What kind of people are more likely to get cervical cancer? Is cervical cancer hereditary?

Cervical cancer is the fourth most common malignant tumor affecting women's health worldwide (the first three are breast cancer, colorectal cancer and lung cancer). According to reports, there are an estimated 600,000 new cases of cervical cancer and about 340,000 deaths worldwide in 2020. According to data released by the National Cancer Center of China, in 2016, more than 120,000 Chinese women were newly diagnosed with cervical cancer and more than 37,000 died from cervical cancer.

Persistent infection with high-risk human papillomavirus (HPV) is the main cause of cervical cancer. The HPV virus is a large family, like a mafia organization, with more than 200 members. Some of these members are relatively harmless and do not participate in serious crimes (cervical cancer), but they do some petty thefts (such as genital warts). We call them low-risk HPV, such as HPV6 and HPV11. Other members are more vicious and have been involved in serious crimes (cervical cancer) for a long time, such as HPV16, 18, 31, 33 and 45. Among them, the behavior of the organization's number one leader (HPV16) and number two leader (HPV18) is the worst. According to statistics, more than 70% of serious crimes (cervical cancer) are committed by these two guys.

After mastering the above criminal clues, the justice messengers developed different weapons (vaccines) to arrest and eliminate these "criminals". Among them, the bivalent vaccine can effectively deal with the two main leaders HPV16 and HPV18. The quadrivalent vaccine can deal with HPV6 and HPV11, two low-risk HPVs, in addition to HPV16 and HPV18. The nine-valent vaccine can simultaneously fight against nine types of HPV: HPV16, 18, 6, 11, 31, 33, 45, 52, and 58.

The mechanism of cervical cancer

The lower part of the uterus is called the cervix. High-risk HPV first infects the epithelial cells of the cervix. At this time, the body will initiate an immune response to eliminate HPV and return to normal. If the body fails to successfully eliminate the HPV virus, the HPV virus will integrate its genes into the genome of the host cell, and then it will develop into cervical intraepithelial neoplasia stage 1 (CIN 1). If the infection persists, it will progress to intraepithelial neoplasia stage 2 and stage 3 (CIN2 and CIN3). During this continuous infection process, the virus's E6 and E7 proteins can inhibit host cell apoptosis, cell cycle checkpoints, T cell responses, and macrophage activation, which reduces the body's immune response and genome stability, uncontrolled cell proliferation, and ultimately leads to cervical cancer.

In fact, human papillomavirus infection is a very common phenomenon, and most women will experience multiple infections in their lifetime. However, less than 4% of HPV-infected people will experience persistent infection and develop into cervical intraepithelial neoplasia (CIN), and even fewer will eventually develop into invasive cervical cancer, which shows that different people have different susceptibility to cervical cancer.

What factors cause this difference? What kind of people are more likely to get cervical cancer?

Considering that persistent infection with high-risk HPV is the most direct and main cause of cervical cancer, if a person has an unhealthy lifestyle that increases the risk of high-risk HPV infection (such as early sexual activity, multiple sexual partners, etc.), then this person’s risk of cervical cancer will be higher than others.

In addition, individual genetic variation also plays an important role in the occurrence of cervical cancer. Hearing this, many people may be confused. Can cervical cancer also be inherited?

Don't worry, it won't happen.

However! Cervical cancer does have the phenomenon of family aggregation. The current family studies on cervical cancer show that the heritability of cervical cancer is about 27%.

In the past 10 years, scientists have used genome-wide association analysis (GWAS) to discover some human genetic variation sites that may be significantly associated with cervical cancer susceptibility. Among them, the most numerous (more than ten independent signals) and most significant variations are located in the HLA region (human MHC region) of chromosome 6p21.3. This region contains many genes encoding antigen peptide presenting proteins, and these proteins happen to play an important role in the regulation of immune system function. Perhaps these genetic variations explain why each person has different immune responses and virus clearance capabilities when facing HPV infection, and thus has different susceptibility to cervical cancer.

In addition to the HLA region, the correlation between chromosome 2q13 (‎‎PAX8‎‎), 5p15.33 (‎‎TERT-CLPTM1L) and 17q12‎‎ (‎‎GSDMB‎‎) and the risk of cervical cancer has also been verified in GWAS studies of different populations, but the biological mechanism by which these genetic variants affect the development of cervical cancer remains to be elucidated.

Although we currently know relatively little about cervical cancer susceptibility mutations, the good news is that now we not only have a preventive vaccine for cervical cancer, but the screening methods for cervical cancer are also relatively mature. As long as vaccination and screening work can be done well, cervical cancer is expected to be the first cancer to disappear from the earth.

References

1. Li Zhexuan, Zhang Yang, Zhou Tong, et al. Interpretation of the 2020 Global Cancer Statistics Report[J]. Electronic Journal of Comprehensive Oncology Treatment, 2021, 7(2):14.

2. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660

3. Ramachandran D, Dörk T. Genomic Risk Factors for Cervical Cancer. Cancers (Basel). 2021;13(20):5137. Published 2021 Oct 13. doi:10.3390/cancers13205137