KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases.
ABSTRACT Background:Mucosal melanomas in the head and neck region are most frequently located in the nasal cavity and paranasal sinuses. Sinonasal mucosal melanoma (SNMM) comprises <1% of all melanomas. The aim was to determine the KIT, NRAS and BRAF mutation frequencies in a large series of primary SNMMs.Methods:Laser capture microdissection was used to isolate tumour cells from 56 formalin-fixed paraffin-embedded tumours. The tumour cells were screened for KIT, NRAS and BRAF mutations by direct sequencing.Results:Overall, 21% (12 out of 56) of SNMMs harboured KIT, NRAS or BRAF mutations. Mutations in these oncogenes occurred in a mutually exclusive manner. Both KIT and BRAF mutations were identified at a similar frequency of 4% each (2 out of 56), whereas NRAS mutations were detected in 14% (8 out of 56) of the SNMMs. Four of the NRAS mutations were located in exon 1. Mutations in these oncogenes were significantly more common in melanomas located in the paranasal sinuses than in nasal cavity (P=0.045). In a multivariate analysis, patients with melanomas in the nasal cavity had a significantly better overall survival than those with tumours in the paranasal sinuses (P=0.027).Conclusion:Our findings show that KIT and BRAF mutations, which are accessible for present targeted therapies, are only rarely present in SNMMs, whereas NRAS mutations seem to be relatively more frequent. The data show that majority of SNMMs harbour alterations in genes other than KIT, NRAS and BRAF.British Journal of Cancer advance online publication 16 July 2013; doi:10.1038/bjc.2013.373 www.bjcancer.com.
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ABSTRACT: Extracutaneous melanomas are poorly characterized tumors that include ocular (OM), mucosal (MM) and leptomeningeal melanomas, often lacking standardized staging and treatment guidelines. We analyzed cases of cutaneous melanoma (CM, N=219,890), OM (N=7,069) and MM (N=2,755) of different anatomical origins, diagnosed between 1988 and 2010, recorded in the Surveillance Epidemiology and End Results (SEER) database. Relative survival was studied in patients grouped by summary stage classification (localized, regional or distant disease) and in multivariate models adjusting for varying distribution of baseline factors. Unlike in CM, the incidence rate in MM increased exponentially with age. Five-year relative survival was significantly worse for OM (78%) and for most mucosal sites (aggregate 34%, range 3%-69%) compared with CM (89%). The differences between primary sites were particularly pronounced in localized disease, with a hazard ratio of 5.7 for OM, 4.3-9.0 for external genital or oral cavity MM and 19.8-90.4 for other mucosal locations. Melanomas of the pharynx, gastrointestinal, urinary tract and vagina had poor outcomes regardless of clinical stage. In contrast to CM, there was no evidence of improved survival in OM and MM during the study period. A substantial proportion of patients with operable OM or MM underwent radical organ resections (13-88% depending on site and stage) or perioperative radiotherapy (0-66%). In conclusion, extracutaneous melanomas have a markedly worse survival than CM and aggressive locoregional management appears to be insufficient for their control. Because of poor outcomes in MM, studies of systemic therapy are warranted regardless of the extent of disease at presentation. © 2013 Wiley Periodicals, Inc.International Journal of Cancer 11/2013; · 6.20 Impact Factor
Article: Update on primary mucosal melanoma.[Show abstract] [Hide abstract]
ABSTRACT: Mucosal melanomas are aggressive cancers of mucosal surfaces with clinical and pathologic characteristics distinct from cutaneous melanomas, warranting different staging systems and treatment approaches. Surgical resection is performed frequently for the primary tumor, although the utility of lymph node surgery and radiation therapy is not established. Therapies targeted against C-KIT activating mutations, identified in many mucosal melanomas, are emerging as promising treatments.Journal of the American Academy of Dermatology 05/2014; · 4.91 Impact Factor
KIT, NRAS and BRAF mutations in sinonasal
mucosal melanoma: a study of 56 cases
A Zebary*,1,3, M Jangard2,3, K Omholt1, B Ragnarsson-Olding1and J Hansson1
1Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden and2Department of
Oto-Rhino-Laryngology, Head and Neck Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Background: Mucosal melanomas in the head and neck region are most frequently located in the nasal cavity and paranasal
sinuses. Sinonasal mucosal melanoma (SNMM) comprises o1% of all melanomas. The aim was to determine the KIT, NRAS and
BRAF mutation frequencies in a large series of primary SNMMs.
Methods: Laser capture microdissection was used to isolate tumour cells from 56 formalin-fixed paraffin-embedded tumours. The
tumour cells were screened for KIT, NRAS and BRAF mutations by direct sequencing.
Results: Overall, 21% (12 out of 56) of SNMMs harboured KIT, NRAS or BRAF mutations. Mutations in these oncogenes occurred
in a mutually exclusive manner. Both KIT and BRAF mutations were identified at a similar frequency of 4% each (2 out of 56),
whereas NRAS mutations were detected in 14% (8 out of 56) of the SNMMs. Four of the NRAS mutations were located in exon 1.
Mutations in these oncogenes were significantly more common in melanomas located in the paranasal sinuses than in nasal cavity
(P¼0.045). In a multivariate analysis, patients with melanomas in the nasal cavity had a significantly better overall survival than
those with tumours in the paranasal sinuses (P¼0.027).
Conclusion: Our findings show that KIT and BRAF mutations, which are accessible for present targeted therapies, are only rarely
present in SNMMs, whereas NRAS mutations seem to be relatively more frequent. The data show that majority of SNMMs harbour
alterations in genes other than KIT, NRAS and BRAF.
Approximately 1–2% of all melanomas originate from the mucosal
membranes in the digestive, respiratory and genitourinary tracts
(Clifton et al, 2011; The National Board of Health and Welfare
(1960-2009)). Mucosal melanomas in the head and neck region are
most frequently located in the nasal cavity, followed by paranasal
sinuses and oral cavity (Jethanamest et al, 2011). Primary sinonasal
mucosal melanoma (SNMM), however, comprises o1% of all
melanomas (Clifton et al, 2011), and conversely, SNMMs amount
to only 1–9% of all malignant lesion of the nasal tract (Harbo et al,
1997; Norlander et al, 2003).
The incidence of SNMM in Sweden has increased significantly
from 1960 through 2000, although not at the same pace as that of
cutaneous melanoma (Jangard et al, 2013). For women, the
incidence has doubled and for men it almost tripled comparing
1960–1964 vs 1995–2000. Patients with SNMM have a poor
prognosis with 5-year survival rates of 20–28% (Lund et al, 2012;
Jangard et al, 2013).
The mitogen-activated protein kinase and phosphatidylinositol-
3 kinase-Akt pathways have critical roles in the pathogenesis of
melanoma. Activation of these pathways in cutaneous and mucosal
melanomas commonly occur through activating mutations in the
BRAF, NRAS and KIT genes (Jovanovic et al, 2008; Omholt et al,
2011). However, mucosal melanomas have a distinct genetic
background compared with cutaneous melanomas. For example,
the frequency of BRAF mutation is significantly higher in
melanoma arising in the trunk and skin without chronic sun
damage than in mucosal melanomas (Curtin et al, 2005; Ellerhorst
et al, 2011; Lee et al, 2011). On the other hand, NRAS mutations
are frequently detected in melanomas located in extremities and
skin with chronic sun damage (Ellerhorst et al, 2011; Lee et al,
*Correspondence: Dr A Zebary; E-mail: firstname.lastname@example.org
3These authors contributed equally to this work.
Received 4 April 2013; revised 13 June 2013; accepted 22 June 2013; published online 16 July 2013
& 2013 Cancer Research UK. All rights reserved 0007– 0920/13
Keywords: sinonasal melanoma; KIT; NRAS; BRAF
British Journal of Cancer (2013) 109, 559–564 | doi: 10.1038/bjc.2013.373
2011). Mucosal melanomas frequently harbour mutations and/or
amplifications of the KIT gene, but very rarely contain BRAF
mutations (Curtin et al, 2006; Beadling et al, 2008). Approximately
50 and 20% of cutaneous melanomas harbour BRAF and NRAS
mutations, respectively (Davies et al, 2002; Omholt et al, 2003;
Edlundh-Rose et al, 2006; Lee et al, 2011), whereas KIT mutations
are detected in about o2% of melanomas in skin without chronic
sun damage (Curtin et al, 2006; Handolias et al, 2010).
Interestingly, in a recent study of mucosal melanomas from
several different sites, we found a significantly higher frequency of
KIT mutations in vulvar melanomas compared with tumours of
other sites (35% vs 10%), suggesting that the KIT mutation rate in
mucosal melanomas varies with anatomical site (Omholt et al,
2011). So far, all of the published studies have analysed a small
number of SNMM samples and the reported frequencies of
mutations in SNMM vary considerably between these studies; KIT,
0–40%; NRAS, 22–60% and BRAF 0–6% (Cohen et al, 2004;
Beadling et al, 2008; Carvajal et al, 2011; Schoenewolf et al, 2012;
Turri-Zanoni et al, 2012).
Although most of the primary SNMMs are localised at
diagnosis, radical surgical resection is difficult (Bradley, 2006)
and therefore effective, alternative treatment options are essential
for patients with these tumours. Molecular targeted therapy is now
available for patients with malignant melanomas. A phase III trial
has shown that vemurafenib, a selective BRAF inhibitor, improves
both progression-free and overall survival compared with standard
systemic chemotherapy (Chapman et al, 2011). Phase II trials and
case reports have shown promising effects of targeted therapy with
imatinib and dasatinib for patients with KIT mutant melanomas
(Woodman and Davies, 2010; Carvajal et al, 2011). Very recently, a
phase II trial showed that patients with NRAS mutant melanomas
might benefit from treatment with MEK1/2 inhibitor (Ascierto
et al, 2013). These novel therapeutic advances stress the
importance of investigating the mutations in these oncogenes in
patients with SNMM.
Given the rarity of SNMM, the frequency of KIT, NRAS and
BRAF mutations has not been well characterised in these tumours.
The purpose of the current study was to evaluate a large number of
primary SNMMs in order to better define the frequency of KIT,
NRAS and BRAF mutations.
MATERIALS AND METHODS
Tumour samples. Archival materials of formalin-fixed paraffin-
embedded blocks of 61 SNMMs were collected from pathology
departments throughout Sweden. Patients were diagnosed between
1986 and 2011 and were reported to the Swedish National Cancer
Registry. All clinical records and pathological reports were
collected and reviewed. We retrieved information on diagnosis,
classification, disease site, overall survival and clinical features such
as clinically reported pigmentation of tumours and reports of
ulceration in pathological assessment. When data could not be
appropriately determined, they were coded as missing. Five
samples were excluded because the sections contained too few
tumour cells. Thus, overall 56 primary SNMMs were included and
12 of these cases were part of a previously published data set
(Omholt et al, 2011). This study was approved by the Research
Ethics Committee, Karolinska Institutet, Stockholm, Sweden.
Laser capture microdissection and DNA extraction. Sections of
5mm thickness were cut from formalin-fixed paraffin-embedded
blocks and placed on plain slides. Sections were deparaffinised with
two washes of xylene, rehydrated in increasing concentrations
of ethanol, rinsed with deionised water, shortly stained with
haematoxylin, rinsed with deionised water and dehydrated in
decreased concentrations of ethanol and two washes of xylene.
Tumour cells were microdissected from sections by laser capture
microdissection (LCM) using the Arcturus PixCell LCM System
(Arcturus Engineering, Mountain View, CA, USA) according to
the manufacturer’s recommendations. Samples were incubated
overnight with proteinase K-enriched digestion buffer (PicoPure
DNA Extraction KIT, Arcturus Engineering) to extract the DNA
from the dissected cells. Proteinase K was then inactivated by
heating samples at 951C for 10min.
Mutation analysis. Genomic DNA was subjected to first and
nested PCR to amplify BRAF (exon 15), NRAS (exons 1 and 2) and
KIT (exons 11, 13 and 17) genes. In the first PCR, the DNA was
amplified in a 10ml mixture reaction containing 2.5mM deox-
ynucleotide triphosphate, 5Uml?1platinumTaq DNA polymerase
(Invitrogen, Carlsbad, CA, USA), 50pmolml?1of each primer,
10? PCR buffer, 50mM MgCl2 and 10mgml?1bovine serum
albumin. Two microlitres of the first PCR reaction was used as
DNA template for the nested PCR. The DNA was extracted and
purified from agarose gels by using QIAquick Gel Extraction Kit
(Qiagen, Valencia, CA, USA). Sequencing reactions were per-
formed in a final volume of 20ml using BigDye Terminator V1.1
Cycle Sequencing kit (Applied Biosystems, Foster City, CA, USA).
The sequencing products were purified by ethanol precipitation,
and automated DNA sequencing was performed by ABI
PRISM3130xl Genetic Analyzer (Applied Biosystems). All muta-
tions were confirmed by a second independent PCR and
sequencing reaction. The primers used for amplification and
sequencing are described in Supplementary Table 1.
Statistical analysis. Fisher’s exact test was used to correlate the
mutation status with clinicopathological features such as gender,
ulceration, anatomical site and pigmentation. Age at diagnosis was
compared between the mutated and wild-type group using
Wilcoxon rank-sum test. Overall survival was estimated from
the date of diagnosis to the date of death or last follow-up
(1 November 2012). Patients who were alive at end of the study were
censored. Survival data were available for all patients. Multivariate
Cox regression model, Log-rank test and Kaplan–Meier graphs
were used to assess the association of anatomical site with overall
survival. All P-values were two-sided. P-valueso0.05 were
considered statistically significant.
Clinicopathological characteristics. Patient and tumour charac-
teristics are listed in Table 1. Overall, there were 35 females and
21 males with a median age at diagnosis of 76 years. Thirty-four
tumours were located in the nasal cavity and 22 in the paranasal
sinuses (10 in the maxillary sinuses, 6 in the ethmoid sinuses and 6
tumours invaded the surrounding structures: 4 involved the orbit;
one the skull base and another one spread to the retromaxillary
Mutation analysis. Of the 56 primary SNMMs analysed, 12 (21%)
harboured KIT, NRAS or BRAF mutations and 44 (79%) were wild
type. Mutations in KIT, NRAS and BRAF occurred in a mutually
exclusive manner. The difference between KIT, NRAS and BRAF
mutation frequencies in SNMMs was borderline significant
KIT mutations were detected in 2 of the 56 SNMMs (4%). Both
tumours with KIT mutations contained the hotspot mutation
L576P in exon 11 (Table 2). No mutations were observed in exons
13 and 17. In our previous study, we identified a much higher
frequency of KIT mutations in vulvar melanomas, with mutations
in 8 of 23 tumours (35%; Omholt et al, 2011). Thus, in our material
the difference between the updated results on KIT mutation
BRITISH JOURNAL OF CANCER
KIT, NRAS and BRAF mutations in sinonasal melanoma
frequency in SNMMs and that previously presented for vulvar
melanomas is statistically significant (P¼0.001).
NRAS mutations were identified in 8 (14%) and BRAF
mutations in 2 (4%) of the 56 SNMMs. Among the identified
NRAS mutations, four were found in exon 1 (G12C, G12D, G12A
and G13D) and four in exon 2 (Q61K, Q61R and Q61H (n¼2)).
The BRAF mutations consisted of one V600E and one V600K
change. Both BRAF mutated tumours were located in maxillary
sinuses (Table 2).
Association of mutations with clinicopathological features. As
the number of mutations identified was small, we compared the
clinicopathological features between tumours with KIT, NRAS or
BRAF mutations and those lacking these mutations. Tumours with
mutations were more likely to be located in the paranasal sinuses,
whereas the wild-type lesions were more often found in the nasal
cavity and the difference was statistically significant (P¼0.045,
Table 3). There was no difference between the mutated and wild-
type group with respect to age at diagnosis, gender, ulceration and
Survival. In univariate analysis, the age, anatomical site and
clinical stage were significantly associated with overall survival.
Patients with melanoma in the nasal cavity had a significantly
better prognosis than those with a tumour in the paranasal sinuses
(median survival, 39 vs 16 months; Log-rank P¼0.027; Figure 1).
This effect remained significant in a multivariate analysis after
adjusting for age at diagnosis, gender, ulceration, pigmentation and
clinical stage (P¼0.001). The mutation status of the tumours
showed no association with the overall survival.
Mutational data on SNMM are rare and there are only a few
published reports with limited number of tumours (listed in
Table 4). In this study, which is the largest of its kind, to our
knowledge, we screened primary SNMM for mutations in some of
the most commonly mutated oncogenes in cutaneous melanoma.
We identified KIT, NRAS and BRAF mutations in 4%, 14% and 4%
of tumours, respectively. The finding of KIT mutations in only 2 of
56 SNMMs suggests that KIT mutations differ between mucosal
melanomas at different sites, and that they are very rare in this
subtype of mucosal melanomas. Altogether, the present results and
those of our previous study on mucosal melanomas from several
different sites show that the KIT mutation frequency in SNMM is
Table 1. Patient and tumour characteristics
Age at diagnosis, year
Gender, n (%)
Anatomical site, n (%)
Ulceration, n (%)
Pigmentation, n (%)
Median survival, month (range)a
aLast updated on 1 November, 2012.
Table 2. Summary of mutations identified in primary SNMM (n¼56)
CaseGender AgeAnatomical site Gene ExonNucleotide change Amino-acid change
1F63 Nasal cavityKIT 11c.1727T4C p.L576P
2M 65 Maxillary sinusKIT11c.1727T4C p.L576P
3M 88Maxillary sinus NRAS1c.34G4Tp.G12C
5M 78Ethmoid sinusNRAS1 c.35G4Cp.G12A
6F 97Nasal cavityNRAS1c.38G4Ap.G13D
7M 70 Nasal cavityNRAS2c.181C4A p.Q61K
8F 58Maxillary sinus NRAS2c.182A4G p.Q61R
9M68 Maxillary sinusNRAS2 c.183A4C p.Q61H
10F82Nasal cavityNRAS2c.183A4C p.Q61H
11F 80Maxillary sinusBRAF 15 c.1799T4A p.V600E
12F 52Maxillary sinusBRAF15c.1798GT4AAp.V600K
Abbreviations: F¼female; M¼male; SNMM¼sinonasal mucosal melanoma.
KIT, NRAS and BRAF mutations in sinonasal melanoma
BRITISH JOURNAL OF CANCER
significantly lower than that in vulvar melanomas (Omholt et al,
2011). Our results are also supported by Schoenewolf et al (2012),
who in a recent study on sinonasal and vulvovaginal melanomas
found no KIT mutations in 12 sinonasal tumours compared with
5 mutations in 11 vulvovaginal tumours (45%). Beadling et al (2008)
also found a lower frequency of KIT mutations in melanomas of
the head and neck (3 of 36; 8%) compared with melanomas of the
anorectum/vulva/vagina (4 of 9; 44%).
In contrast to KIT mutations, the frequency of BRAF mutations
is generally low in mucosal melanomas and does not seem to vary
significantly between different sites (Omholt et al, 2011). In the
current study, BRAF mutations were identified in 4% of SNMMs,
which is similar to that detected in mucosal melanomas from other
sites such as the vulva, vagina and anorectum (Curtin et al, 2006;
Omholt et al, 2011).
The frequency of NRAS mutations that we identified in SNMM
(14%) seem to be similar to that seen in cutaneous melanomas
(Omholt et al, 2003; Edlundh-Rose et al, 2006; Lee et al, 2011).
Interestingly, however, the types of NRAS mutations that we
detected in SNMM differ from the types that predominate in
cutaneous melanomas. In cutaneous melanomas, substitutions of
glutamine for either arginine or lysine at codon 61 (Q61R and
Q61K) represent the two most common NRAS mutations (Hocker
and Tsao, 2007). In the current study, only two of eight NRAS-
mutated tumours contained either of these mutations, whereas two
had other alterations at codon 61 and four tumours contained
mutations at codon 12 or 13 in exon 1. This indicates that NRAS
mutations in mucosal melanomas, as opposed to cutaneous
melanomas, are present in exon 1 and 2 with similar frequencies
(Omholt et al, 2011; Turri-Zanoni et al, 2012). The NRAS
mutations at codon 12 and 13 also predominate in other
malignancies such as haematological cancers (Ward et al, 2012).
The different pattern of NRAS mutations in mucosal melanoma,
compared with cutaneous melanoma, possibly indicate an
aetiology hitherto unknown but different from UV-radiation.
Interestingly, we found that mucosal melanomas located in the
sinuses have a higher frequency of KIT, NRAS or BRAF mutations
than those located in the nasal cavity. We also found that patients
with disease emerging from the sinuses have a worse prognosis
compared with those with tumours originating from the nasal
cavity. This has also been observed in other studies (Lie ´tin et al,
2010; Jethanamest et al, 2011). In the current study, the poor
prognosis might be the result of more advanced tumour stage
because in six cases the paranasal tumours invaded the surround-
ing structures. It remains to be addressed whether the adverse
prognosis is associated with more aggressive biology and whether
this is linked to the presence of oncogene mutations. Here we
found no difference in overall survival between patients with
mutated melanomas and those with wild-type melanomas;
Survival time (years)
Number at risk
Figure 1. Overall survival of patients with SNMM located in the nasal
cavity and paranasal sinuses.
Table 4. Summary of KIT, NRAS and BRAF mutations in SNMM
5.9% (1/17) Cohen et al (2004) 17
Beadling et al (2008)298.4% (3/36)ab
Carvajal et al (2011)5 40.0% (2/5)60.0% (3/5)0.0% (0/5)
Schoenewolf et al (2012)120.0% (0/12)——
Turri-Zanoni et al (2012) 3212.5% (4/32) 21.9% (7/32)3.1% (1/32)
Current study563.6% (2/56) 14.3% (8/56)3.6% (2/56)
Total151 7.8% (11/141)19.3% (18/93) 2.9% (4/139)
Abbreviation: SNMM¼sinonasal mucosal melanoma; ‘—’¼not determined.
a29 melanomas were sinonasal and 7 were oral melanomas.
bThe NRAS mutation frequency was not specified by anatomical site.
Table 3. Association of mutation status with clinical features in primary
0.347Median age, year (range)
Gender, n (%)
Anatomical site, n (%)
Ulceration, n (%)
Pigmentation, n (%)
Abbreviation: SNMM¼sinonasal mucosal melanoma.
aMutated in KIT, NRAS or BRAF.
bWild type in KIT, NRAS and BRAF.
BRITISH JOURNAL OF CANCER
KIT, NRAS and BRAF mutations in sinonasal melanoma
however, the number of mutations identified are too small, which
can skew the results. In our previous study, we found that KIT
mutations as well as NRAS mutations associated with poor survival
in univariate but not in multivariate analysis (Omholt et al, 2011).
In contrast to our results, a recent Chinese study showed that KIT
mutations adversely affected survival (Kong et al, 2011); however,
in this report mucosal melanomas were combined with cutaneous
melanomas and a multivariate analysis was not performed.
The frequencies of KIT and BRAF mutations in SNMMs suggest
that only a minority of patients with SNMM may benefit from
treatment with KIT and BRAF inhibitors. The higher proportion of
NRAS-mutated tumours suggest that it may be worthwhile to
perform studies using MEK inhibitors, which have shown
promising phase II results in cutaneous melanoma with NRAS
mutations (Ascierto et al, 2013). It would be intriguing to
investigate whether tumours with codon 12–13 activating muta-
tions have similar therapeutic outcome as cutaneous melanomas
with codon 61 mutations. Mutation analysis might yield positive
results particularly in tumours from paranasal sinuses, as our
results indicate that tumours from these areas more probably
harbour mutations in KIT, NRAS or BRAF than the tumours from
the nasal cavity. Still, a majority of SNMM has other unknown
underlying oncogenic driver mutations that need to be addressed
in future studies. Very recently, a high frequency of somatic
mutations have been discovered in the promoter of telomerase
reverse transcriptase (TERT) in cutaneous melanoma, resulting in
increased transcriptional activity at the TERT promoter that might
act as driver mutations (Horn et al, 2013; Huang et al, 2013).
Presence of mutations in TERT promoter is still waiting to be
determined in mucosal melanomas.
In conclusion, our results show that KIT, NRAS and BRAF
mutations occur at low frequencies in SNMM, and confirm our
recent findings that the frequency of KIT in mucosal melanoma
mutations vary significantly between different anatomical sites.
We express our gratitude to Bo Nilsson for advice and help with
statistical analyses. Drs Lena Kanter and Lars Olding for help
with the re-evaluating tumour histopathology. We also thank Diana
Linde ´n, Lisa Viberg and Susanne Thorell for collecting tumour
samples. This study was financed by grants from the Swedish
Cancer Society, the Radiumhemmet Research Funds, the Karolinska
Institutet Research Funds and the ACTA Otolaryngologica
Foundation. The Ministry of Higher Education and Scientific
Research in Iraqi-Kurdistan Regional Government is acknowledged
for financial support (AZ).
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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