"The Lancet" Sub-Journal: Why are some HPV infected people more likely to develop cervical cancer?

Cervical cancer ranks third in the global cancer incidence and is the most common gynecological cancer in developing countries.
There are approximately 530,000 new cases and 275,000 deaths worldwide every year [1].

When it comes to cervical cancer, the first thing we will think of should be HPV and HPV vaccines.

According to statistics, about 80% of people will be infected with HPV.

As early as 1980 [2], German virologist Harold established the link between genital HPV infection and cervical cancer.
Up to now, "persistent infection of high-risk HPV is closely related to the occurrence of cervical cancer" has become a popular science.
Scientific consensus.

The good news is that most cervical high-risk HPV infections are short-lived, and only a small percentage develop into cervical cancer.

Previous studies have shown that the main risk factors associated with the development of cervical cancer include high-risk HPV infection, age, smoking, childbirth, use of oral contraceptives, and diet.

[3] In addition to the above factors, the influence of genetic variation on cervical cancer susceptibility has also been controversial.

Studies on family clustering and heritability estimation have shown that heredity contributes as much as 27-36% to the risk of cervical cancer [4].

However, previous genome-wide association studies (GWAS) were limited by the sample size and the rarity of invasive cervical cancer.
The phenotype of cervical cancer was largely dominated by precancerous diseases, and there was no separate analysis of cancer.
The results are not consistent, and further work is needed to determine the genetic susceptibility of cervical cancer.

Recently, a research team led by Sarah Bowden of Imperial College London, UK published an important research result in the “Lancet” sub-Journal “Lancet Oncology”.
They found 6 areas of PAX8, CLPTM1L and HLA.
Independent sites are related to cervical intraepithelial neoplasia grade three (CIN3) and invasive cervical cancer. In addition, they also confirmed that smoking and the number of sexual partners are risk factors for cervical cancer, while older age at first pregnancy is a protective factor.

Screenshot of the paper’s homepage.
The Bowden team’s research samples come from the British Biobank.
A total of 4,005 women with CIN3, 764 women with invasive cervical cancer, and 145,545 control women, all aged 40-69 years, were included.
between.

The researchers used the Axiom array to genotype the participants' DNA samples and excluded samples that did not meet the research requirements.
Finally, 235,716 samples were obtained for analysis.

The study used a univariate Logistic regression model to analyze the genetic variation associated with invasive cervical cancer or CIN3.
In order to determine the association more rigorously, the study also verified the association of candidate genes in an independent population (FinnGen).

The results showed that among the 9600464 determined and estimated single nucleotide polymorphisms (SNPs), 6 independent sites in the PAX8, CLPTM1L and HLA regions of the British Biobank were related to CIN3 and invasive cervical cancer.

There are three SNPs: PAX8 (rs10175462), CLPTM1L (rs27069) and HLA-DQA1 (rs9272050) have been repeatedly verified in FinnGen data.

Among them, HLA-DQA1 plays an important role in the adaptive immune response to infection; CLPTM1L encodes a transmembrane protein, which is related to regulating cell growth cycle and affecting cell apoptosis; PAX8 also plays a regulatory role in the carcinogenic process of many tumors.

[5] The trial design flow chart allows us to return to the mechanism of cervical cancer.

After high-risk HPV infection of the cervical epithelium, on the one hand, it causes the silence of various tumor suppressor factors, on the other hand, it causes various tumor-promoting factors to function abnormally, which in turn leads to changes in the host genome.

A variety of HPV-derived carcinogens enter the host genome of cervical epithelial cells, causing imbalance and instability to promote the development of tumors [1].

The impact of viruses on human genetics and epigenetics is evident.
In addition, environmental risk factors also play an important role in the development of cervical cancer.

In order to determine the impact of environmental risk factors on cervical cancer, the study conducted Mendelian randomization of two samples, confirming that smoking (OR 2.
46) and the number of sexual partners (OR 1.
95) are risk factors for cervical cancer, and the first pregnancy is older ( OR 0.
80) is the protective factor.

The sentinel SNP area diagram of conditional analysis: PAX8 (A), CLPTM1L (B) and HLA (C and D) related to CIN3 and invasive cervical cancer.
Smoking suppresses cell-mediated immune response and humoral immune response, leading to HPV infection Increased sensitivity.

Nicotine, as an addictive substance in cigarette smoke, has also been proven to be the main immunosuppressive component of cigarette smoke [6].

The female reproductive tract faces a large number of and frequent antigen exposures.
After sexual activity begins, the reproductive tract needs to deal with more antigens from the male reproductive tract.
The sexual behavior of multiple sex partners not only easily causes cervical trauma, but also increases the probability of infection with pathogens.

It is worth thinking about that high-risk sexual behavior and smoking may be confounding factors for HPV infection.
Studies have found that sexual behavior between smokers and multiple sexual partners is more common [7].

When the researchers controlled the number of sexual partners, the effect of premature first pregnancy did not diminish, indicating that young pregnancy has an independent effect on cervical cancer, which may be caused by the mechanism of early cervical trauma or early hormonal changes.

Overall, this study determined the genetic susceptibility of cervical cancer and supplemented the host's susceptibility to invasive cervical cancer and the analysis of CIN3.

This study also provides new evidence for the role of PAX8, CLPTM1L and HLA genes in the development of cervical cancer.
In connection with the function of the gene itself, it is not difficult to find the importance of destroying cell apoptosis and immune function in the development of cervical cancer.

At the same time, in order to facilitate the screening and treatment of CIN3 and invasive cervical cancer, we need to better explore the impact of the virus on the human genotype and genotype.
The functional role of SNP sites in HLA also needs to be further explored, which is helpful To better understand the pathogenesis of cervical tumors and potential therapeutic targets. Although it is not easy to make appointments for HPV vaccines, we can also change our living habits to better protect ourselves by reducing the factors affecting cervical cancer.

Girls should smoke less and avoid high-risk sex! Finally, although the focus of cervical cancer prevention is HPV vaccination, the early screening of cervical cancer and the medical management of HPV infection, preneoplastic lesions, and invasive cervical cancer found in the screening still need to be improved.

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Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study.
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Medicina (Kaunas).
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Published 2018 Jul 27.
doi:10.
3390/medicina54040050 Responsible EditorBioTalkerPAX8 is transcribed aberrantly in cervical tumors and derived cell lines due to complex gene rearrangements.
Int J Oncol.
2016;49(1):371-380.
doi:10.
3892/ijo.
2016.
3515[6].
Kaderli R, Schnüriger B, Brügger LE.
The impact of smoking on HPV infection and the development of anogenital warts.
Int J Colorectal Dis.
2014;29(8):899-908.
doi:10.
1007/s00384-014-1922-y[7].
Zacharis K, Messini CI, Anifandis G, Koukoulis G, Satra M, Daponte A.
Human Papilloma Virus (HPV) and Fertilization: A Mini Review.
Medicina (Kaunas).
2018;54(4):50.
Published 2018 Jul 27.
doi:10.
3390 /medicina54040050 Chief EditorBioTalkerPAX8 is transcribed aberrantly in cervical tumors and derived cell lines due to complex gene rearrangements.
Int J Oncol.
2016;49(1):371-380.
doi:10.
3892/ijo.
2016.
3515[6].
Kaderli R, Schnüriger B, Brügger LE.
The impact of smoking on HPV infection and the development of anogenital warts.
Int J Colorectal Dis.
2014;29(8):899-908.
doi:10.
1007/s00384-014-1922-y[7].
Zacharis K, Messini CI, Anifandis G, Koukoulis G, Satra M, Daponte A.
Human Papilloma Virus (HPV) and Fertilization: A Mini Review.
Medicina (Kaunas).
2018;54(4):50.
Published 2018 Jul 27.
doi:10.
3390 /medicina54040050 Chief EditorBioTalker1007/s00384-014-1922-y[7].
Zacharis K, Messini CI, Anifandis G, Koukoulis G, Satra M, Daponte A.
Human Papilloma Virus (HPV) and Fertilization: A Mini Review.
Medicina (Kaunas).
2018 ;54(4):50.
Published 2018 Jul 27.
doi:10.
3390/medicina54040050 Responsible EditorBioTalker1007/s00384-014-1922-y[7].
Zacharis K, Messini CI, Anifandis G, Koukoulis G, Satra M, Daponte A.
Human Papilloma Virus (HPV) and Fertilization: A Mini Review.
Medicina (Kaunas).
2018 ;54(4):50.
Published 2018 Jul 27.
doi:10.
3390/medicina54040050 Responsible EditorBioTalker