Background: We reported that a novel oncosuppressor-mutated cell (OMC)-based platform has the potential for early cancer detection in healthy individuals and for identification of cancer patients at risk of developing metachronous metastases. Objective: Herein, we sought to determine the diagnostic accuracy of this novel OMC-based platform in a consecutive cohort of patients operated for suspicious head and neck masses. Methods: OMCs (BRCA1-deficient fibroblasts) were exposed to blood serum from patients with head and neck nodules before surgical removal. These cells were analyzed for their proliferation and survival. Treated OMCs were inoculated subcutaneously in NOD/SCID mice, and tumor growth was monitored over time. Results: OMCs exposed to serum from patients with malignant lesions displayed increased proliferation compared to those exposed to serum from patients with benign lesions. Only OMCs exposed to serum from patients diagnosed with malignant thyroid neoplasia generated a cancerous mass. The sensitivity of the test was 92%, with only 1 false negative out of 34 patients. Immunohistochemical staining showed that the cancerous masses were poorly differentiated adenocarcinomas with high proliferative index. Conclusions: These data show that liquid biopsy combined with an OMC-based in vivo platform has the potential to diagnose benign head and neck masses and predict whether a thyroid nodule is malignant. These results strengthen the concept that OMCs can be used to detect circulating malignant factors in cancer patients.

1.
Haynes
J
,
Arnold
KR
,
Aguirre-Oskins
C
,
Chandra
S
.
Evaluation of neck masses in adults
.
Am Fam Physician
.
2015
;
91
(
10
):
698
706
..
2.
Guth
S
,
Theune
U
,
Aberle
J
,
Galach
A
,
Bamberger
CM
.
Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination
.
Eur J Clin Invest
.
2009
;
39
(
8
):
699
706
. .
3.
Asa
SL
.
The current histologic classification of thyroid cancer
.
Endocrinol Metab Clin North Am
.
2019
;
48
(
1
):
1
22
. .
4.
Hincza
K
,
Kowalik
A
,
Kowalska
A
.
Current knowledge of germline genetic risk factors for the development of non-medullary thyroid cancer
.
Genes
.
2019
;
10
(
7
):
482
.
5.
Cancer Fast Stats National Cancer Institute
. Available from: http://seer.cancer.gov/explorer/ Accessed 2020 Jul.
6.
Brito
JP
,
Al Nofale
A
,
Montori
VM
,
Hay
ID
,
Morris
JC
.
The impact of subclinical disease and mechanism of detection on the rise in thyroid cancer incidence: a population-based study in Olmsted County, Minnesota during 1935 through 2012
.
Thyroid
.
2015
;
25
(
9
):
999
1007
. .
7.
Du
L
,
Wang
Y
,
Sun
X
,
Li
H
,
Geng
X
,
Ge
M
, et al.
Thyroid cancer: trends in incidence, mortality and clinical-pathological patterns in Zhejiang Province, Southeast China
.
BMC Cancer
.
2018
;
18
:
291
. .
8.
International Agency for Research in Cancer (IARC), World Health Organization
.
2018
. Available from: http://gco.iarc.fr/today/fact-sheets-cancers. Accessed 2020 Jul.
9.
Goodarzi
E
,
Moslem
A
,
Feizhadad
H
,
Jarrahi
A
,
Adineh
H
,
Sohrabivafa
M
.
Epidemiology, incidence and mortality of thyroid cancer and their relationship with the human development index in the world: an ecology study in 2018
.
Advances Hum Biol
.
2019
;
9
(
2
):
162
7
.
10.
Jegerlehner
S
,
Bulliard
JL
,
Aujesky
D
,
Rodondi
N
,
Germann
S
,
Konzelmann
I
, et al.
Overdiagnosis and overtreatment of thyroid cancer: a population-based temporal trend study
.
PLoS One
.
2017
;
12
(
6
):
e0179387
. .
11.
Panato
C
,
Serraino
D
,
De Santis
E
,
Firgiarina
O
,
Angelin
T
,
Bidoli
E
, et al.
Thyroid cancer in Friuli Venezia Giulia, northeastern Italy: incidence, overdiagnosis, and impact of type of surgery on survival
.
Tumori
.
2019
;
105
(
4
):
296
303
. .
12.
Brito
JP
,
Davies
L
.
Is there really an increased incidence of thyroid cancer?
Curr Opin Endocrinol Diabetes Obes
.
2014
;
21
(
5
):
405
8
. .
13.
Saint-Martin
C
,
Dramé
M
,
Dabakuyo
S
,
Kanagaratnam
L
,
Arveux
P
,
Schvartz
C
.
Overdiagnosis of thyroid cancer in the Marne and Ardennes Departments of France from 1975 to 2014
.
Ann Endocrinol
.
2017
;
78
(
1
):
27
32
. .
14.
Godoi Cavalheiro
B
,
Kober Nogueira Leite
A
,
Luongo de Matos
L
,
Miazaki
AP
,
Lentile
JM
,
Kulcsar
MAV
, et al.
Malignancy rates in thyroid nodules classified as bethesda categories III and IV: retrospective data from a Tertiary Center
.
Int J Endocrinol Metab
.
2017 Dec 13
;
16
(
1
):
e12871
. .
15.
Xing
M
,
Haugen
BR
,
Schlumberger
M
.
Progress in molecular-based management of differentiated thyroid cancer
.
Lancet
.
2013
;
381
(
9871
):
1058
69
. .
16.
Jara
SM
,
Bhatnagar
R
,
Guan
H
,
Gocke
CD
,
Ali
SZ
,
Tufano
RP
.
Utility of BRAF mutation detection in fine-needle aspiration biopsy samples read as “suspicious for papillary thyroid carcinoma”
.
Head Neck
.
2015
;
37
(
12
):
1788
93
. .
17.
Pancer
J
,
Mitmaker
E
,
Ajise
O
,
Tabah
R
,
How
J
.
A thyroid gland with over 30 foci of papillary thyroid carcinoma with activating BRAF V600E mutation
.
Endocrinol Diabetes Metab Case Rep
.
2019 Mar 18
;
2019
:
19-0006
. .
18.
Kay-Rivest
E
,
Tibbo
J
,
Bouhabel
S
,
Tamilia
M
,
Leboeuf
R
,
Forest
V-I
, et al.
The first Canadian experience with the Afirma® gene expression classifier test
.
J Otolaryngol Head Neck Surg
.
2017
;
46
:
25
. .
19.
Abdel-Mageed
ZY
,
Yang
Y
,
Thomas
R
,
Ranjan
M
,
Mondal
D
,
Moroz
K
, et al.
Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes
.
Stem Cells
.
2014
;
32
:
983
97
. .
20.
García-Olmo
DC
,
Domínguez
C
,
García-Arranz
M
,
Anker
P
,
Stroun
M
,
Garcia-Verdugo
JM
, et al.
Cell-free nucleic acids circulating in the plasma of colorectal cancer patients induce the oncogenic transformation of susceptible cultured cells
.
Cancer Res
.
2010
;
70
:
560
7
. .
21.
Trejo-Becerril1
C
,
Perez-Cardenas
E
,
Taja-Chayeb
L
,
Anker
P
,
Herrera-Goepfert
R
,
Medina-Velazquez
LA
, et al.
Cancer progression mediated by horizontal gene transfer in an in vivo model
.
PLoS One
.
2012
;
7
(
12
):
e52754
.
22.
Abdouh
M
,
Zhou
S
,
Arena
V
,
Arena
M
,
Lazaris
A
,
Onerheim
R
, et al.
Transfer of malignant trait to immortalized human cells following exposure to human cancer serum
.
J Exp Clin Cancer Res
.
2014
;
33
(
1
):
86
. .
23.
Hamam
D
,
Abdouh
M
,
Gao
Z-H
,
Arena
V
,
Arena
M
,
Arena
GO
.
Transfer of malignant trait to BRCA1 deficient human fibroblasts following exposure to serum of cancer patients
.
J Exp Clin Cancer Res
.
2016
;
35
:
80
. .
24.
Abdouh
M
,
Hamam
D
,
Gao
ZH
,
Arena
V
,
Arena
M
,
Arena
GO
.
Exosomes isolated from cancer patients’ sera transfer malignant traits and confer the same phenotype of primary tumors to oncosuppressor-mutated cells
.
J Exp Clin Cancer Res
.
2017
;
36
(
1
):
113
. .
25.
Abdouh
M
,
Floris
M
,
Gao
ZH
,
Arena
V
,
Arena
M
,
Arena
GO
.
Colorectal cancer-derived extracellular vesicles induce transformation of fibroblasts into colon carcinoma cells
.
J Exp Clin Cancer Res
.
2019a
;
38
(
1
):
257
. .
26.
Abdouh
M
,
Gao
ZH
,
Arena
V
,
Arena
M
,
Burnier
MN
,
Arena
GO
.
Oncosuppressor-mutated cells as a liquid biopsy test for cancer-screening
.
Sci Rep
.
2019b
;
9
(
1
):
2384
. .
27.
Maksimovic
S
,
Jakovljevic
B
,
Gojkovic
Z
.
Lymph Node metastases papillary thyroid carcinoma and their importance in recurrence of disease
.
Med Arch
.
2018
;
72
(
2
):
108
11
. .
28.
Chang
YW
,
Kim
HS
,
Jung
SP
,
Kim
HY
,
Lee
JB
,
Bae
JW
, et al.
Significance of micrometastases in the calculation of the lymph node ratio for papillary thyroid cancer
.
Ann Surg Treat Res
.
2017
;
92
(
3
):
117
22
. .
29.
Choi
JB
,
Lee
WK
,
Lee
SG
,
Ryu
H
,
Lee
CR
,
Kang
SW
, et al.
Long-term oncologic outcomes of papillary thyroid microcarcinoma according to the presence of clinically apparent lymph node metastasis: a large retrospective analysis of 5,348 patients
.
Cancer Manag Res
.
2018
;
10
:
2883
91
. .
30.
Kaliszewski
K
,
Diakowska
D
,
Wojtczak
B
,
Forkasiewicz
Z
,
Pupka
D
,
Nowak
L
, et al.
Which papillary thyroid microcarcinoma should be treated as “true cancer” and which as “precancer”?
World J Surg Oncol
.
2019
;
17
:
91
. .
31.
Aydoğan
BI
,
Ersöz
CC
,
Sak
SD
,
Gullu
S
.
The association between lymph node metastasis and molecular markers in differentiated thyroid cancer
.
Acta Endocrinologica
.
2018
;
14
(
1
):
55
65
.
32.
Ng
SC
,
Kuo
SF
,
Chen
ST
,
Hsueh
C
,
Huang
B-Y
,
Lin
J-D
.
Therapeutic outcomes of patients with multifocal papillary thyroid microcarcinomas and larger tumors
.
Int J Endocrinol
.
2017
;
2017
:
4208178
. .
33.
Loyd
RV
,
Osamura
RY
,
Kloppel
G
,
Rosai
J
.
WHO Classification of tumours of endocrine origins
. 4th ed.
Lyon, France
:
International Agency for Research on Cancer
;
2017
.
34.
Abdouh
M
,
Hamam
D
,
Arena
V
,
Arena
M
,
Alamri
H
,
Arena
GO
.
Novel blood test to predict neoplastic activity in healthy patients and metastatic recurrence after primary tumor resection
.
J Circ Biomark
.
2016
;
5
:
1849454416663661
. .
35.
Parente
DN
,
Kluijfhout
WP
,
Bongers
PJ
,
Verzijl
R
,
Devon
KM
,
Rotstein
LE
, et al.
Clinical safety of renaming encapsulatyed follicular variant of papillary thyroid carcinoma: is NIFTP truly benign?
World J Surg
.
2018
;
42
:
321
6
.
36.
Lindforss
U
,
Zetterquist
H
,
Papadogiannakis
N
,
Olivecrona
H
.
Persistence of K-ras mutations in plasma after colorectal tumor resection
.
Anticancer Res
.
2005
;
25
:
657
61
.
37.
Ryan
BM
,
Lefort
F
,
McManus
R
,
Daly
J
,
Keeling
PWN
,
Kelleher
D
.
A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up
.
Gut
.
2003
;
52
:
101
8
. .
38.
Wong
KC
,
Chen
J
,
Zhang
J
,
Lin
J
,
Yan
S
,
Zhang
S
, et al.
Early cancer detection from multianalyte blood test results
.
iScience
.
2019
;
15
:
332
41
. .
39.
Schillaci
O
,
Fontana
S
,
Monteleone
F
,
Taverna
S
,
Di Bella
MA
,
Di Vizio
D
, et al.
Exosomes from metastatic cancer cells transfer amoeboid phenotype to non-metastatic cells and increase endothelial permeability: their emerging role in tumor heterogeneity
.
Sci Rep
.
2017
;
7
(
1
):
4711
. .
40.
Balaj
L
,
Lessard
R
,
Dai
L
,
Cho
Y-J
,
Pomeroy
SL
,
Breakefield
XO
, et al.
Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences
.
Nat Commun
.
2011
;
2
:
180
. .
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