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First Received: 22.06.2021, Accepted: 16.08.2021 doi: 10.5505/aot.2021.25932
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Original Article
Molecular Characterization Reveals the Importance and Diversity of Germline
and Somatic RET Mutations in Cancer
Moleküler Karakterizasyonla Tespit Edilen Germline ve Somatik RET
Mutasyonlarının Kanserdeki Önemi ve Çeşitliliği
İbrahim Şahin1, Haktan Bağış Erdem2
1Department of Medical Genetics, University of Health Sciences, Dışkapı Yıldırım Beyazıt Training
and Research Hospital, Ankara, Turkey
2Department of Medical Genetics, University of Health Sciences, Dr. Abdurrahman Yurtaslan Ankara
Oncology Training and Research Hospital, Ankara, Turkey
ABSTRACT
Aim: Many individuals die due to cancer, and both doctors and researchers work hard to offer accurate
illness, diagnosis, and prognosis monitoring, as well as resistance prediction.
Methods: A liquid biopsy and hereditary cancer panels were performed on 25 patients to examine the
importance, spectrum, and diversity of RET germline and somatic mutations. Most of the patients visited
the clinic with the diagnosis of advanced resistant cancers or hereditary cancer (MEN2). Two groups
were formed: the first group was germline (n=7, 28%), and the second was somatic (n=18, 72%). For
somatic, Tier I-II-III variants; for germline, pathogenic, likely pathogenic, and VUS variants have been
included in the study.
Results: The mean age was 54.64. There were significantly more female participants (n=14, 56%) than
males (n=11, 44%). In the germline group, the most common mutation was ‘RET:c.2410G>A’. Nine
mutations were nonsense or frameshift in the somatic group, and the most common mutations were
‘RET:c.2324delinsGAC’ and ‘RET:c.1784A>G’. Nonsense or frameshift RET variants showed a higher
incidence in the somatic group.
Conclusion: To the best of our knowledge, this is the first research to concentrate on RET mutations in
the context of genetic variability between germline and somatic variants. The current of the study results
indicate that patients with solid tumors, particularly breast cancer, should undergo RET sequencing to
evaluate clinical features and prognosis. Discoveries about the structure and functions of RET gene will
lead to more clinically relevant treatment approaches for cancer patients and will play an essential role
in improving individual risk prediction, treatment, and prognosis.
Keywords: Liquid biopsy, MEN2, RET
ÖZET
Amaç: Pek çok kişi kanser nedeniyle ölmekte. Hem doktorlar hem de araştırmacılar, doğru hastalık,
teşhis ve prognoz takibinin yanı sıra direnç tahmini sunmak için çok çalışıyorlar.
Gereç ve Yöntem: RET germline ve somatik mutasyonların önemini, spektrumunu ve farkını incelemek
için 25 hastaya likit biyopsi ve ailesel kanser paneli uygulandı. Hastaların çoğu ileri dirençli kanser ve /
veya kalıtsal kanser (MEN2) tanısıyla kliniği ziyaret etti. Toplam iki grup oluşturuldu: birinci grup
germline (n=7, %28) ve ikincisi somatik (n= 8, %72). Somatik için, Tier I-II-III varyantları ve germline
için patojenik, muhtemelen patojenik ve VUS varyantları çalışmaya dahil edilmiştir.
Bulgular: Ortalama yaş 54.64 idi. Kadın katılımcılar (n=14, %56) erkeklerden (n=11, %44) önemli
ölçüde daha fazla idi. Germline grubunda en yaygın mutasyon "RET: c.2410G>A" idi. Somatik grupta,
dokuz mutasyon nonsense veya çerçeve kaymasıydı ve en yaygın mutasyonlar "RET:
c.2324delinsGAC" ve "RET: c.1784A>G" idi. Nonsense veya çerçeve kayması RET varyantları,
somatik grupta daha yüksek bir insidans gösterdi.
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Acta Oncologica Turcica 2021; 54: 273-280
Sonuç: Bildiğimiz kadarıyla bu, germline ve somatik varyantlar arasındaki genetik değişkenlik
bağlamında RET mutasyonlarına odaklanan ilk araştırmadır. Mevcut çalışmanın sonuçları, solid
tümörlü hastaların, özellikle meme kanserinin, klinik özellikleri ve prognozu değerlendirmek için RET
sekansına tabi tutulması gerektiğini göstermektedir. RET geninin yapısı ve işlevleri hakkındaki keşifler,
kanser hastaları için klinik olarak daha uygun tedavi yaklaşımlarına yol açacak ve bireysel risk tahmini,
tedavisi ve prognozunun iyileştirilmesinde önemli bir rol oynayacaktır.
Anahtar Kelimeler: Likit biyopsi, MEN2, RET
Introduction
Receptor tyrosine kinases regulate cell
development and differentiation. Some of
them have been shown to behave as
oncogenes in human malignancies. RET
(rearranged during transfection) is a trans-
membrane receptor tyrosine kinase that may
act as both a growth factor receptor and an
oncogenic protein. It is triggered by a complex
that includes a soluble glial cell line-derived
neurotrophic factor (GDNF) family ligand
(GFL) and a glycosylphospha-tidylinositol-
anchored co-receptor, GDNF family receptors
a (GFRa) [1]. GDNF, neurturin (NRTN),
artemin (ARTN), and persephin (PSPN) are
four distinct GFLs that can bind to and
selectively activate RET through their
homologous co-receptors GFRa1–4. RET has
multiple activities in diverse tissues as a signal
transducer of four separate ligand/co-receptor
complexes. It is required for the development
of the enteric nervous system as well as the
regulation of the development of sympathetic,
parasympa-thetic, motor, and sensory neurons
[2].
The RET protein is a receptor tyrosine kinase
that seems to transduce growth and
differentiation signals in a variety of
developmental tissues, including neural crest-
derived tissues. The protein comprises an
extracellular domain containing a ligand-
binding domain, a cadherin-like domain, and
a cysteine-rich region proximal to the cell
membrane. It includes one transmembrane
domain and two tyrosine kinase subdomains,
TK1 and TK2 [3].
Somatic and germline mutations in the same
tumor suppressor gene are widely known, as
detailed in Knudson's two-mutation paradigm
[4]. Similarly, somatic and germline
mutations in the RET protooncogene have
been discovered in a number of hereditary and
non-hereditary human disorders, including
multiple endocrine neoplasia (MEN) 2A and
2B, papillary thyroid cancer, and other
cancers [5].
Multiple endocrine neoplasia type 2 (MEN2),
sometimes referred to as Sipple’s syndrome,
is linked with medullary thyroid carcinoma
(MTC) and hyperplasia of thyroid C cells. It is
an autosomal dominant genetic disorder
caused by a mutation in the RET proto-
oncogene on chromosome 10, which results in
the development of two or more endocrine
adenomas or hyperplasia in the same patient,
either simultaneously or sequentially, and
resulting in the clinical condition defined by
hyperfunctioning glands [6].
MEN2 is classified clinically as MEN2A,
MEN2B, and familial medullary thyroid
cancer, with MEN2A being the most frequent
subtype [1]. Medullary thyroid cancer (MTC),
pheochromocytoma (PHEO), and hyper-
parathyroidism are all characteristics of
MEN2A. Additionally, a tiny percentage of
people develop skin lichen amyloidosis or
Hirschsprung’s disease. MTC is often the
initial symptom of this subtype, with a near-
100 percent prevalence. When patients are
hospitalized, the majority have already
advanced to MTC or have lymph node
metastases. MTC is the leading cause of
mortality in people with MEN2A, and 50% of
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Acta Oncologica Turcica 2021; 54: 273-280
patients are at risk of recurrence [7]. MTC or
MEN2A, on the other hand, may manifest
differently in family members. Specifically,
fundamental lesions may be entirely or
partially manifested, lesions in the affected
endocrine glands may arise at various time
intervals (which may be many years), and
numerous endocrine glands may sometimes
be affected and demonstrate concurrent start.
At the moment, individuals with MEN2A who
demonstrate MTC as an early symptom are
often misdiagnosed [1].
Numerous malignancies are known to be
oncogene-dependent: oncogene addiction has
been shown in a variety of neoplasms [8].
Somatic RET gene fusions are known to be
oncogenic drivers in a variety of tumor types
and are seen in 1–2% of non-squamous
NSCLC patients. Fusions of the RET gene
result in the formation of chimeric, cytosolic
proteins containing a constitutively active
RET kinase domain [9]. The recent approval
of numerous tumor-agnostic medications by
the Food and Drug Administration has
resulted in a paradigm shift in cancer therapy
away from organ/histology-specific strategies
and toward biomarker-guided treatments.
Selpercatinib (LOXO-292), a novel RET-
specific tyrosine kinase inhibitor, has shown
exceptional effectiveness in cancers with RET
fusions or mutations, most notably RET
fusion-positive NSCLC and RET-mutated
MTC [10].
Liquid biopsy techniques have been used to
treat a variety of different forms of cancer in
recent years. A liquid biopsy is utilized in
tumors to determine the patient’s recovery,
prognosis, and even diagnosis. During
apoptosis, tumor cells lose fragments of
biomarkers. These materials’ cellular
components may be examined for genetic
abnormalities. This less intrusive testing
procedure provides a greater likelihood of a
favorable outcome and a better probability of
correct findings [11,12].
In this study, we performed a liquid biopsy
and hereditary cancer panel on 25 patients to
examine the importance, spectrum, and
difference of germline and somatic RET
mutations. Our data broadens the RET
mutations and provides insights for the
diversity and characteristics of somatic and
germline RET mutations.
Materials and methods
Patients
Consent for the publication of the study and
any additional related information was taken
from the patients or their parents involved in
the study. The Ethics Committee approved
(2021-03/1072) the study at the University of
Health Sciences, Dr. Abdurrahman Yurtaslan
Ankara Oncology Training and Research
Hospital. Twenty-five patients visited the
clinic with the diagnosis of advanced resistant
cancers or hereditary cancer (MEN2). Clinical
histories and molecular results were reviewed
for all unrelated patients examined at the
Department of Medical Genetics, University
of Health Sciences, Dışkapı Yıldırım Beyazıt
Training and Research Hospital, and
Department of Medical Genetics, University
of Health Sciences, Dr. Abdurrahman
Yurtaslan Ankara Oncology Training and
Research Hospital, Ankara, Turkey. The
patients underwent the comprehensive liquid
biopsy and hereditary cancer panel between
January 2018 and December 2020 at the
Ankara Central Genetic Laboratory (Turkey).
In the study, a total of two groups were
formed. The first group was germline (n=7,
28%) and the second was somatic (n=18,
72%).
DNA Panels and NGS
From the blood samples collected in EDTA
tubes, the patients’ genomic DNA was
extracted according to the manufacturer’s
standard procedure using the QIAamp DNA
Blood Midi Kit (Qiagen Inc., Hilden,
Germany) by QIAcube (Qiagen Inc.,
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Acta Oncologica Turcica 2021; 54: 273-280
Mississauga, ON, Canada). The DNA samples
were quantified with a NanoDrop 1000
spectrophotometer (Thermo Fisher Scientific
Inc., MA, USA).
Two different multigene panels have been
used for liquid biopsy testing depending on
the dates: ArcherDx Reveal ctDNA 28 Kit and
Sophia Genetics 56 G Oncology. The Sophia
Genetics 56G Oncology Solution was used at
the center from 2018 to 2020, and the
ArcherDx Reveal ctDNA 28 Kit has been used
since 2020. The data were analyzed on the
Archer Analysis Platform (ArcherDX, Inc.,
CO, USA) for the ArcherDx Reveal ctDNA
28 Kit and Sophia DDM software (Sophia
Genetics, Saint‐Sulp) for the Sophia Genetics
56G Oncology Solution.
For hereditary cancers, two different
multigene panels were used depending on the
dates: the Qiagen QIAseq Hereditary Custom
Cancer Panel (from 2017 to 2018) and the
Sophia Hereditary Cancer Solution Panel
(since 2018). The sequencing was performed
on an Illumina MiSeq system (Illumina Inc.,
San Diego, CA, USA). The data were
analyzed using QIAGEN Clinical Insight
(QCI™) Analyze software (Qiagen Inc.,
Hilden, Germany) for the Qiagen QIAseq
Hereditary Custom Cancer Panel and with
Sophia DDM software (Sophia Genetics,
Saint‐Sulp) for the Hereditary Cancer
Solution (v1.1) panel. Visualization of the
data was performed with IGV 2.7.2 (Broad
Institute) software.
Interpretations, Descriptive Statistics &
Graphics
In compliance with the recommendations
issued by the American College of Medical
Genetics and Genomics and the Association
for Molecular Pathology, germline variants
were categorized as pathogenic, likely
pathogenic, variant of uncertain significance
(VUS), likely benign, and benign [13].
Pathogenic, likely pathogenic, and strong
VUS (supports clinical phenotype and no
other responsible mutation detected)
variations were included in the study. Somatic
variants were categorized as tier I, variants
with strong clinical significance; tier II,
variants with potential clinical significance;
tier III, variants with unknown clinical
significance; and tier IV, variants that are
benign or likely benign, in compliance with
the recommendations issued by the
Association for Molecular Pathology,
American Society of Clinical Oncology, and
College of American Pathologists [14]. Tier I-
II-III variations have been included in the
study. Further, descriptive statistical
calculations have been done, and the graphic
has been prepared with Python 3.9.2 (IPython
7.19.0).
Results
The mean age was 54.64, with a minimum age
of 35 and a maximum of 70. There were six
patients below 50 years of age, and all of them
were females. There were significantly more
female participants (n=14, 56%) than males
(n=11, 44%) (Table 1-2).
In the germline group, the mean age was
50.57, and all the mutations were missense
and heterozygous. There were three
pathogenic, two likely pathogenic, and two
variant of uncertain significance (VUS)
variants. The most common mutation was
‘RET:c.2410G>A’ (Table 1, Figure 1).
In the somatic group, the mean age was 56.22,
and the variant fractions were between 0.1-
10%. The majority of the patients have
advanced-metastatic cancers. Nine mutations
were nonsense or frameshift. The most
common mutations detected were
‘RET:c.2324delinsGAC’ and ‘RET:c.1784
A>G’. The ‘RET:c.2324delinsGAC’ mutation
has been observed seven times. (Figüre 1) In
breast cancer, frameshift RET mutations were
more predominant when compared with other
groups (Table 2).
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Table 1. RET germline mutations
Gender
Age
Indication
Gene
Mutation
Protein
Zygosity
Pathogenicity
F
53
colon
RET
c.1681A>T
p.Ser561Cys
heterozygous
Likely Pathogenic
F
35
MEN2
RET
c.224C>T
p. Thr75Met
heterozygous
Likely Pathogenic
F
41
MEN2
RET
c.785T>C
p.Val262Ala
heterozygous
VUS
M
67
MEN2
RET
c.341G>A
p.Arg114His
heterozygous
VUS
M
52
MEN2
RET
c.2370G>T
p.Leu790Phe
heterozygous
Pathogenic
F
56
MEN2
RET
c.2410G>A
p.Val804Met
heterozygous
Pathogenic
M
50
MEN2
RET
c.2410G>A
p.Val804Met
heterozygous
Pathogenic
Table 2. RET somatic mutations
Figure 1. Somatic and germline RET mutations.
Bar plots showing the somatic (A) and germline (B) RET mutations in the study.
Gender
Age
Indication
Gene
Mutation
Protein
F
53
advanced-metastatic
RET
c.1162G>A
p.Val388Ile
M
58
advanced-metastatic
RET
c.1784A>G
p.Glu595Gly
M
61
advanced-metastatic
RET
c.2071G>A
p.Gly691Ser
F
59
advanced-metastatic
RET
c.2372A>T
p.Tyr791Phe
M
66
advanced-metastatic
RET
c.1972C>T
p.His658Tyr
M
60
advanced-metastatic
RET
c.2324delinsGAC
p.Glu775Glyfs*6
F
48
breast
RET
c.1906A>C
p.Thr636Pro
M
62
advanced-metastatic
RET
c.1784A>G
p.Glu595Gly
M
51
advanced-metastatic
RET
c.1784A>G
p.Glu595Gly
F
37
breast
RET
c.2338_2339insC
p.Lys780Thrfs*64
F
69
breast
RET
c.2324delinsGAC
p.Glu775Glyfs*6
F
46
breast
RET
c.2324delinsGAC
p.Glu775Glyfs*6
M
57
advanced-metastatic
RET
c.2324delinsGAC
p.Glu775Glyfs*6
F
55
breast
RET
c.2324delinsGAC
p.Glu775Glyfs*6
F
37
breast
RET
c.2324delinsGAC
p.Glu775Glyfs*6
M
58
advanced-metastatic
RET
c.2341C>T
p. Gln781Ter
F
70
lung
RET
c.2324delinsGAC
p.Glu775Glyfs*6
F
65
advanced-metastatic
RET
c.2657G>A
p.Arg886Gln
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Discussion
Mutations in the RET gene result in various
clinical symptoms and disease manifestations
[2]. Based on RET’s normal function, it is
conceivable to identify various probable
explanations for the disparate phenotypes.
The signaling capability of various RET
variants may be determined by subcellular
location, substrate selectivity, turnover rate,
percentage of activated RET, and genetic
background. As a result, distinct types of
clinical symptoms associated with RET may
need treatment with different sorts of
medications targeting specific domains of
RET [2].
While germline mutations in codons 768
(exon 13), 804 (exon 14), and 891 (exon 15)
are strongly related to MTC, they account for
a small proportion of cases. These locations
are located inside the domain of the
intracellular tyrosine kinase. Exon 13
mutations are less prevalent in MEN2A/MTC
(codons 790 and 791). Gatekeeper mutations
in codon 804 have been found. Codon 804
mutation was found in two patients in the
germline group in this study. (Figure 1)
Changes at this location affect access to the
RET ATP-binding domain, resulting in
decreased sensitivity to some RET-targeting
multi-kinase inhibitors [15]. Mutations in the
intracellular TK2 domain are responsible for
MEN2B-associated malignancies. A single
918 Met to Thr mutation in exon 16 accounts
for almost 95% of MEN2B cases and is
unique to this illness. Met 918 is a crucial
component of the substrate recognition pocket
found in the RET protein’s tyrosine kinase
catalytic core. Mutations arise as new (de
novo) germline alterations in more than 50%
of cases of MEN2B with codon 918
mutations. Another mutation, alanine to
phenylalanine at codon 883 in exon 15, was
discovered in some unrelated MEN2B
relatives [16]. Dual (tandem) mutations in
codons 804 and 806 or 804 and 904 may result
in atypical MEN2B [17].
MEN2 RET mutations in the germline result
in a gain of function. This contrasts with many
other hereditary predispositions to neoplasia,
which is caused by heritable “loss-of-
function” mutations in tumor suppressor
proteins. The functional restrictions imposed
by such activating lesions are likely
responsible for the rarity of RET mutations, a
regulation that benefits molecular diagnostics
in this condition [18].
Extensive research on large families
demonstrates a clear genotype-phenotype
link. MEN2B has a higher rate of morbidity
and death than MEN2A. Survival is
comparable between individuals with
MEN2B and those with spontaneous MTC
who had somatic RET mutations identical to
the most prevalent germline mutations
causing MEN2B. The genotype also affects
the age at which MTC is first diagnosed and
the result of thyroidectomy [19].
RET gene rearrangements are essential for
solid tumors. In this study, nonsense and
frameshift RET mutations were frequent in
the somatic group, particularly breast cancer.
‘RET, c.2324delinsGAC, p.Glu775Glyfs* 6’
mutation was the most common. (Table 2,
Figure 1) All the nonsense and frameshift
RET mutations were on the 13th exon and in
the kinase domain. The majority of the
somatic group mutations were around the
kinase domain. Most of the kinase domain
RET mutations are oncogenic and associated
with poor prognosis and drug resistance,
particularly in thyroid cancers [20].
In contrast to the germline group, frameshift
and kinase domain RET mutations were
predominant in the somatic group. Many
nonsense and frameshift RET mutations are
also associated with gain of function
according to databases (OncoKB), and they
are likely oncogenic, unlike other genes.
These mutations, particularly ‘RET,
c.2324delinsGAC, p.Glu775Glyfs*6’, could
be responsible for drug resistance,
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Acta Oncologica Turcica 2021; 54: 273-280
progression, and metastasis. Further studies
are needed to clarify the roles of these
nonsense and frameshift RET mutations.
The current study’s results indicate that
patients with solid tumors, particularly
advanced-metastatic cancers and breast
cancer, should undergo RET sequencing to
evaluate clinical features and prognosis.
Discoveries about the structure and functions
of RET gene will lead to more clinically
relevant treatment approaches for cancer
patients and will play an essential role in
improving individual risk prediction,
treatment, and prognosis.
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Corresponding author e-mail: ibrahimsahinmd@gmail.com
Orcid ID:
İbrahim Şahin 0000-0002-6050-816X
Haktan Bağış Erdem 0000-0002-4391-1387
Doi: 10.5505/aot.2021.25932
