J Gynecol Oncol.

2019 Jul;30(4):e52
https://doi.org/10.3802/jgo.2019.30.e52
pISSN 2005-0380·eISSN 2005-0399

Original Article Human papillomavirus genotype-

specific risk in cervical carcinogenesis
Kyeong A So ,1 In Ho Lee ,2 Ki Heon Lee ,2 Sung Ran Hong ,3
Young Jun Kim ,4,5 Hyun Hee Seo ,4 Tae Jin Kim 1
1
Department of Obstetrics and Gynecology, Konkuk University School of Medicine, Seoul, Korea
Department of Obstetrics and Gynecology, Cheil General Hospital & Women's Healthcare Center, Dankook
2

University College of Medicine, Seoul, Korea

Department of Pathology, Cheil General Hospital & Women's Healthcare Center, Dankook University
3

College of Medicine, Seoul, Korea

4
Laboratory of Research and Development for Genomics, Cheil General Hospital and Women's Healthcare
Center, Dankook University College of Medicine, Seoul, Korea
5
Department of Health Science, Hanyang University, Seoul, Korea

Received: Aug 21, 2018

Revised: Jan 3, 2019
ABSTRACT
Accepted: Jan 9, 2019
Objective: To evaluate the risk of genotype-specific human papillomavirus (HPV) infections
Correspondence to for the spectrum of cervical carcinogenesis and the distribution of HPV types according to
Tae Jin Kim age and different cervical lesions
Department of Obstetrics and Gynecology,
Methods: This study included HPV-positive women who underwent cervical biopsy at the
Konkuk University School of Medicine, 120-1
Neungdong-ro, Gwangjin-gu, Seoul 05030,
Cheil General Hospital & Women's Healthcare Center between July 1, 2011 and December 31,
Korea. 2017. HPV genotyping was conducted using a Cheil HPV DNA chip kit.
E-mail: kimonc111@naver.com Results: The study sample consisted of 400 normal, 399 cervical intraepithelial neoplasia
(CIN) 1, 400 CIN 2, 400 CIN 3, and 389 cervical cancer cases. HPV 16 was the most common
Copyright © 2019. Asian Society of
Gynecologic Oncology, Korean Society of
type found with a prevalence of 9.5% in normal, 6.8% in CIN 1, 15.0% in CIN 2, 44.5% in CIN
Gynecologic Oncology 3, and 64.3% in cervical cancer. The most common HPV types were 16, 52, 58, 53, 51, 56, 68,
This is an Open Access article distributed and 18 in all study samples. HPV 16, 31, 33, and 58 were more common in CIN 2/3 and cancer,
under the terms of the Creative Commons and HPV 39, 51, 53, 56, 66, and 68 were more common in CIN 1 and normal cases (p<0.001).
Attribution Non-Commercial License (https:// In CIN 3 and cervical cancer, HPV 16 was the most common type in all age groups. HPV 52
creativecommons.org/licenses/by-nc/4.0/)
was the most common type in CIN 2 (all age groups) and in CIN 1/normal (age ≤30 years)
which permits unrestricted non-commercial
use, distribution, and reproduction in any cases. Among the high-risk HPV types, 16, 31, 33, 52, and 58 showed significant risk for high-
medium, provided the original work is properly grade disease.
cited. Conclusions: HPV 16, 31, 33, 52, and 58 showed the significant risk of high-grade disease for
cervical carcinogenesis.
ORCID iDs
Kyeong A So
Keywords: Human Papilloma Virus; Genotype; Cervical Intraepithelial Neoplasia;
https://orcid.org/0000-0002-3566-8436
In Ho Lee
Cervical Cancer
https://orcid.org/0000-0001-8856-3243
Ki Heon Lee
https://orcid.org/0000-0002-4079-9035
Sung Ran Hong
INTRODUCTION
https://orcid.org/0000-0002-6828-2345
Young Jun Kim Cervical cancer is the fourth most commonly diagnosed cancer in females worldwide [1]. In
https://orcid.org/0000-0003-0154-9161 Korea, it was the fifth most common female cancer and the third most common cancer among
Hyun Hee Seo 15–34-year-old women [2]. Oncogenic human papillomavirus (HPV) infection is a major risk
https://orcid.org/0000-0001-7414-331X
factor for cervical cancer. The overall prevalence of high-risk human papillomavirus (HR-HPV)
Tae Jin Kim
https://orcid.org/0000-0002-5322-2745
increases from 12% in normal cytology to 89% in cervical cancer [3]. Globally, HPV 16/18 are
the 2 most common genotypes in approximately 70% of invasive cervical cancer cases [4].

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HPV type-specific risk in cervical carcinogenesis

Presentation The remaining 30% are caused by other HR-HPV types. HPV infections are common among
This study has been presented in the 33rd young women and most spontaneously clear within 1–2 years [5]. Persistent infection with HR-
Annual Meeting of The Korean Society of
HPV is considered essential for the development of cervical cancer [6]. However, the trend of
Gynecologic Oncology.
persistent infection differed by HPV genotype and age. The most persistent types are 16, 31, 33,
Funding and 52 and the least persistent types are 35, 51, 66, and 68 [7]. The association between age and
This study was supported in part by a research persistent infection is inconsistent. Previous studies suggested that women over 30 years of age
grant from Investigator-Initiated Studies have a higher rate of persistent HPV infection than women under 30 years of age [7,8]. Other
Program of Merck Sharp & Dohme Corp.
studies showed that the persistence of HPV infection was not related to age [9,10].
Conflicts of Interest
Dr. Kim reports grants from Merck Sharp & In addition, HPV type-specific prevalence is different between low-grade squamous intraepithelial
Dohme Corp., during the conduct of the study. lesion (LSIL) and malignancy. HPV 16, 18, and 45 are more frequent in invasive cervical cancer
Other authors declare no conflicts of interest.
than in any other grade of cervical disease, whereas HPV 51, 52, and 31 are more frequently
Author Contributions detected in precancerous lesions than in invasive cervical cancer [11]. However, the risk of
Conceptualization: S.K.A. Data curation: individual HPV type and the pattern of age-specific prevalence in cervical carcinogenesis are still
S.K.A., H.S.R. Formal analysis: K.Y.J. Funding not fully understood. A clear understanding of the individual risk according to HPV genotype
acquisition: K.T.J. Investigation: K.Y.J., S.H.H.
would provide basic data for the prediction of vaccine effects and the clinical use of cervical cancer
Methodology: S.H.H. Resources: L.I.H., L.K.H.,
H.S.R. Supervision: L.K.H., K.T.J. Writing -
prevention. Thus, we performed this study to evaluate the genotype-specific risk for cervical
original draft: S.K.A. Writing - review & editing: carcinogenesis and the distribution of HPV types according to age in different cervical lesions.
L.I.H., K.T.J.

MATERIALS AND METHODS

1. Study population
This study was a retrospective case-control analysis after Institutional Review Board approval
(approval No. CGH-IRB-2016-48). Study samples were collected from HPV-positive women
who underwent cervical biopsy between July 2011 and December 2017 at the Department of
Obstetrics and Gynecology, Cheil General Hospital and Women's Healthcare Center, Dankook
University College of Medicine. A total of 1,988 samples were collected from women with
normal (n=400), cervical intraepithelial neoplasia (CIN) 1 (n=399), CIN 2 (n=400), CIN 3
(n=400), cervical cancer (n=399). According to a large meta-analysis and a Korean HPV cohort
study the prevalence of the 5 most common HR-HPVs was 7.2%–18.7% in LSIL [12,13]. Therefore
400 samples per disease grade are required to make up at least 30 cases for the five most
common HR-HPVs that is needed to be statistically analyzed. Women were screened by cervical
cytology and HPV test prior to biopsies. The women with abnormal cervical cytology and/or HR-
HPV underwent a cervical biopsy. The pathologic result of chronic inflammation was included
in the normal group. The inclusion criteria of this analysis were evidence of HPV infection and
biopsy result. Women with previous hysterectomy were excluded from the analysis.

2. HPV DNA testing

The cervical samples were analyzed for HPV genotype using a Cheil HPV DNA chip kit (Cheil
General Hospital, Seoul, Korea). HPV genotyping was based on a SYBR Green real-time
polymerase chain reaction (RT-PCR) method. RT-PCR for HPV DNA was performed using the
Light Cycler 480 (Roche Diagnostics, Rotkreuz, Switzerland). Post-amplification SYBR Green
RT-PCR products were mixed with the hybridization buffer, and the mixture was incubated
on the Cheil HPV DNA Chip. A total of 36 HPV types were identified using a chip scanner
(NimbleGen MS 200; Roche NimbleGen, Vienna, Austria) and analyzed with GenePix® Pro
6.0 software (Axon Instruments, Union, CA, USA). The 36 HPV genotypes included 19 high-
risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68a, 68b, 69, and 82) and 17
low-risk types (6, 11, 30, 32, 40, 42, 43, 44, 54, 55, 62, 70, 72, 81, 84, 90, and 91).

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HPV type-specific risk in cervical carcinogenesis

Table 1. Rate of HPV infection and age distributions in study samples

Variables Normal CIN 1 CIN 2 CIN 3 Cervical cancer Total
Number 400 399 400 400 399 1,988
Age 31.4±7.5 34.5±10.0 32.9±7.3 32.3±7.0 51.0±13.1 36.3±11.8
HPV infection (%)
HR-HPV 389 (97.3) 365 (91.5) 398 (99.5) 398 (99.5) 386 (99.2) 1,936 (97.4)
Single 303 (77.9) 257 (70.4) 268 (67.3) 281 (70.6) 356 (92.2) 1,465 (75.7)
Multiple 86 (22.1) 108 (29.6) 130 (32.7) 117 (29.4) 30 (7.8) 471 (24.3)
Only LR-HPV 11 (2.7) 34 (8.5) 2 (0.5) 2 (0.5) 3 (0.8) 52 (2.6)
HR+LR HPV 122 (30.5) 123 (30.8) 109 (27.3) 74 (18.5) 11 (2.8) 439 (22.1)
Values are presented as number of patients (%) or mean ± standard deviation.
HPV, human papillomavirus; HR, high-risk; LR, low-risk.

3. Statistical analysis
The data were analyzed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). Categorical
variables were indicated as numbers and percentages. To assess the risk of severe disease
associated with HPV genotype, the odds ratio (OR) with 95% confidence interval (CI) was
estimated using the χ2 test. All p-values <0.05 were considered statistically significant.

RESULTS
Among a total of 1,988 patients, normal, CIN 1, CIN 2, CIN 3, and cancer cases accounted
for 400, 399, 400, 400, and 389, respectively (Table 1). The overall prevalence of HR-HPV
infection was 97.4%. The rate of single HR-HPV infection in the cancer group (92.2%) was
higher than that in the other groups (67.3%–77.9%). Multiple HR-HPV infection was more
frequent in normal and CIN 1/2/3 cases. Except in cervical cancer, multiple HR-HPV infection
was more frequent in women <30 years old.

The prevalence of HPV genotype is summarized in Table 2. The 10 most common HR-HPV
types were 16 (27.8%), 52 (16.7%), 58 (12.2%), 53 (9.3%), 51 (9.1%), 56 (7.7%), 68 (6.8%), 18
(6.0%), 39 (5.7%), and 31 (5.2%). Genotype-specific HPV infection varied according to the
different grades of disease (Fig. 1). The most common HR-HPV genotypes identified were

Table 2. Prevalence of HPV genotypes (n=1,988)

High-risk No. (%) Low-risk No. (%)
16 553 (27.8) 54 89 (4.5)
52 332 (16.7) 84 78 (3.9)
58 242 (12.2) 70 73 (3.7)
53 184 (9.3) 62 60 (3.0)
51 180 (9.1) 81 48 (2.4)
56 152 (7.7) 44 47 (2.4)
68 135 (6.8) 42 43 (2.2)
18 120 (6.0) 6 39 (2.0)
39 113 (5.7) 30 35 (1.8)
31 103 (5.2) 43 30 (1.5)
33 81 (4.1) 55 26 (1.3)
35 64 (3.2) 11 24 (1.2)
59 56 (2.8) 91 23 (1.2)
66 44 (2.2) 72 13 (0.7)
82 44 (2.2) 32 12 (0.6)
45 38 (1.9) 90 5 (0.3)
67 36 (1.8) 40 0
69 5 (0.3)
HPV, human papillomavirus.

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HPV type-specific risk in cervical carcinogenesis

70 Normal CIN 1 CIN 2 CIN 3 Cervical cancer

60

50

40

%
30

20

10

0
16 18 31 33 35 39 45 51 52 53 56 58 59 66 67 68 69 82

Fig. 1. Genotype-specific prevalence of HR-HPV in different cervical disease grades.

CIN, cervical intraepithelial neoplasia; HR-HPV, high-risk human papillomavirus.

16 (64.3%), 58 (8.7%), 33 (6.4%), 31 (5.9%), 18 (5.4%), and 52 (5.1%) in cervical cancer; 16

(44.5%), 52 (20%), 31 (10.8%), 58 (8.7%), and 68 (6.3%) in CIN 3; 52 (24%), 58 (19%), 16
(15%), 51 (15%), and 53 (9%) in CIN 2; 52 (17%), 53 (16%), 56 (16%), 51 (12%), and 39 (11%)
in CIN 1; and 52 (17%), 53 (14%), 51 (12%), 56(12%), and 38 (11%) in normal cases.

The distribution of HR-HPV according to age is shown in Fig. 2. Three HPV genotypes (16,
52, and 58) were most common in all age groups (≤30 years, n=799; 31–40 years, n=502; ≥41
years, n=653). In addition to HPV 16, 52, and 58, common types were HPV 51 and 53 in those
aged ≤30 years; 53 and 68 in those aged 31–40 years; and 18 and 56 in those aged ≥41 years.
The prevalence of HR-HPV was analyzed according to age and disease grade (Fig. 3). The
genotypes showed a similar distribution according to disease grade regardless of age. The
most common type was HPV 16 in cervical cancer and CIN 3. Young women with cervical
cancer had fewer HPV types than older women. Only 3 types of HR-HPV, 16/31/52 were
associated with cervical cancer in women ≤30 years of age. In all age groups, common HR-
HPV types in CIN 2 and CIN 1 were 52/58 and 52/53/56, respectively.

40

35

30

25

20
%

15

10

0
≤30 31–40 ≥41
HPV 16 HPV 18 HPV 31 HPV 33 HPV 35 HPV 39 HPV 45 HPV 51 HPV 52
HPV 53 HPV 56 HPV 58 HPV 59 HPV 66 HPV 67 HPV 68 HPV 69 HPV 82
Fig. 2. Genotype-specific distribution of HR-HPV according to age.
HPV, human papillomavirus; HR-HPV, high-risk human papillomavirus.

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HPV type-specific risk in cervical carcinogenesis

Cervical cancer CIN 3

100 60

80 50

40
60
30
%

%
40
20
20 10

0 0
≤30 31–40 ≥41 ≤30 31–40 ≥41

CIN 2 CIN 1
30 25

25 20
20
15
15
%

10
10

5 5

0 0
≤30 31–40 ≥41 ≤30 31–40 ≥41

HPV 16 HPV 18 HPV 31 HPV 33 HPV 35 HPV 39 HPV 45 HPV 51 HPV 52

HPV 53 HPV 56 HPV 58 HPV 59 HPV 66 HPV 67 HPV 68 HPV 69 HPV 82
Fig. 3. Prevalence of HR-HPV according to age and disease grades.
CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; HR-HPV, high-risk human papillomavirus.

However, the distribution of genotype-specific HPV according to the severity of cervical

lesions showed significant differences (Table 3). HPV 16, 31, 33, and 58 were significantly
more common in the CIN 2/3/cancer group than in the normal/CIN 1 group. Conversely, HPV
39, 51, 53, 56, 66, and 68 were significantly more common in the normal/CIN 1 group than in
the high-grade disease group (p<0.001).

The genotype-specific risks in the CIN 2/3/cancer group in comparison to those in the
normal/CIN 1 group are shown in Table 4. Compared with the normal group, genotype-
specific risk for cancer was found with HPV 16 (OR=17.1; CI=11.6–22.5; p<0.001) and HPV

Table 3. Genotype-specific HPVs according to the severity of cervical lesions

HPV type Histopathology p-value
Normal/CIN 1 (n=799) CIN 2/3/Cervical cancer (n=1,189)
16 65 (8.1%) 488 (41.0%) <0.001
31 16 (2.0%) 87 (7.3%) <0.001
33 17 (2.1%) 64 (5.4%) <0.001
58 72 (9.0%) 170 (14.3%) <0.001
39 70 (8.8%) 43 (3.6%) <0.001
51 98 (12.3%) 82 (6.9%) <0.001
53 119 (14.9%) 65 (5.5%) <0.001
56 108 (13.5%) 44 (3.7%) <0.001
66 68 (8.5%) 31 (2.6%) <0.001
68 75 (9.4%) 60 (5.0%) <0.001
HPV, human papillomavirus.

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HPV type-specific risk in cervical carcinogenesis

Table 4. HPV genotype-specific risks of CIN 2/3/Cancer compared with normal/CIN 1

Cervical lesion Genotype OR 95% CI p-value
Cervical cancer vs. Normal HPV 16 17.1 11.6–25.4 <0.001
HPV 33 3.4 1.5–7.6 0.002
CIN 3 vs. Normal HPV 16 7.6 5.2–11.3 <0.001
HPV 31 3.9 2.0–7.5 <0.001
HPV 33 3.1 1.4–7.1 0.006
CIN 2 vs. Normal HPV 58 2.0 1.3–3.0 0.001
HPV 16 1.7 1.1–2.6 0.023
HPV 52 1.6 1.1–2.1 0.014
Cervical cancer vs. CIN 1 HPV 16 24.8 15.9–38.6 <0.001
HPV 31 6.2 2.1–18.1 <0.001
HPV 33 3.0 1.5–6.6 0.005
CIN 3 vs. CIN 1 HPV 16 11.0 7.1–17.1 <0.001
HPV 31 11.9 4.2–33.5 <0.001
HPV 33 2.8 1.3–6.0 0.012
CIN 2 vs. CIN 1 HPV 31 5.5 1.9–16.1 0.001
HPV 16 2.4 1.5–3.9 <0.001

33 (OR=3.4; CI=1.5–7.6; p=0.002). HPV 16, 31, and 33 were associated with high risk for
CIN 3. HPV 58, 16, and 52 were associated with high risk for CIN 2. In contrast to CIN 1,
a significantly high risk of cancer was associated with HPV 16 (OR=24.8; CI=15.9–38.6;
p<0.001), 31 (OR=6.2; CI=2.1–18.1; p<0.001), and 33 (OR=3.0; CI=1.5–6.6; p=0.005). HPV 16,
31, and 33 were associated with a high risk for CIN 3. HPV 31 and 16 were associated with a
high risk for CIN 2.

DISCUSSION
This study analyzed the genotype-specific risk for the spectrum of cervical carcinogenesis
and investigated genotype-specific age distribution for different grades of cervical disease.
Although the distributions of HPV infections are different according to geographical region,
our results are in agreement with previous studies, with a point prevalence of HPV 16 [3,14].
HPV 16 was the most common type, especially in CIN 3 and cervical cancer. HPV 52, 58, 53,
and 51 followed HPV 16 in the top 5. HPV 18 (6.0%) and 45 (1.8%) were not common in this
study, consistent with the less common types in East Asia [15]. HPV genotypes 16, 52, and 58
were the most common in all age groups according to cervical disease grade. The prevalence
of multiple infections was approximately 30% in this study. Multiple HR-HPV infections were
more frequent in precancerous lesion and more common in women <30 years old. Several
previous studies reported a multiple infection rate of 20%–40% [16,17]. Multiple infections
present more frequent in younger women with high-grade CIN and the infection rate decline
with increasing age [11]. The potential significance of multiple infections is their common
presence in young women and women with multiple sexual partners, and in specimens with
abnormal cytology [16,18].

HPV 16/31/33/58 types were more frequently detected in women with high-grade CIN and
cervical cancer, whereas HPV 39/51/53/56/66/68 were more frequently detected in women
with normal and low-grade CIN. Several HR-HPV types (HPV 53/56/51/39/66/68) were
prominent in low-grade CIN but disappeared in high-grade CIN and cancer. The results
suggest that there is genotype-specific risk of HR-HPV developing into high-grade CIN and
cancer by causing persistent infection. Indeed, these HR-HPV types belong to alpha-9 species
(HPV 16/31/33/35/52/58/67) and are likely to have biological properties similar to those of HPV

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HPV type-specific risk in cervical carcinogenesis

16 [19]. HPV types in the alpha-9 species are more persistent and more likely to progress to
CIN 3 or worse, compared with HPV types in the alpha-5 (HPV 51), 6 (HPV 53/56/66) and 7
(HPV 18/39/45/59/68) groups [20].

This study estimated genotype-specific risks. HPV 16, 31, and 33 were associated with higher
risk of CIN 2/3 and cervical cancer compared with normal and CIN 1 cases. HPV 52 and 58
were only associated with higher risk for CIN 2 compared with the normal group. The results
showed that relative carcinogenic potential varied. HPV 16/31/33 infection may be a consistent
and strong risk for carcinogenesis. Carcinogenic risk of HPV 31 and 33 has been reported
[7,21,22]. A 12-year follow-up study in Denmark showed that the absolute risk of CIN 3 or
worse among those infected with HPV 31 was 14.3% (CI=9.1–19.4), with 14.9% for HPV 33
(CI=7.9– 21.1) [20]. HPV 52 and 58 are among the 5 most common types associated with
cervical cancer in Eastern and Southeastern Asia [13,14,23]. In this study, overall prevalence
of HPV 52 and 58 infections was more common than HPV 31/33 infection (28.9% vs 9.3%).
Therefore, the prevention of HPV 52 and 58 infections is important to reduce the burden of
precancerous cervical disease.

Most HPV infections are self-regulated for one to 2 years, and development of cervical cancer
may take a long time even in patients with persistent HPV infection. This study is not a
prospective study with repeated HPV results in the same patient so that actual progression
from normal to cervical cancer for individual HPV types may be an indirect consideration.
However, this study has strengths that relatively large sample size including all grades of
disease in the cervical carcinogenesis. The cases of each disease group are well balanced.
The results of our study provide important information regarding difference in the CIN2/3/
cancer and normal/CIN1 prevalence of individual HPV types and different distribution of HR-
HPV according to age. The results can be helpful for individualized management with HPV
genotype-based screening.

Our study indicates that HPV 16, 31, 33, 52, and 58 infections are associated with significant
risk of high-grade disease and might play important roles in the development of cervical
cancer. Fortunately, these oncogenic HPV infections can be prevented by vaccination. The
quadrivalent and bivalent HPV vaccines prevent precancerous lesions related to HR-HPV
16 and 18 [24,25]. Recently, a nonavalent vaccine became available to protect against HR-
HPV 31, 33, 45, 52, and 58, in addition to HPV 16 and 18 [26]. Our data will be useful in the
assessment of effectiveness of HPV vaccination and will provide additional information on
the risk of developing cervical cancer in HPV infected women.

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