 4

risk group of the AFIP risk stratification. This was true for all
mutations types except for PDGFRA mutants in which 50% of
the patients were reclassified as low risk, leaving only 7% of
patients in the high-risk group of the AFIP classification (vs 57%
when using the NIH classification; Table 4). The distribution of
PDGFRA mutant tumours between the low- and high-risk
categories was significantly different from that of KIT mutant or
wild-type tumours when using the AFIP classification (P¼0.005,
Kruskal–Wallis test), but not when using the NIH classification
(P¼0.452, Kruskal–Wallis test). This difference of distributions is
likely the consequence of the association of PDGFRA mutations
with tumours of gastric origin (Lasota et al, 2004).
DISCUSSION
This study is the first to date to report incidence with molecular
analysis of GIST based on a prospectively collected exhaustive
population sample (5958320 inhabitants in the Rho ˆne-Alpes
region). Overall, our data are in agreement with previously
reported series in terms of primary tumour location, size and
gender (Braconi et al, 2008). One of the key findings is the
differences in the frequency of PDGFRA mutations that seem
almost twice as high as that reported in patients with advanced
disease (Debiec-Rychter et al, 2006; Braconi et al, 2008; Braggio
et al, 2008; Du et al, 2008; Heinrich et al, 2008) (Table 5), including
in patients with localised disease. These differences may be
because of the more indolent behaviour of tumours bearing
mutant PDGFRA (Lasota et al, 2004; Dematteo et al, 2008), whereas
some KIT exon 11 and KIT exon 9 mutations have a higher risk of
relapse after surgical excision. Other recently reported series have
found somewhat lower frequencies of PDGFRA mutations: Braggio
et al (2008) reported frequencies of 7.3% in patients with
completely resected GIST in a specific population from Brazil. In
both their series and ours, the small numbers preclude any
definitive conclusion and these observations must be confirmed by
larger studies. Emile et al (2009) recently reported a large series of
GIST with molecular epidemiology and found that PDGFRA
mutation were twice as high in localised GIST than that previously
reported for patients with advanced disease. This series, which
used different inclusion criteria (expert pathology referral),
confirms what was found in our series. However, unlike Emile
et al (2009), we could not find any significant difference in age
between patients with PDGFRA-mutated tumours and those with
other mutation type (Kruskal–Wallis nonparametric test P¼0.295
for PDGFRA mutants vs other mutation types). Furthermore, in
contrast with what Emile et al (2009) found, the frequency of KIT
exon 9 mutations in patients with localised disease in our series
was comparable to that previously reported in patients with
advanced disease (approximately 10%; Heinrich et al, 2003a;
Debiec-Rychter et al, 2006)
Although the predictive role of KIT mutations have been studied
and reported in patients with advanced disease (Heinrich et al,
2003a; Debiec-Rychter et al, 2006; Van Glabbeke et al, 2007), the
precise role of mutations in the biology of localised GISTs and
their correlation with prognosis remains debated, although
PDGFRA mutations seem associated with a rather indolent course
(Lasota et al, 2004), whereas deletions of KIT exon 11 encompass-
ing codons 557 and 558 were found to have poor prognosis (Martin
et al, 2005). More data regarding the prognostic significance of
different kinase mutations will likely be generated from the control
arms of the adjuvant trials that have now finished accrual
(Dematteo et al, 2009; Gronchi et al, 2009).
These observations are of importance considering the recent
introduction of adjuvant imatinib treatment in high-risk GIST.
PDGFRA exon 18 mutations (D842V), which affect the activation
loop of the PDGFRa kinase, are biochemically less sensitive to
imatinib than the more common KIT exon 11 mutations. As they
may also have a better prognosis, the molecular characterisation
may prove to be useful in selecting those patients in whom
adjuvant imatinib is truly required. It is noteworthy that although
57% of the tumours with PDGFRA mutations in our series were
classified as intermediate or high risk according to the NIH
consensus (Fletcher et al, 2002), most of these tumours were
classified as low or very low risk according to the AFIP risk
classification (Miettinen and Lasota, 2006). The main reason for
Table 3Results of mutation analysis
Year of sample collection
20052006Overall
Type of mutationN%a
N%a
N%
NA
Wild type
c-KIT
Exon 9
12
11
35
13
7
36
25
18
71
20
64
14
71
17
67
Duplications
Exon 11
Deletions
Missense
Insertion
Deletion and missense
Deletion and insertion
Duplications
Exon 13
Missense
Exon 17
476 12109
15
9
2
2
1
1
27
16
4
4
2
2
10
6
3
5
0
2
20
12
6
10
0
4
25
15
5
7
1
3
24
14
5
7
1
3
1
0
2
0
3
1
6
2
4
1
4
1
PDGFRA
Exon 12
Deletions
Exon 18
Missense
Insertion
Deletions
915816 1716
240022
5
0
2
9
0
4
5
1
2
10
2
4
10
1
4
9
1
4
Abbreviation: NA¼not available.
patients for whom mutation status was available (n¼55 for 2005, 51 for 2006 and
106 overall).
aPercentages are calculated on the number of
Table 4
AFIP risk classifications for the 94 patients with both localised disease and
molecular data
Correlation of mutation type and risk using the NIH and the
NIH AFIP
Low HighNA LowHighNA
Total NN%N%N%N%N%N%
Overall 9430 32 60 644 4 4548 414489
Kit 62
49
9
3
1
20 32 38
16 33 31
2 22
2 67
00
61
63
67
0
4
2
1
1
0
6 27
4 23
11
33
0
44 29
47 22
22
67
0
47
45
67
0
6
4
1
1
0
10
8
11
33
0
Exon 11
Exon 9
Exon 13
Exon17
6
0
1 100
2
2
0
6
0
1 100
PDGFRA
Exon 12
Exon 18
14
2
12
6 43
1 50
5 42
8
1
7
57
50
58
0
0
0
0 12
0
0 10
861
0
1
7
0
8
1
0
1
7
2 100
838
Wild type18 4 22 1478006 33 11 6116
Abbreviations: NA¼not available; NIH¼National Institute of Health; AFIP¼Armed
Forces Institute of Pathology.
Incidence and molecular partition of GIST
PA Cassier et al
168
British Journal of Cancer (2010) 103(2), 165–170
& 2010 Cancer Research UK
Clinical Studies

Page 5

this shift is likely the gastric origin of most of the tumours
harbouring PDGFRA mutations (15 of 17, 88%). Similarly, the
identification of exon 9 may be needed to propose the adequate
dose of adjuvant imatinib (Van Glabbeke et al, 2007).
Finally, the absolute incidence of GIST may be largely under-
estimated as suggested by the reports of Agaimy et al (2007) and
Kawanowa et al (2006), which reported the so-called ‘microGIST’
in up to 50% of specimens of gastrectomies performed for other
causes. Conversely, most of these tumours never become ‘clinically
significant’, as the rate of clinically detected GIST is 12–15 per
million inhabitants in Western countries as shown by our data and
others (Nilsson et al, 2005; Monges et al, 2007). It is noteworthy
that three patients in the 2005 cohort and one in the 2006 cohort
had a diagnosis of GIST after surgery for another cause.
Furthermore, new diagnostic or imaging procedures, such as
endoscopic ultrasound, may lead to an increase in the diagnosis
of small GIST. The ‘true incidence’ of GIST may therefore be
a moving concept in the future.
ACKNOWLEDGEMENTS
We thank Mrs Sylvie Baldassini for her precious collaboration in
the assessment of KIT and PDGFRA mutations. We also thank all
the pathologists from the Rho ˆne-Alpes region who participated in
this study: Prof. F Berger, Prof. E Brambilla, Prof. M Devouassoux,
Prof. D Seigneurin, Prof. F Thivolet-Bejui and Drs C Agard,
F Alliasmontmayeur, R Angonin, M Augros Monavon, B Balme,
B Bancel, R Barnoud, N Ben-Lagha, L Bensaadi, N Berger Dutrieux,
I Beschet, F Billard, V Blanc, N Bottero, J Bourloux, J Boutonnat,
R Bouvier, C Bozon, B Bringeon, A Buenemd, M Buyck-Mabrut,
B Cantero, C Cavailles, L Chalabreysse, P Chalabreysse, M-L Chambon-
niere, J Chanoz, G Chanoz-Poulard, M Chevalier, B Chouvet, A Ciapa,
C Clarte-Tourner, A Clemenson, S Collardeaufrachon, A Corrand-
Faure, L Corsois, F Crozes, I Cruel, R Dardelin, C David, M Decaussin,
J-F Denier, J Depardon-Dolce, P Derolland, B Descombes-Thivolet,
A Dieny, F Dijoud, C Donne, A-V Donsbeck, J-P Donzel, C Douchet,
J Dumollard, A Economides, N Elbaz, B Fabre, M Faisant, C Faure,
M Faysse, P Felman, C Feutry, M Ffrench, M Fior-Golzan, L Frappart,
F Gasnier, A Gentil-Perret, A Glehen, W Godard, J Godeneche,
C Gouarderes, F Gouzygrosjean, A Griot, C Guillaubey, C Guillaud,
C Herve, V Hervieu, S Isaac-Pinet, L Istier, M Jouffre-Cottier, A Jouvet,
J Kanitakis, P Kermanac’h, A Khaddage, J-F Knopf, M-H Koeb,
M Labadie, B Lamouliatte, S Lantuejoul, I Laurent, C Lauro-Colleaux,
M-H Laverriere, F Le Breton, F Le Marc’hadour, P Lucht-Versini, B Mac
Gregor, J-P Machayekhi, M Maisonneuve, H Martin, F Megelechevallier,
P Mesguich, D Meyronet, I Morand-Dusserre, J-L Morcillo, F Morel,
A Morens, B Muller, C Muller,M Ney, M Neyra, B Pasquier, D Pasquier,
C Paulin, M Peoc’h, G Perrot, J Pialat, E Piaton, N Picchetti, N Pienel,
P Pocachard, G Pugens, I Remy, J Richard, V Rouault-Plantaz, J-J Roux,
M-G Roux-Gilly, L Saint-Genis, G Saint-Pierre, D Salameire, M Salle,
C Salon, F Serain, L Siche, M-S Soubeyrand, N Streichenberger,
N Sturm, Y Suignard, P Terdjman, S Vancina, B Vaunois, A Vercherin,
F Vittetat, M Vochk-Bonnet, L Zappatini.
REFERENCES
Agaimy A, Wunsch PH, Hofstaedter F, Blaszyk H, Rummele P, Gaumann A,
Dietmaier W, Hartmann A (2007) Minute gastric sclerosing stromal
tumors (GIST tumorlets) are common in adults and frequently show
c-KIT mutations. Am J Surg Pathol 31: 113–120
Blackstein ME, Corless CL, Ballman KV, Antonescu CR, Blanke CD,
Demetri GD, von-Mehren M, Maki RG, Pisters PW, Dematteo RP (2010)
Risk assessment for tumor recurrence after surgical resection of localized
primary gastrointestinal stromal tumor (GIST): North American
Intergroup phase III trial ACOSOG Z9001. 2010 Gastrointestinal Cancer
Symposium. Abstract 6. 2010. Orlando, FL
Braconi C, Bracci R, Bearzi I, Bianchi F, Costagliola A, Catalani R,
Mandolesi A, Ranaldi R, Galizia E, Cascinu S, Rossi G, Giustini L,
Latini L, Valeri N, Cellerino R (2008) KIT and PDGFRalpha mutations in
104 patients with gastrointestinal stromal tumors (GISTs): a population-
based study. Ann Oncol 19: 706–710
Braggio DA, Braggio E, Small IA, Bacchi CE, Lopes LF, Valadao M, Portella S,
Romano S, Guimaraes DP, Ferreira CG (2008) The profile of platelet-
derived growth factor receptor alpha (PDGFRA) gene alterations in GIST
patients (pts) from Brazil. J Clin Oncol (Meeting Abstracts) 26: 10561
Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P,
Shiraga S, Bainbridge T, Morich J, Heinrich MC (2005) PDGFRA
mutations in gastrointestinal stromal tumors: frequency, spectrum and
in vitro sensitivity to imatinib. J Clin Oncol 23: 5357–5364
Debiec-Rychter M, Sciot R, Le CA, Schlemmer M, Hohenberger P,
van Oosterom AT, Blay JY, Leyvraz S, Stul M, Casali PG, Zalcberg J,
Verweij J, Van GM, Hagemeijer A, Judson I (2006) KIT mutations and
Table 5
(advanced+localised)
Comparison of the frequencies of PDGFRA mutations among series of patients depending on the setting: advanced disease vs population based
Setting
Advanced disease—
clinical trial
Population
based
Population based,
exhaustive
Author
Debiec-Rychter
et al (2006)
Heinrich
et al (2008)
Braconi
et al (2008)
Braggio
et al (2008)
Du
et al (2008)
Current
series
Number of patients included
Number analysed for mutations
946
377
746
378
104
94
81
55
141
141
131
106
MutationsN%N%N%N%N%N%
Kit 315
58
248
84
15
66
314
31
275
83
8
73
1
1
81
11
69
0
1
86
12
73
0
1
40
2
38
0
0
73
4
69
0
0
10877
6
70
1
0
71
10
56
4
1
67
Exon 9
Exon 11
Exon 13
Exon17
89
99
1
0
53
6
3
2
1
3
4
4
1
PDGFRA
Exon 12
Exon 18
103
0
2
6
0
6
2
0
2
13
3
10
14
3
11
4
3
1
7
5
2
8
0
8
6
0
6
17
2
15
16
1
9
2
15
Wild type52 145815 1011 11 202518 18 17
Incidence and molecular partition of GIST
PA Cassier et al
169
British Journal of Cancer (2010) 103(2), 165–170
& 2010 Cancer Research UK
Clinical Studies