How to cite this article: Flores-Miramontes MG, Torres-Reyes LA, Aguilar-Lemarroy A, Vallejo-Ruíz V, Piña-Sánchez P, Cortés-Gutiérrez E, Reyes-Leyva J, Jave-Suárez LF. HPV genotypes prevalence in México and worldwide detected by linear array. Rev Med Inst Mex Seguro Soc. 2015;53 Supl 2:S122-30.
Received: February 16th 2015
Accepted: March 4th 2015
María G. Flores-Miramontes,a,b Luis A. Torres-Reyes,a,b Adriana Aguilar-Lemarroy,a Verónica Vallejo-Ruíz,c Patricia Piña-Sánchez,d Elva Cortés-Gutiérrez,e Julio Reyes-Leyva,c Luis Felipe Jave-Suáreza
aCentro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Guadalajara, Jalisco
bDoctorado en Ciencias Biomédicas, Universidad de Guadalajara, Guadalajara, Jalisco
cCentro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social, Metepec, Puebla
dLaboratorio de Oncología Molecular, Unidad de Investigación Médica en Enfermedades Oncológicas (UIMEO), Instituto Mexicano del Seguro Social, Distrito Federal
eCentro de Investigación Biomédica del Noreste (CIBIN), Instituto Mexicano del Seguro Social, Monterrey, Nuevo León
Communication with: Luis Felipe Jave-Suárez
Telephone: (33) 3617 0060, extensión 31926
Infection with human papillomavirus (HPV) is the main factor associated with the development of cervical cancer (CC). Knowing about the prevalence of HPVs at different stages in the development of CC is important for determining the HPV oncogenic risk, the development of screening strategies, the evaluation of prevention programs, and also for vaccine designing. This paper is a meta-analysis of HPV prevalence worldwide and in Mexico from studies using the Linear Array® HPV Genotyping Test as a diagnostic test (it is the commercial test that, up to date, identifies the largest number of HPV genotypes in a single sample) in DNA of cervical samples from women with normal cytology, with low grade squamous intraepithelial lesions (LGSIL), with high grade squamous intraepithelial lesions (HGSIL) and with CC. The most prevalent genotypes after HPV-16 and -18 in women with CC varies depending on geographic region, which supports the need to develop detection and prevention strategies according to the characteristics of the population.
Keywords: HPV, Papillomavirus, Cervical cancer.
Cervical cancer is a public health problem in developing countries, including Mexico. There are many factors associated with the development of this cancer, such as early sexual activity, multiple sexual partners, multiple births, smoking, and certain dietary deficiencies.
Infection with certain genotypes of human papillomavirus (HPV) is the main risk factor associated with cervical cancer (CC).1 To date, approximately 200 HPV genotypes have been identified; however, it has been reported that about 40 infect the anogenital tract and only HPV types -16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, and -59 have been classified as type 1 carcinogens, due to the prevalence and viral types found in the normal and cancerous cervical epithelium. There are other HPV viral types such as HPV-68, classified as probably carcinogenic (Group 2A), and the HPV types -26, -30, -34, -53, -66, -67, -69, -70, -73, -82, -85, and -97, classified as possibly carcinogenic (Group 2B).2 The types most commonly associated with cervical cancers globally are HPV-16, -18, and -45.2 However, some HPV types are found more frequently than others, depending on the geographical region; for example, HPV-31 and -33 are more prevalent in Europe and the U.S., while types -35 and -45 are more common in Africa and types -52 and -58 in Asia.3
In Mexico, CC is the second most frequent malignancy and the fourth leading cause of cancer incidence and mortality in women worldwide. In the Mexican population it has been reported that genotypes HPV-16, -18, -31, -45, and -58 are the most prevalent in cervical samples;4 however, most of these studies have certain limitations due to methodologies for screening and genotyping (as they have only identified certain viral types) seeing as a percentage of 5 to 8% did not detect HPV in cervical cancer, when it is reported that less than 0.1% of samples of cervical cancer are negative for HPV. In addition, the methods employed failed to identify co-infections. A few years ago, a more sensitive and specific method, based on polymerase chain reaction (PCR) and reverse hybridization line, made it possible to detect 37 HPV genotypes and identify coinfections in the sample.5 Considering this, the goal of the study was to conduct a meta-analysis to determine the prevalence of HPV genotypes worldwide, in samples without cervical lesions (normal), with precursor lesions, and with cervical cancer using the method of Linear Array® HPV Genotyping Test, and to make a comparison with the prevalence found in Mexico by our working group.
A search was performed in PubMed, ScienceDirect, SpringerLink, and Wiley databases to identify articles published to date with the following criteria: HPV genotyping done by Linear Array® HPV Genotyping Test, reporting the HPV prevalence according to diagnosis (women without cervical lesion, with low-grade squamous intraepithelial lesion LSIL, with high-grade squamous intraepithelial lesion HSIL, or with CC), and in which all HPV genotypes detected by the test were reported. About 60 manuscripts were reviewed, of which 32 did not meet all inclusion criteria, because they only reported the HPV genotypes considered high-grade, did not group data according to histological diagnosis, or did not verify diagnosis of samples. Thus, a total of 12 studies were included, which met all the selection criteria mentioned above (Table I).
|Table I Prevalence of HPV genotypes found in different world regions according to diagnosis|
|n||1 °||2 °||3 °||4 °||5 °||6 °||7 °||8 °||9 °||10 °||Reference|
|Mexico||356||16, 62||51, 84||18||53, Cp6108||52, 70, 54, 55||Aguilar-Lemarroy et al. 2015|
|US||670||16||52||54||31||18||84||51, 53||Cp6108||Wentzensen et al. 2010|
|42||54, 61, 73||18, 39, 51, 84||31, 55, 58,62 66 Cp6108||6, 33,
|35, 67, 72, 81, 82||Froberg et al. 2008|
|Tanzania||148||58||66||82||26||16||18, 45||Vidal et al. 2011|
|South Africa||23||16, 35||33, 51, 56||26, 39, 42, 53, 55, 58, 59, 61, 68, 69, 83||Marais et al. 2008|
|Australia||170||16||53||Cp6108||73||52||31||51||18, 39, 56, 58, 59||45, 66||35||Stevens et al. 2009|
|Mexico||315||16||84||58||59||62||18||66, 39||31, 51, 53, 70||52, 56, Cp6108||61||Aguilar-Lemarroy et al. 2015|
|Canada||508||16||51||39||52||53||Cp6108||66||31, 42||18, 56||58||Coutlee F et al. 2011|
|US||280||16||51||18, 53||59||39, 66||52||6||31||35, 58||33||Wentzensen al. 2010|
|Sweden||39||42, 84||16, 52, Cp6108||31, 56, 61, 62, 66||35, 58, 59||6, 18, 39, 45, 51, 67, 70, 73, 83||Froberg et al. 2008|
|South Africa||18||35||16, 18, 45, 53, 56||51, 58, 59, 62, 66||Marais et al. 2008|
|Australia||196||16||31, Cp6108||51, 53||52||66||39, 56||58, 59, 6||73||45||18||Stevens et al. 2009|
|n||1 °||2 °||3 °||4 °||5 °||6 °||7 °||8 °||9 °||504||Reference|
|Mexico||30||16||31||18, 70||6, 51, 59, 66, Cp6108||35, 58, 56, 62, 61, 42,||33, 39, 52, 84, 53, 71, 69, 11, 26||Aguilar-Lemarroy et al. 2015|
|Canada||238||16||18, 31||52||39||33, 51||53, 61, Cp6108||56, 62||54, 59||58||42, 45||Coutlee F et al. 2011|
|US||165||16||18, 31||51||33||52||45||58||59||35, 68||53, 54, 82||Wentzensen et al. 2010|
|US||89||16||31||52||33, 58||18||45||35, 51||39, IS39||68, 53, 67||Hariri et al. 2012|
|Norway||643||16||31||33||52, 18||51||58, 45||39||54, 52||42, 56, 61, 65, 53, 70, 73||35, Cp6108||Sjoeborg et al. 2010|
|South Africa||62||16||18||35||31||33, 52, 58||39, 53, 56, 66, 68||26, 45, 51||Marais et al. 2008|
|Australia||329||16||31||52||51||33||39||18||Cp6108||58||56||Stevens et al. 2009|
|Mexico||122||16||18||45||52, 58||39||66, 53, 68||33, 35, 51, 70, 6, 71||31, 56, 69||Aguilar-Lemarroy et al. 2015|
|Canada||252||16||18||52||45||33||31||39, 53||56, 59, 62, 81, Cp6108||42, 58, 83, 84||Coutlee F et al. 2011|
|US||107||16||18||45||33||39, 52||Wentzensen et al. 2009|
|US||86||16||45||18||45||33||39, 52||73||31, 51, 58, 66, 69, 82||Hariri et al. 2012|
|Brazil||143||16||31||33||18||35||45||52, 58, 73||56, 62||11, 39, 53, 72, 84||Mendes de Oliveira et al. 2013|
|Tanzania||48||16||35||45||18||31||52||Vidal et al. 2011|
|Thailand||99||16||52||18, 33||58||31||45||66, 11||Siriaunkgul et al. 2008|
|Saudi Arabia||100||16||31||45||18||73||6, 59, 64||Aisbeih et al. 2011|
|HPV = human papillomavirus; LSIL = low-grade squamous intraepithelial lesion; HISL = high-grade squamous intraepithelial lesion; US = United States|
In addition, more than 800 DNA samples were included from Mexican women from different parts of the Republic (results obtained by the Red de Investigación de VPH of the Instituto Mexicano del Seguro Social, IMSS), which had diagnosis confirmed by cytology/histopathology and whose genotyping was performed using the Linear Array® HPV Genotyping Test. The results are described in detail by Aguilar-Lemarroy et al. in the Journal of Medical Virology, 2015. In total, this meta-analysis included 1425 normal cytology samples, 1356 samples with LSIL, 1556 samples with HSIL, and 957 samples with CC from different countries, such as Mexico, the United States, Canada, Brazil, Sweden, Tanzania, South Africa, Thailand, Saudi Arabia, and Australia (Table I). In addition, studies were included in which the same genotyping method was used, but whose samples were not divided by diagnostic group or did not have diagnosis (Table II).
|Table II Prevalence of HPV genotypes found in different world regions in samples of histological diagnosis|
et al. 2008
|Native American women,
|235||61||52, 59||16||62||18, 68, 45||51, 55, 72||58, 66, 81||71, 83,
|6, 11, 31,
53, 54, 73
|33, 35, 39, 40, 84||Schmidt-
et al. 2011
|246||16||59||53||39, 61, 62||18||54||51, 52,
|6,45, 83||35,40, 42,
56, 58, 72,
et al. 2011
|US||255||16||52||18||31, 33, 58||45||51||35||56||Hariri
et al. 2012
|Chile||1110||84, 61||16||62, Cp6108||52, 53||70||58, 71||81||51||56||31, 45, 66, 42, 83||Ferrecio
et al. 2008
et al. 2011
|Egypt||443||16||62||31, 51||52||59, 84||18, 58, 6||66, 40, Cp6108||56, 73, 26,
53, 61, 67,
70, 81, 83
et al. 2014
|Asia||396||52||16||58||51||18||53, 56||66||33, 68||39||84||Wong
et al. 2012
et al. 2009
|Spain, France, and Italy||311||16||31||53||58||33||51||56||59, 66||52||35||Halfon
et al. 2013
et al. 2011
|HPV = human papillomavirus; US = United States|
Determination of HPV genotypes, both in the reports selected and in the samples from Mexican women, was done by Linear Array® HPV Genotyping Test (Roche Molecular Diagnostics TM), which is based on:
This test also includes amplification of the human beta globin gene as an internal control. The analysis of results was done visually with a reference guide included in the kit. All procedures were performed following the manufacturer's instructions.
The Linear Array® HPV Genotyping Test detects 37 HPV genotypes with high and low risk: -6, -11, -16, -18, -26, -31, -33, -35, -39, -40, -42, -45, -51, -52, -53, -54, 55, -56, -58, -59, -61, -62, -64, -66, -67, -68, -69, -70 , - 71, -72, -73 (MM9), -81, -82 (MM4), -83 (MM7), -84 (MM8), IS39 (HPV-82 subtype) and Cp6108 (commonly known as HPV-89).
HPV prevalence according to diagnostic groups in Mexico
Derived from testing in Mexican women, HPV infection was found in 12.36% of normal samples, 46.03% in LSIL, and 100% of samples diagnosed with HSIL and CC (Aguilar-Lemarroy et al. J Med Virol, 2015).
The prevalence of HPV genotypes by diagnostic group showed that HPV-16 was the most frequent viral type in all groups; followed by HPV-62, -51/-84, -18 and -53/-Cp6108 in controls; HPV-84, -58, -59 and -62 in LSIL; HPV-31, -18/-70 and -6/-51/-59/-66/-Cp6108 in HSIL; and HPV-18, -45, -52/-58 and -39 in CC (Table I).
HPV prevalence according to diagnostic groups worldwide
Women without lesions
In the group classified as women without cervical lesions, the results of each of the studies worldwide are shown in Table I. The HPV genotype most commonly found is HPV-16, except for in Central Africa (Tanzania), where HPV-58 is detected more often and HPV-16 ranks fifth. It is noteworthy that HPV-58 is also found in Sweden (fifth place), South Africa (third place) and Australia (eighth place).
After HPV-16 infection, the frequency of other HPV genotypes is highly variable in each of the regions: in the United States, Sweden, and Mexico the genotypes -52, -53, -54, -84, and Cp6108 predominate; -52, -53, and Cp6108 are also common in Australia; while in South Africa -35, -33, -51, and -56 prevail. HPV-51 is commonly found in Mexico and South Africa. The presence of HPV-62 and -70 was only reported in Mexico and Sweden; while HPV-31 was only identified in the United States, Sweden, and Australia.
Women with low-grade intraepithelial lesion
Concerning the HPV genotypes identified with greater frequency in the group of patients with LSIL, in all regions HPV-16 was at the top, followed by HPV-51 (less frequent only in Mexico).
HPV-84 was found among the first places in Mexico and Sweden, and Cp6108 in Sweden and Australia. Significantly, unlike other regions, HPV-42 was the most frequently found in Sweden (together with -84) and HPV-35 in South Africa. Among the HPV reported found in all studies for diagnosis were HPV-18, -51, -53, -58, and -66. Except for South Africa, HPV-31 and -39 have also been reported in all regions in women with LSIL (Table I).
Women with high-grade intraepithelial lesion
As can also be seen in Table I, in the group of women with high-grade intraepithelial lesions, the most common HPV genotypes are more homogeneous; in all regions HPV-16 was first, followed by HPV -31, -18, -52, and -51. Interestingly, HPV-35, which ranks third in South Africa, was also reported in this grade of lesion in Mexico and the United States. Importantly, HPV-70, which is third in prevalence in Mexico, was not reported in any other region except Norway, where it ranks ninth in prevalence (Table I).
Women with cervical cancer
In the group of women with developed cervical cancer, as in HSIL samples, a more homogeneous group of HPV genotypes is seen present in all regions. HPV-16 is again the one with the highest prevalence above other viral genotypes; subsequently, in the top places of prevalence in all regions, are the genotypes -18, -45, -31, and -35 (the latter two less frequently in Mexico and Canada). Importantly, HPV-52, which is the second most prevalent in Thailand, ranks fourth in Mexico, third in Canada, fifth in the U.S., and seventh in Brazil; additionally, HPV-58 is in fourth place in both Mexico and Thailand, seventh place in Brazil and the United States, and in tenth place in Canada. Another genotype also prevalent in various regions is HPV-33 (except for Tanzania and Saudi Arabia). It is of considerable interest to mention that the presence of HPV-39 in CC is reported only in countries of the Americas, such as Canada, the U.S., Mexico, and Brazil (Table I).
Infection with certain types of HPV has been considered the major risk factor for CC, and multiple studies have reported that more than 99% of the samples of this disease are positive for HPV of high oncogenic potential.1 The previous study of this working group (Aguilar-Lemarroy et al, J Med Virol, 2015) found 100% of HSIL and CC samples infected with some form of HPV; previous studies in Mexico have identified between 95 and 98% of positive cases, possibly because of the lower sensitivity of the methods used for detection. Meanwhile, we detected 12.36% of HPV infection in cytology without neoplastic changes. These observations are consistent with those reported globally.6 Previous studies in the Mexican population have reported an HPV infection rate of 10 to 12% in healthy women in Mexico City, 16.7% in the state of Morelos, and high percentages (between 35 and 40%) in women in southern Mexico.7 This discrepancy may possibly be due to different regional areas analyzed or to the sensitivity of the diagnostic method used in the study, or it could even be attributed to differences in cytological diagnosis.
HPV-16 is the most prevalent type in all diagnostic groups, a finding that was also reported by a number of authors worldwide and in Mexico. The exceptions where other HPV genotypes were found in first place were: cervix without lesion, HPV-58 in Tanzania;8 in LSIL, HPV-42 and -84 in Sweden9 and -35 in South Africa.10 However, the prevalence of other genotypes differs depending on the severity of the lesion.
In samples from the group of women without cervical lesions, the HPV that are present in different regions are very heterogeneous. It is of considerable interest that the HPV genotypes found in Mexican women are the same as those identified in male external genitalia (glans, penis crown, groove, shaft, and scrotum) in the United States, Mexico, and Brazil; in this report, the HPV genotypes most frequently found were -62, -84, -16, Cp6108, and -51.11 In addition to this, in an open study of Chilean women, the high prevalence of HPV-84, -16, -62, and Cp6108 was also reported.12
Regarding the HPV genotypes most commonly found in LSIL, as can be seen in Table I, in addition to HPV-16, a high prevalence of infection with HPV-84 is found in Mexico (Aguilar-Lemarroy et al., 2015) and Sweden.9 Other studies (Table II) have also reported a high frequency of this viral genotype in Chile12 and Egypt.13
In contrast to any other region, the most prevalent genotype in South Africa is HPV-35, which is also in fourth place in Sweden in LSIL samples,9 while in the United States and some European countries it is little prevalent in cervical samples without diagnosis. HPV-62 is within the first four places of prevalence in Sweden, South Africa, and Mexico (Table I) in this type of lesion; it has also been found within the top of prevalence in some other countries (Chile,12 Turkey,14 U.S.,15 Egypt13), although the diagnostic group is not specified.
As for the group with HSIL, a significant prevalence was found in Mexico of viral genotypes -16, -31, -18, -70, and -51. All of them, except for HPV-70, have also been reported as prevalent in this diagnostic group in Canada,16 United States,17 Norway,18 South Africa,10 and Australia.19 Additionally, they have been reported in other studies in Spain,20 Switzerland,21 Portugal,22 and Ireland.23
In connection with HPV-70, it is of interest to mention that this viral genotype was found in all diagnostic groups in Mexican women (Aguilar-Lemarroy et al, J Med Virol, 2015); it has also frequently been found in Finland,24 Terceira Island,25 Denmark,26 and Chile.12 Within the studies found that were done using the Linear Array® HPV Genotyping Test, it is found in Sweden only in the groups of women without lesion and with low-grade cervical lesion,9 and in Norway in the group of women with high-grade cervical lesion,27 so one can add that this is a common viral type in Mexico (Aguilar-Lemarroy et al. J Med Virol, 2015), but rare in other populations.
Finally, in the CC group in Mexico, HPV genotypes -16, -18, and -45 were the most frequently found, followed by HPV-52, -58, and -39. HPV-52 was also reported within the first five places in Canada,16 United States28,29 and Thailand,30 as well as some countries in Asia,31 and also in Chile.12 It is worth mentioning that this viral genotype has not only been reported in CC, but is also prevalent in low- and high-grade lesions, and in samples from patients without cervical lesion.9,17,19 The prevalence of HPV-58 is reported fourth in Mexico (Aguilar-Lemarroy et al., 2015) and Thailand30 in CC samples, and with lower prevalence in Canada, the United States, and Brazil in this diagnostic group (Table I). It has been reported in different types of cervical lesions in Sweden, South Africa, Australia, United States, and Canada (Table I); as well as in Chile, Egypt, and some European countries (Table II). Importantly, it is very common in East Asia;31 in fact, researchers on this continent are currently developing vaccines that include protection against this viral genotype.32 Interestingly, HPV-58 has also been reported frequently found in southeastern Mexico (Yucatan).33 While this genotype is classified as high-risk, we can also find it in groups of women without cervical lesion, as is the case in Sweden, Tanzania, South Africa, and Australia (Table I). With respect to HPV-39, in Mexico it has fifth place in samples of CC; although there are few reports, it has been considered that HPV-39 has significant prevalence in the United States and Canada;16,28 its presence has also been reported in Brazil, although less prevalent.34 An important observation is that all of these countries belong to the American continent, so it could probably be involved a more aggressive variation of this genotype.
Another important point that should be mentioned is that HPV-71 was present only in samples of LSIL and CC in Mexican population; so far this genotype has not been assigned oncogenic potential. While it has been reported that the E6 oncoprotein of HPV-71 has the ability to efficiently degrade p53,35 and that in the Mexican population it has a very similar prevalence to HPV-33, -39, and -52 (in HSIL) and -33, -35, and -51 (in CC), it could be classified as a "probably" carcinogenic HPV for humans, but it would require further study to determine its oncogenic potential.
As it regards HPV types classified as "probably" or "possibly" carcinogenic, such as HPV-26 and -67, in Mexico the presence of these viral genotypes was not detected in cervical cancer samples, so these genotypes are not considered to be associated with cancer in our population. However, HPV-66 and -70 were detected in samples of CC in Mexican women. Likewise, HPV-66 was found in samples in the United States and Thailand (Table I), so its oncogenic potential and its contribution to transformation should be thoroughly evaluated.
Considering other HPV genotypes, regardless of the type of histological lesion, a very low frequency in the Mexican population was found of HPV-6, -26, -40, -54, -55, -67, -73, -72, and -82.
This analysis showed that in addition to HPV-16 and -18, the genotypes -31, -33, -35, -45, -52, and -58 are very prevalent, especially in CC in most geographic regions, so it is necessary to implement appropriate detection and prevention strategies.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.