Status and molecular genetic parameters of papillomavirus infection: individual characteristics and associative links with clinical and morphological factors of cervical cancer Текст научной статьи по специальности «Клиническая медицина»

South Russian Journal of Cancer. 2024. Vol. 5, No. 2. P. 53-65

https://doi.org/10.37748/2686-9039-2024-5-2-6

https://elibrary.ru/qmhkdo

4.0

ORIGINAL ARTICLE

South Russian

Journal of Cancer

Status and molecular genetic parameters of papillomavirus

Южно-Российский

онкологический журнал

Vol. 5

infection: individual characteristics and associative links with No. 2, 2024

clinical and morphological factors of cervical cancer

L. S. Mkrtchyan1, V. I. Kiseleva1, L. I. Krikunova1, B. V. Boyko1, V. R. Gusarova1, G. P. Bezyaeva1, L. V. Panarina1, S. A. Ivanov1,3, A. D. Kaprin2,3,4, I. A. Zamulaeva1,5

1 A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation

2 National Medical Research Radiological Centre, Obninsk, Russian Federation 3 Peoples Friendship University of Russia (RUDN University), Moscow, Russian Federation 4 P. A. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Moscow, Russian Federation

5 Joint Institute for Nuclear Research, Dubna, Russian Federation liana.mko@gmail.com

ABSTRACT

Purpose of the study. Study of the characteristics of human papillomavirus (HPV) infection, comparison of HPV status, molecular and genetic parameters of HPV high risk (HR) with the clinical and morphological characteristics of cervical cancer.

Materials and methods. The study included 240 patients with morphologically verified cervical cancer stages I–III, in whom the presence of HPV DNA of 14 genotypes was examined before treatment; upon detection, viral load (VL), the presence and degree of DNA integration into the genome of the host cell were examined.

Results. A number of statistically significant associative relationships have been identified between the molecular and genetic parameters of HPV infection and clinical and morphological indicators of the tumor process, in particular the relationship of HPV-negative CC with age and stage of the disease; HPV infection with several genotypes and HPV genotype – with the histological type of tumor; VL – with age, stage and histological type of tumor. Significant associative connections have been established between the molecular genetic parameters of the virus itself: genotype and level of VL, genotype and integration of HPV DNA into the host genome, as well as a negative linear correlation between VL and the degree of integration.

Conclusion. The obtained data on the relationship between the molecular and genetic parameters of HPV infection and traditional prognostic factors can become the basis for further research on the development of prognostic models for the purpose of personalizing multimodal treatment programs.

Keywords: human papillomavirus (HPV), high carcinogenic risk (HCR), cervical cancer (CC), HPV genotype, multiple infection, viral load, HPV status, virus DNA integration into the cell genome For citation: Mkrtchyan L. S., Kiseleva V. I., Krikunova L. I., Boyko B. V., Gusarova V. R., Bezyaeva G. P., Panarina L. V., Ivanov S. A., Kaprin A. D., Zamulaeva I. A. Status and molecular genetic parameters of papillomavirus infection: individual characteristics and associative links with clinical and morphological factors of cervical cancer. South Russian Journal of Cancer. 2024; 5(2):53-65.

https://doi.org/10.37748/2686-9039-2024-5-2-6, https://elibrary.ru/qmhkdo For correspondence: Liana S. Mkrtchian – Dr. Sci. (Med.), leading researcher, A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation Address: 10 Marshal Zhukov str., Obninsk 249031, Russian Federation E-mail: liana6969@mail.ru

ORCID: https://orcid.org/0000-0002-5027-5331

SPIN: 3352-0814, AuthorID: 147713

ResearcherID: JBJ-0493-2023

Scopus Author ID: 6601999343

Compliance with ethical standards: the work followed the ethical principles set forth in the World Medical Association Declaration of Helsinki, 1964, ed. 2013. The study was approved by the local Ethics committee of the A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation (extract from the protocol of the meeting No. 103 dated 09/17/2015). All patients signed an informed consent to participate in the study Funding: this work was not funded

Conflict of interest: Ivanov S. A., Kaprin A. D. has been the member of the editorial board of the South Russian Journal of Cancer since 2024, however he has no relation to the decision made upon publishing this article. The article has passed the review procedure accepted in the journal.

The authors did not declare any other conflicts of interest

The article was submitted 11.03.2024; approved after reviewing 23.04.2024; accepted for publication 09.05.2024

© Mkrtchyan L. S., Kiseleva V. I., Krikunova L. I., Boyko B. V., Gusarova V. R., Bezyaeva G. P., Panarina L. V., Ivanov S. A., Kaprin A. D., Zamulaeva I. A., 2024

53

Южно-Российский онкологический журнал. 2024. Т. 5, № 2. С.53-65

https://doi.org/10.37748/2686-9039-2024-5-2-6

https://elibrary.ru/qmhkdo

3.1.6. Онкология, лучевая терапия

ОРИГИНАЛЬНАЯ СТАТЬЯ

Статус и молекулярно-генетические параметры папилломавирусной

инфекции: индивидуальные особенности и ассоциативные связи с клинико-морфологическими факторами рака шейки матки

Л. С. Мкртчян1, В. И. Киселева1, Л. И. Крикунова1, Б. В. Бойко1, В. Р. Гусарова1, Г. П. Безяева1, Л. В. Панарина1, С. А. Иванов1,3, А. Д. Каприн2,3,4, И. А. Замулаева1,5

1Медицинский радиологический научный центр им. А. Ф. Цыба – филиал ФГБУ «Национальный медицинский исследовательский центр

радиологии» Министерства здравоохранения Российской Федерации, г. Обнинск, Российская Федерация

2ФГБУ «Национальный медицинский исследовательский центр радиологии» Министерства здравоохранения Российской Федерации, г. Обнинск, Российская Федерация

3ФГАОУ ВО «Российский университет дружбы народов», г. Москва, Российская Федерация

4Московский научно-исследовательский онкологический институт им. П. А. Герцена – филиал ФГБУ «Национальный медицинский

исследовательский центр радиологии» Министерства здравоохранения Российской Федерации, г. Москва, Российская Федерация

5Объединенный институт ядерных исследований, г. Дубна, Российская Федерация

liana.mko@gmail.com

РЕЗЮМЕ

Цель исследования. Изучение особенностей папилломавирусной (ВПЧ) инфекции, сопоставление ВПЧ-статуса, молекулярно- генетических параметров ВПЧ высокого канцерогенного риска (ВКР) с клинико- морфологическими

характеристиками рака шейки матки (РШМ).

Материалы и методы. В исследование были включены 240 больных с морфологически верифицированным РШМ

I–III стадий, у которых до начала лечения исследовали наличие ДНК ВПЧ 14 генотипов, при выявлении – вирусную

нагрузку (ВН), наличие и степень интеграции ДНК в геном клетки- хозяина.

Результаты. Выявлен ряд статистически значимых ассоциативных связей между молекулярно- генетическими параметрами ВПЧ-инфекции и клинико- морфологическими показателями опухолевого процесса, в частности связь

ВПЧ-негативного РШМ с возрастом и стадией заболевания; ВПЧ-инфицирования несколькими генотипами и генотипа

ВПЧ – с гистологическим типом опухоли; ВН – с возрастом, стадией и гистологическим типом опухоли. Установлены

значимые ассоциативные связи между молекулярно- генетическими параметрами самого вируса: генотипа и уровня

ВН, генотипа и интеграции ДНК ВПЧ в хозяйский геном, а также отрицательная линейная корреляция между ВН

и степенью интеграции.

Заключение. Полученные данные о взаимосвязи молекулярно- генетических параметров ВПЧ-инфекции с традици-онными прогностическими факторами могут стать основой для дальнейших исследований по разработке прогно-стических моделей с целью персонализации мультимодальных лечебных программ.

Ключевые слова: вирус папилломы человека (ВПЧ), высокий канцерогенный риск (ВКР), рак шейки матки (РШМ), генотип ВПЧ, множественная инфекция, вирусная нагрузка, ВПЧ – статус, интеграция ДНК вируса в клеточный геном

Для цитирования: Мкртчян Л. С., Киселева В. И., Крикунова Л. И., Бойко Б. В., Гусарова В. Р., Безяева Г. П., Панарина Л. В., Иванов С. А., Каприн А. Д., Замулаева И. А. Статус и молекулярно- генетические параметры папилломавирусной инфекции: индивидуальные

особенности и ассоциативные связи с клинико- морфологическими факторами рака шейки матки. Южно- Российский онкологический

журнал. 2024; 5(2):53-65. https://doi.org/10.37748/2686-9039-2024-5-2-6, https://elibrary.ru/qmhkdo Для корреспонденции: Мкртчян Лиана Сирекановна – д. м. н., ведущий научный сотрудник МРНЦ им. А. Ф. Цыба – филиал ФГБУ

«Национальный медицинский исследовательский центр радиологии» Министерства здравоохранения Российской Федерации, г. Обнинск, Российская Федерация

Адрес: 249031, Российская Федерация, г. Обнинск, ул. Маршала Жукова, д. 10

E-mail: liana6969@mail.ru

ORCID: https://orcid.org/0000-0002-5027-5331

SPIN: 3352-0814, AuthorID: 147713

ResearcherID: JBJ-0493-2023

Scopus Author ID: 6601999343

Соблюдение этических стандартов: в работе соблюдались этические принципы, предъявляемые Хельсинкской декларацией Всемирной

медицинской ассоциации (World Medical Association Declaration of Helsinki, 1964, ред. 2013). Исследование одобрено локальным

этическим комитетом МРНЦ им. А. Ф. Цыба – филиал ФГБУ «НМИЦ Радиологии» Минздрава России (выписка из протокола заседания

№ 103 от 17.09.2015 г.). Все пациенты подписали добровольное информированное согласие на участие в исследовании

Финансирование: финансирование данной работы не проводилось

Конфликт интересов: Иванов С. А., Каприн А. Д. являются членам редакционной коллегии журнала «Южно- Российский онкологический

журнал» с 2024 г., но не имеет никакого отношения к решению опубликовать эту статью. Статья прошла принятую в журнале процедуру

рецензирования. Об иных конфликтах интересов авторы не заявляли

Статья поступила в редакцию 11.03.2024; одобрена после рецензирования 23.04.2024; принята к публикации 09.05.2024

54

Южно-Российский онкологический журнал 2024. Т. 5, № 2. С. 53-65

Мкртчян Л. С., Киселева В. И., Крикунова Л. И., Бойко Б. В., Гусарова В. Р., Безяева Г. П., Панарина Л. В., Иванов С. А., Каприн А. Д., Замулаева И. А. Статус

и молекулярно- генетические параметры папилломавирусной инфекции: индивидуальные особенности и ассоциативные связи с клинико- морфологическими

факторами рака шейки матки

INTRODUCTION

Some researchers pay attention to a statistically

significant relationship between high viral load (VL)

Cervical cancer (CC) ranks first among malignant

and the risk of metastatic lymph node damage, tu-

neoplasms of the female genital organs [1]. Annually,

mor size [14], others – to the correlation of low VL

more than 600 thousand new cases are detected in

with the stage of the disease and enlarged lymph

the world and about 342 thousand deaths from this

nodes [15]. However, the heterogeneity of the sam-

pathology are registered [2]. In the Russian Federa-

ples with the lack of a comprehensive assessment

tion, breast cancer is the leading cause of death from

of the relationship of the entire spectrum of mo-

cancer in the female population aged 30–39 years

lecular genetic parameters of HPV infection with

(21.5 %) [3].

prognostically known clinical and morphological

Human papillomavirus (HPV) of high carcinogenic

factors often determines the contradictory nature

risk (HCR) is a proven factor in the development of

of the data obtained and makes it relevant to further

breast cancer [4]. Among the total number of pa-

studies in homogeneous groups of patients with

tients with breast cancer, 88–95 % are HPV-positive,

breast cancer with the inclusion of the maximum

according to various authors [5, 6]. The most com-

number of criteria studied.

mon HPV genotypes, according to most literature

sources, are types 16 and 18, which are collectively

MATERIALS AND METHODS

detected in almost 75–85 % of cases of HPV-positive

breast cancer [6–9]. In 2020, the World Health Orga-

The study on the topic of HPV infection features,

nization introduced a new classification of cervical

the comparison of HPV status, molecular genetic

epithelial tumors based on the presence/absence

parameters of HPV HCR with the clinical and mor-

of HCR HPV, the so-called HPV status [10, 11]. The

phological characteristics of the tumor process was

cited sources indicate that HPV-negative status is

performed in 240 patients with morphologically ver-

an indicator of an unfavorable prognosis of the ef-

ified stage I–III breast cancer (FIGO) who under-

fectiveness of treatment, but, as noted above, the

went examination and treatment in the department

proportion of such patients is small, which dictates

of radiation and combined methods of treatment

the need to search for prognostic markers in the ma-

of gynecological diseases of the A. F. Tsyb Medi-

jority other breast cancer patients with HPV-positive

cal Radiological Research Centre – Branch of the

status. It is known that HPV infection is character-

National Medical Research Radiological Centre of

ized by significant diversity at the molecular genetic

the Ministry of Health of the Russian Federation,

level, and, importantly, some of its parameters can

Obninsk, Russian Federation [16]. The study is

affect the sensitivity of tumor cells to antitumor

a retrospective- prospective cohort, conducted in

effects (according to the results of studies on cell

accordance with the protocol approved by the local

cultures in vitro). In this regard, it could be assumed ethics committee of the A. F. Tsyb Medical Radiolog-that studying the features of HPV infection in cer-

ical Research Centre – Branch of the National Medi-

vical cancer can provide additional information for

cal Research Radiological Centre of the Ministry of

stratification of patients in a prognostic aspect, will

Health of the Russian Federation, Obninsk, Russian

allow to personalize multimodal treatment programs

Federation (Protocol No. 103 dated 09/17/2015).

for breast cancer and, ultimately, improve the effec-

The ethical principles set forth by the Helsinki Dec-

tiveness of treatment.

laration of the World Medical Association (World

Data on the relationship between the clinical and

Medical Association Declaration of Helsinki, 1964,

morphological characteristics of breast cancer and

ed. 2013). Prior to inclusion in the study, the patients

the molecular genetic parameters of HPV infection

signed a voluntary informed consent to participate

are widely presented in the literature. The authors

in the study and determine in vitro the parameters

report the presence of an association between HPV

of HPV infection in the biomaterial of the cervix.

status and lymphovascular invasion [12], HPV HCV

The inclusion criteria were: morphologically verified

genotypes and the morphological form of the tumor,

stage I–III breast cancer, lack of specialized treat-

the relationship of HPV type 18 with the presence of

ment for this disease; non–inclusion criteria – preg-

deep stromal invasion and lymph node damage [13].

nancy, stage IV breast cancer, specialized treatment

55

South Russian Journal of Cancer 2024. Vol. 5, No. 2. P. 53-65

Mkrtchyan L. S., Kiseleva V. I., Krikunova L. I., Boyko B. V., Gusarova V. R., Bezyaeva G. P., Panarina L. V., Ivanov S. A., Kaprin A. D., Zamulaeva I. A. Status and molecular genetic parameters of papillomavirus infection: individual characteristics and associative links with clinical and morphological factors of cervical cancer for this disease in the anamnesis; exclusion crite-copies of HPV DNA per 105 cells is equal to or more

ria – refusal of patients from further participation

than 3, but less than 5 (3 ≤ VL < 5) – moderate viral

in the study. The average age of the patients was

load; c) lg of the number of copies of HPV DNA per

47.2 ± 12.0 years. Locally advanced forms of breast

105 cells is more than or equal to 5 (VL ≥ 5) – high

cancer (stages II and III of the disease) prevailed –

viral load. In case of multiple infection, the quantita-

in total in 186 (77.5 %) patients. According to the

tive load of all established HPV HCV genotypes was

morphological structure of the tumor, squamous

determined, the highest indicators corresponded to

cell carcinoma of various degrees of differentiation

the leading genotype of the virus.

was most often verified in patients – in 216 (90 %).

The presence of HPV DNA integration was as-

According to the form of growth, endophytic and

sessed by the ratio of the number of genomic equiv-

mixed prevailed, respectively, in 59 (24.6 %) and

alents of the E7/E2 virus, taking into account the

136 (56.6 %) patients; according to the variant of

standard deviation and the coefficient of variation

the spread of the tumor process, parametric in var-

of the data in accordance with the developed algo-

ious variations and metastatic, respectively, in 174

rithm [17]. Its principle is based on the fact that the

(93.5 %) and 66 (66.7 %) patients.

E7 gene remains intact during the integration of viral

The presence of HPV DNA of 14 genotypes was

DNA into the DNA of the host cell, respectively, its

studied in all 240 patients before treatment: 16, 18,

amount in both forms of the virus – episomal and

31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Bi-

integrated – is the same. In most cases, the E2 gene

opsies and/or joint scrapings of the epithelium of

is destroyed during integration and its amount de-

the cervical canal (endocervix) and the outer wall

creases. The analysis was performed using TagMan

served as the material for the study cervical sur-

technology in real-time multiplex PCR format using

faces (exocervix) taken before the start of treat-

a set of reagents that allows differentiated determi-

ment. All stages of the subsequent analysis of the

nation of the number of E2 and E7 viral genes and

obtained biomaterial samples were performed on

the β-globin cellular gene. In one test tube, sections

domestic test systems produced by the Federal

of the E7 and E2 virus genes and a section of human

State Budgetary Institution of the Central Research

β-globin DNA, ICS, were amplified. At the same time,

Institute of Epidemiology of Rospotrebnadzor. DNA

standard samples with known concentrations of

isolation was carried out by the sorbent method

HPV 16 and 18 DNA and β-globin DNA were ampli-

using a set of reagents "DNA-sorb- AM". The pres-

fied in each experiment. All samples, both clinical

ence, differentiated determination of the genotype

and standard, were amplified in three repeats. For

and quantitative load of HPV was carried out by

each of the repeats, the amount of E7 and E2 was

multiplex PCR with the detection of a fluorescent

calculated using calibration curves and a regression

signal over four channels in real time on the Rotor

equation obtained on standard samples in accor-

Gene amplifier (Corbett Research, Australia) using

dance with the program for amplification of these

the reagents "HPV Amplification HCR genotype- titer

genes. The degree of HPV DNA integration was es-

FL". In this test system, the viral genes E1, E6, E7 and timated by the formula (1 – E2/E7) × 100 %. The

the β-globin cellular gene are amplified. Only data

absence of an amplification signal for the E2 gene

for samples with a positive result of β-globin anal-

in the presence of such a signal for the E7 gene

ysis are considered valid. This gene serves as an

corresponds to 100 % integration of viral DNA into

internal control of the reaction (EQ), and also allows

the cell genome.

you to estimate the number of cells in a sample (1

Statistical data processing was performed using

cell contains 2 β-globin molecules) and normalize

the Statistica 10.0 software package (StatSoft, Inc.).

the results of amplification of viral genes for the

For descriptive statistics, average values and stan-

same number of cells. The results of the study were

dard error (SE) were used. The comparison of groups

processed in the Excel software add-in attached

by qualitative characteristics was carried out using

to the test system and interpreted in accordance

the Fisher criterion, by quantitative characteristics –

with the following criteria: a) logarithm (lg) of the

using the Mann- Whitney U-test. Spearman's nonpara-

number of HPV DNA copies per 105 cells less than

metric correlation method with the calculation of the

3 (VL < 3) – low viral load; b) lg of the number of

rank correlation coefficient (r) was used to evaluate

56

Южно-Российский онкологический журнал 2024. Т. 5, № 2. С. 53-65

Мкртчян Л. С., Киселева В. И., Крикунова Л. И., Бойко Б. В., Гусарова В. Р., Безяева Г. П., Панарина Л. В., Иванов С. А., Каприн А. Д., Замулаева И. А. Статус

и молекулярно- генетические параметры папилломавирусной инфекции: индивидуальные особенности и ассоциативные связи с клинико- морфологическими

факторами рака шейки матки

the linear relationships between variables. Multivari-

The total proportion of other types of HPV HCR (35,

ate analysis was performed using the Agglomerative

51, 52, 58, 59, 66, 68) It was 6.4 %. A similar share

clustering (AGNES) method with the construction of

distribution in the countries of the European region,

tree diagrams – dendrograms.

in particular the Russian Federation, is reported in

numerous publications, which also indicate the prev-

STUDY RESULTS AND DISCUSSION

alence of HPV genotypes 16 and 18 in 70–75 % of

cases [18–20]. In the study group of 215 HPV-posi-

HPV status and genotype

tive patients, genotypes or their combinations with

The presence of HPV HCR was registered in the

the dominant genotype belonging to the phyloge-

overwhelming number of patients in the study co-

netic group A9 were most often found (16, 31, 33,

hort – in 215 (89.6 %) out of 240. The average age

35, 52, 58) – in 76.7 % of cases. The share of rep-

of HPV-infected patients with breast cancer was

resentatives of the A7 group (18, 39, 45, 59) was

46.7 ± 11.8 years, which is much lower than in Eu-

more than 3.4 times lower – 22.3 %. The remaining

rope (54 ± 14 years) [9]. The average age of patients

2 groups A5 (51) and A6 (56, 66) were represented

in whom HPV HCR was not detected was 50.6 ± 14.0

in isolated cases (0.5 %). The peak occurrence of

years and did not differ from that of HPV-infected

group A9 genotypes occurred at a young age – up

patients ( p > 0.05). However, HPV-negative breast

to 30 years (78.6 %), and A7 – in the age category

cancer was 3.5 times more common among patients

up to 45 years (31.3 %), however, without statistically

over 55 years of age ( p = 0.004) (Fig. 1), which is

significant differences, which is consistent with the

consistent with data from other studies [18, 19].

results of multifactorial analysis [21], although some

There was a statistically significant increase in the

studies demonstrate the presence of a link between

frequency of HPV-negative forms of the disease at

the HPV genotype and the age of patients with breast

stage III (18.2 %) compared with stages II (3.4 %)

cancer [9].

and I (7.4 %) (respectively p = 0.001 and p = 0.05), In squamous cell carcinoma, the prevalence of

as mentioned by domestic researchers [18].

genotypes of group A9 (80.0 %) ( p = 0.0002) with

Among all the genotypes found in patients with

the dominance of HPV 16 (74.3 %) ( p = 0.0002)

breast cancer, prevailed 16 (62,6 %), 18 (13 %) and

was noted; in adenocarcinoma, groups A7 (66.7 %)

45 (6.1 %) types of HPV HCR, followed by 31 (4,1 %),

( p = 0.0003) with the predominance of HPV 18

33 (2,8 %), 39 and 56 types (2.5 % each) (Fig. 2).

(60.0 %) ( p < 0.0001). HPV type 16 (86 %) was sig-

31 35 3

100 %

9 68

7.3

66

25.6

33 4

80 %

5

92.7

52 56

60 %

74.4

58 59 5

16

1

40 %

1

8

20 %

0 %

≤ 55 y.o.

> 55 y.o.

HPV (+)

HPV (-)

Fig. 1. Features of high risk HPV infection in patients with breast Fig. 2. Prevalence of 14 high risk HPV genotypes in patients with cancer, depending on age

breast cancer, including cases of multiple infection

57

South Russian Journal of Cancer 2024. Vol. 5, No. 2. P. 53-65

Mkrtchyan L. S., Kiseleva V. I., Krikunova L. I., Boyko B. V., Gusarova V. R., Bezyaeva G. P., Panarina L. V., Ivanov S. A., Kaprin A. D., Zamulaeva I. A. Status and molecular genetic parameters of papillomavirus infection: individual characteristics and associative links with clinical and morphological factors of cervical cancer nificantly more common among HPV 16/18-associ-Viral load

ated squamous cell carcinomas, and HPV type 18

Viral load was determined in 199 HPV-positive pa-

(64.3 %) in adenocarcinoma ( p = 0.0001). A similar

tients with stage I–III breast cancer, 175 (87.9 %) of

associative relationship of phylogenetic groups and,

them with a single infection, 24 (12.1 %) cases with

accordingly, genotypes with the histological type of

multiple infection. In the study group, high VL was

tumor has been revealed in other studies [9, 22].

most often observed (average level 6.4 ± 1.3) – in 142

The distribution of the most common phylogenetic

(71.4 %) cases. In 50 (25.1 %) patients, VL was mod-

groups (A9 and A7) did not significantly differ de-

erate (average level 4.4 ± 0.54), and only in 7 (3.5 %)

pending on the stage of the disease, the form of

it was low (average level 2.4 ± 0.1). When comparing

tumor growth, and in patients with locally advanced

the data on VL obtained during the processing of

breast cancer, including the variant of the spread of

various biological materials – cervical scrapings and

the tumor process (presence/absence of infiltration

biopsies of the same patients ( n = 47) – a fairly high of parametria, metastatic variant) ( p > 0.05), which is correlation of these indicators was revealed among

also confirmed by the results of other research [23].

themselves (r = 0.72,  p < 0.0000001) (Fig. 3).

Infection with several types of HPV HCV (multiple

There was a statistically significant increase in

infection) was detected in 25 (11.6 %) of 215 HPV-in-

the proportion of cases with low VL with increasing

fected patients (19–2 genotypes, 6–3 genotypes).

age (r = 0.86, p = 0.04), and no cases of low VL were There were no statistically significant differences in

detected in the age group under 30 years (Fig. 4).

the incidence of single or multiple HPV infection de-

In HPV 16, high virus load was most common,

pending on age, stage of the disease, form of growth

and in HPV 18, moderate and high loads were ob-

and variant of tumor spread, which is confirmed in

served with almost the same frequency (Fig. 5): the

the study by N. Jing et al. (2003) [24]. However, it

average VL level in HPV 16 (6.0 ± 1.7) turned out to

should be noted that multiple infection occurred only

be statistically significantly higher than the same

in patients with morphologically verified squamous

indicator in HPV 18 (5.0 ± 1.1) ( p < 0.001). This pat-cell carcinoma ( p < 0.0001 when compared with the

tern was maintained for the phylogenetic groups

glandular morphotype of the tumor, p = 0.038 when

to which these genotypes belonged: 6.0 ± 1.6 and

compared with undifferentiated cancer), this pattern

4.9 ± 1, respectively, for the genotypes of the A9 and

was noticed by other researchers [25].

A7 groups ( p < 0.001).

16

ток

14

Older

8.3

25

66.7

кле5

than 65

0/1 12

Е7

56-65

2.8

19.4

77.8

10

об), lg

8

45-55

4.9

26.2

68.9

(соск

6

узка

30-44

2.6

27.3

70.1

4

Younger

23.1

76.9

2

than 30

усная нагр

Вир

0

0

20 %

40 %

60 %

80 %

100 %

VL < 3

3 ≤ VL < 5

VL ≥ 5

-2

2

3

4

5

6

7

8

9

10

Вирусная нагрузка (биоптат), lg Е7/105 клеток

Fig. 3. Analysis of the correlation dependence of the HPV viral load Fig. 4. Viral load (VL) in patients with CC depending on age

in epithelial samples and corresponding biopsies of the cervix of patients with CC

58

Южно-Российский онкологический журнал 2024. Т. 5, № 2. С. 53-65

Мкртчян Л. С., Киселева В. И., Крикунова Л. И., Бойко Б. В., Гусарова В. Р., Безяева Г. П., Панарина Л. В., Иванов С. А., Каприн А. Д., Замулаева И. А. Статус

и молекулярно- генетические параметры папилломавирусной инфекции: индивидуальные особенности и ассоциативные связи с клинико- морфологическими

факторами рака шейки матки

In stage III of the disease, the average VL level

101 out of 168 people (60.1 %), which confirms

(6.2 ± 1.6) was significantly higher than in stage

the results of a number of studies on the high

I (5.4 ± 1.9) and II (5.4 ± 2.1), respectively, p = 0.006

incidence of invasive PCV virus in the integrated

and p = 0.02. Our data are consistent with the latest state [26, 28]. In the remaining 67 (39.9 %) patients,

results of domestic studies on relatively low VL in

there was a lack of integration of HPV DNA into

the early stages of the disease [19, 26].

the cellular genome (episomal form according to

In squamous cell carcinoma, more cases of high

the criterion of preserving the E2 gene in an intact

VL (73.9 %) ( p = 0.08) were detected, and in adeno-

state). It should be noted that the failure to inte-

carcinoma – low load (13.3 %) ( p = 0.07) (Fig. 6).

grate HPV DNA into the genome of the host cell in

Accordingly, the average level of VL was higher in

accordance with the algorithm described above

squamous cell carcinoma (5.8 ± 1.6) compared

cannot be unambiguously interpreted as the pres-

with adenocarcinoma (5.0 ± 1.6) ( p = 0.10). The

ence of only the episomal form of the virus, since

relationship of low load with cervical adenocar-

such integration can occur with the participation

cinoma and HPV type 18 is also noted by other

of various other viral genes [29– 30]. However, this

authors [27].

process is mainly associated with a violation of the

According to our data, there were no statistically

integrity of the E2 gene of the virus [31], which is

significant differences in the level of VL in different

explained by the high availability of this viral gene

forms and variants of the spread of the tumor process.

for various types of genetic rearrangements. More-

over, we have obtained data suggesting a higher

HPV DNA Integration 16/18

biological significance of the E2-mediated pathway

The presence of virus DNA integration, both

of integration of the viral genome into the cellular

complete and partial, was studied in patients in-

one, as opposed to integration invoVLing other viral

fected with HPV types 16 and 18 (140 and 28 cas-

genes [32].

es, respectively), which are the most aggressive

A comparative analysis of the data on the degree

and account for the vast majority of all genotypes

of integration of viral DNA in scrapings and biop-

detected in breast cancer. Such patients accounted

sies of the cervix obtained from the same patients

for 78.1 % of all HPV-positive cases in our study. In

( n = 47) revealed a fairly high correlation of the in-the studied cohort, the majority of patients revealed

dicators with each other: the correlation coefficient

the integration of virus DNA (integrated form) – in

R = 0.89 at a significance level p < 0.000001 (Fig. 7).

78.9

44.8

73.9

54.3

100 %

100 %

80 %

80 %

60 %

48.3

60 %

40 %

40 %

33.3

23.9

16.3

20 %

20 %

13.3

4.8

6.9

2.2

0

0

HPV 16

HPV 18

Squamous cell carcinoma

Adenocarcinoma

VL ≥ 5 3 ≤ VL < 5 VL < 3

VL ≥ 5 3 ≤ VL < 5 VL < 3

Fig. 5. Viral load (VL) in HPV-positive patients with CC, depending Fig. 6. Viral load (VL) in HPV-positive patients with CC depending on the genotype of the virus

on the morphological form of the tumor

59

South Russian Journal of Cancer 2024. Vol. 5, No. 2. P. 53-65

Mkrtchyan L. S., Kiseleva V. I., Krikunova L. I., Boyko B. V., Gusarova V. R., Bezyaeva G. P., Panarina L. V., Ivanov S. A., Kaprin A. D., Zamulaeva I. A. Status and molecular genetic parameters of papillomavirus infection: individual characteristics and associative links with clinical and morphological factors of cervical cancer

%

100

HPV 18 17.9 17.8

64.3

apings),

(scr

80

ation

60

integr

40

HPV 16

2.6

15.0

40.7

HPV

risk

20

0

20 %

40 %

60 %

80 %

100 %

high of 0

Integration (-)

vel

Integration < 50 %

Le

-20

Integration ≥ 50 %

-20

0

20

40

60

80

100

Level of high risk HPV integration (biopsy material), %

Fig. 7. Analysis of the correlation dependence of the degree of Fig. 8. Physical status and degree of integration of HPV 16 and high risk HPV integration in epithelial scrapings and corresponding HPV 18 DNA in patients with CC

biopsies of the cervix of patients with cervical cancer. The degree of integration varies from 0% (the episomal form of the virus) to 100 % (full integration of viral DNA into the cellular genome). The intermediate values correspond to the mixed form of high risk HPV–

the presence of both episomal and integrated forms; the quantitative indicator – the degree of integration corresponds to the proportion of integrated forms of high risk HPV

Table 1. Distribution of CC patients depending on the qualitative and quantitative parameters of HPV 16/18

Viral form

Episomal abs (%)

Integrated abs (%)

Viral load

< 50 %

≥ 50 %

VL < 3 ( n = 5)

1 (20.0)

0

4 (80.0)

3≤ VL < 5 ( n = 39)

11 (28.2)

5 (12.8)

23 (59.0)

VL ≥ 5 ( n = 124)

55 (44.4)

21 (16.9)

48 (38.7)

100

80

vel,%

60

le

ation

40

Integr

20

Fig. 9. Correlation analysis of the molecular genetic parameters of HPV infection in CC patients (n = 168): 0 % – lack of integration (episomal form of the virus), 100 % – complete integration of HPV

0

DNA into the genome of the host cell. The intermediate values correspond to the mixed form of HCR HPV – the presence of both 0

2

4

6

8

10

12

14

episomal and integrated forms; the quantitative indicator – the degree of integration – corresponds to the proportion of integrated Number of copies of DNA HCR HPV, 1g Е7/105

forms of HPV 16/18

60

Южно-Российский онкологический журнал 2024. Т. 5, № 2. С. 53-65

Мкртчян Л. С., Киселева В. И., Крикунова Л. И., Бойко Б. В., Гусарова В. Р., Безяева Г. П., Панарина Л. В., Иванов С. А., Каприн А. Д., Замулаева И. А. Статус

и молекулярно- генетические параметры папилломавирусной инфекции: индивидуальные особенности и ассоциативные связи с клинико- морфологическими

факторами рака шейки матки

Taking into account these data, as well as similar re-

Associative relationship of viral load and

sults of a comparative analysis of HCV, it is possible

HPV DNA status 16/18

to recommend the use of scraping of the cervical

The molecular genetic parameters of viral infec-

epithelium for the molecular genetic study of HPV

tion were studied in 168 HPV 16/18-positive patients

parameters, since the informative value of the ma-

with stage I–III breast cancer. As the HCV increased,

terial obtained by this method is not inferior to the

there was an increase in the proportion of episomal

informative value when performing a more traumatic

and a decrease in the proportion of highly integrated

procedure – cervical biopsy.

forms of the virus (Table 1).

The integrated form of HPV HCR was most com-

Low viral load only in a single case (20.0 %) ac-

mon in patients over 65 years of age – in 66.7 % of

companied the liposomal form of the virus; all other

cases, while in 44.4 % of cases it was in the form of

cases of low viral load (80.0 %) were combined with

complete (100 %) integration. When infected with

100 % integration. Previously, we had established

HPV 18, compared with HPV 16, integrated forms of

an inverse linear correlation between VL and the de-

the virus prevailed (82.1 % and 55.7 %, respectively,

gree of integration of HPV DNA into the cellular ge-

p = 0.01) with a predominance of highly integrated

nome [35]. Subsequently, the sample of patients was

(DNA integration ≥ 50 %) forms (64.3 % and 40.7 %,

significantly increased, and this pattern remained

respectively, p = 0.019), a high percentage of which with high significance (r = – 0.41, p < 0.0001) (Fig. 9).

was full (100 %) integration HPV DNA (50.0 % vs.

20.7 %, p = 0.003) (Fig. 8). The more frequent de-

Multivariate analysis

tection of HPV type 18 in the integrated state com-

In order to study possible associative relation-

pared with HPV type 16 is also reported in foreign

ships between various parameters characterizing

studies [33].

the tumor process and HPV infection, a multidimen-

The analysis of the presence/absence and degree

sional exploratory analysis was performed using the

of integration depending on clinical and morpholog-

clustering method, which allowed us to identify the

ical characteristics did not reveal statistically signif-

most interrelated parameters – the morphological

icant associative relationships, which is consistent

form of the tumor and HPV status (Fig. 10), and in

with the literature data [34].

HPV-positive breast cancer – the morphological form

Dendrogram for 6 valuables

Dendrogram for 9 valuables

Single link method

Single link method

The Euclidean distance

The Euclidean distance

Age

Age

Stage

Stage

Distribution type

Distribution type

Growth type

Morphological type

Growth type

Number of

genotypes

Morphological type

Genotype

Integration

HCR HPV

Viral load

8

10

12

14

16

18

20

8

9

10 11 12 13 14 15

Distance merges

Distance merges

Fig. 10. Dendrogram of CC patients with HPV status ( n = 240) Fig. 11. Dendrogram of HPV-associated CC patients taking into account the entire spectrum of molecular genetic parameters of HCR HPV ( n = 174)

61

South Russian Journal of Cancer 2024. Vol. 5, No. 2. P. 53-65

Mkrtchyan L. S., Kiseleva V. I., Krikunova L. I., Boyko B. V., Gusarova V. R., Bezyaeva G. P., Panarina L. V., Ivanov S. A., Kaprin A. D., Zamulaeva I. A. Status and molecular genetic parameters of papillomavirus infection: individual characteristics and associative links with clinical and morphological factors of cervical cancer of the tumor and the following features of HPV in-vealed the presence of correlations between HPV sta-

fection: the number of HPV HCV genotypes present,

tus, HPV genotype, the number of genotypes present

genotypes 16 and 18, the physical status of viral

and a known prognostic factor – the morphological

DNA – the presence/absence of integration into the

form of cervical cancer. At the same time, our work

genome of the host cell (Fig. 11).

shows the absence of a relationship between such

Thus, multifactorial exploratory analysis made

molecular genetic parameters of HPV infection as the

it possible to detect associative relationships that

genotype and the level of integration of virus DNA into

were not obtained by pairwise comparison of various

the cellular genome with the main traditional factor in

factors, but which could be assumed indirectly when

predicting the effectiveness of treatment – the stage

studying the results of a single- factor analysis.

of the disease. This fact suggests the possibility of

a prognostic value of these parameters independent

CONCLUSION

of the stage and justifies the expediency of conduct-

ing further studies to assess the prognostic value of

The study of possible associative relationships be-

the level of integration of HPV DNA of various gen-

tween a wide range of molecular genetic parameters

otypes (primarily the most common types 16 and

of HPV infection and the clinical and morphological

18) as potential independent biomarkers for predict-

characteristics of a malignant tumor of the cervix re-

ing the effectiveness of treatment of breast cancer.

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Information about authors:

Liana S. Mkrtchian – Dr. Sci. (Med.), leading researcher, A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation ORCID: https://orcid.org/0000-0002-5027-5331, SPIN: 3352-0814, AuthorID: 147713, ResearcherID: JBJ-0493-2023, Scopus Author ID: 6601999343

Valentina I. Kiseleva – Cand. Sci. (Biol.), leading researcher, A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation ORCID: https://orcid.org/0000-0003-3565-1981, SPIN: 2865-4070, AuthorID: 81608, ResearcherID: T-1073-2017, Scopus Author ID: 7004413804

Lyudmila I. Krikunova – Dr. Sci. (Med.), professor, chief researcher, A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation ORCID: https://orcid.org/0000-0003-1842-156X, SPIN: 2845-6710, AuthorID: 93505, ResearcherID: JCT-3165-2023, Scopus Author ID: 6506081959

Boris V. Boyko – PhD Student, A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation ORCID: https://orcid.org/0009-0009-6821-5335, ResearcherID: JDC-4676-2023

Victoria R. Gusarova – PhD student, A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation ORCID: https://orcid.org/0000-0002-7819-2730, ResearcherID: HMD-3406-2023

Galina P. Bezyaeva – research associate, A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation ORCID: https://orcid.org/0000-0002-4942-6892, SPIN: 8900-4710, AuthorID: 87889, ResearcherID: JFJ-8132-2023, Scopus Author ID: 6506415163

Larisa V. Panarina – research associate, A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation ORCID: https://orcid.org/0009-0001-9237-2869, SPIN: 9602-8908, AuthorID: 113918, ResearcherID: JFJ-8238-2023, Scopus Author ID: 6506225026

Sergei A. Ivanov – Dr. Sci. (Med.), professor, corresponding member of the Russian Academy of Sciences (RAS), director of A. F. Tsyb Medical Radiological Research Centre – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation; professor of the Department of Oncology and Radiology named after V. P. Kharchenko at the Medical Institute, Peoples Friendship University of Russia, Moscow, Russian Federation

ORCID: https://orcid.org/0000-0001-7689-6032, SPIN: 4264-5167, AuthorID: 710405, ResearcherID: N-8221-2017, Scopus Author ID: 16070399200

Andrey D. Kaprin – Dr. Sci. (Med.), professor, Academician of the Russian Academy of Sciences, Academician of the Russian Academy of Education, director of P. A. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Moscow, Russian Federation; general director of National Medical Research Radiological Centre, Obninsk, Russian Federation; head of the Department of Oncology and Radiology named after V. P. Kharchenko at the Medical Institute, Peoples Friendship University of Russia, Moscow, Russian Federation

ORCID: https://orcid.org/0000-0001-8784-8415, SPIN: 1759-8101, AuthorID: 96775, ResearcherID: K-1445-2014, Scopus Author ID: 6602709853

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Южно-Российский онкологический журнал 2024. Т. 5, № 2. С. 53-65

Мкртчян Л. С., Киселева В. И., Крикунова Л. И., Бойко Б. В., Гусарова В. Р., Безяева Г. П., Панарина Л. В., Иванов С. А., Каприн А. Д., Замулаева И. А. Статус

и молекулярно- генетические параметры папилломавирусной инфекции: индивидуальные особенности и ассоциативные связи с клинико- морфологическими

факторами рака шейки матки

Irina A. Zamulaeva – Dr. Sci. (Biol.), professor, head of the Department of Radiational Biochemistry, A. F. Tsyb Medical Radiological Research Centre

– Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, Russian Federation ORCID: https://orcid.org/0000-0002-6136-8445, SPIN: 9542-6211, AuthorID: 87777, ResearcherID: R-4906-2016, Scopus Author ID: 6603693422

Contribution of the authors:

Mkrtchyan L. S. – scientific processing of literature data on the topic of publication, collection of clinical material, statistical analysis of clinical and experimental data, writing the text of the article, discussion and interpretation of research results; Kiseleva V. I. – optimization of molecular and genetic research methods, analysis of the results obtained and maintenance of the database, participation in writing and editing the text of the article; Krikunova L. I. – planning the clinical part of the study, discussion of the obtained clinical data; Boyko B. V. – collection and design of literature, translation of the text into English; Gusarova V. R. – collection and analysis of literature;

Bezyaeva G. P. – collection and processing of biological material, conducting PCR studies for the presence of HCR HPV DNA; Panarina L. V. – collection and processing of biological material, conducting PCR studies for the presence of HCR HPV DNA; Ivanov S. A. – scientific editing and approval of the final text; Kaprin A. D. – scientific summary;

Zamulaeva I. A. – development of the concept and scientific design of the study, interpretation of the obtained clinical and experimental data, scientific editing of the article, summarizing the results obtained, formulation of conclusions.

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