Lecture 17 HPV and Cervical Cancer Bottom line One of those deadliest but preventable diseases catch early PAP SMEAR DNA tests and prevent HPV infection don t have sex vaccinate HPVA is like the common cold everybody gets it HPV infection leads to integration of oncogenes into DNA of epithelial cells lining cervix and throat and can cause cancer Sex plus differences in access to health care equates to lots of disparity in incident and death rates across the world and even in US Vaccination of youth decreases incident rates individual versus the herd Cervical Cancer History Epidemiologists working in the early 20th century noted the following Cervical cancer was common in female sex workers It was rare in nuns except for those who had been sexually active before entering the convent It was more common in the second wives of men whose first wives had died from cervical cancer About 20 years ago cervical cancer was linked o human papilloma virus infection Now over 100 strains of HPV are known 85 of deaths due to cervical cancer occurs in developing countries Common HPV Types High risk types of HPV cause growths that are usually flat and nearly invisible as compared with the warts caused by HPV 6 and HPV 11 100 types of HPV 23 are present in the genital tract 12 Main types associated with cancer and are considered high risk Most women will clear an HPV infection within 9 15 months Women with persistent high risk HPV infection are 300 times more likely to develop cervical cancer The Cervical Cancer and HPV Over 99 of all cervical cancer cases stem from infection with HPV which is transmitted through sexual contact How Does HPV cause Cancer HPV gene expression timing Viruses express their genes in 2 phases early E and late L The HPV early genes E6 and E7 are associated with cancer viral oncogenes E6 protein causes P53 tumor suppressor degradation and promotes telomerase activity E7 protein causes Rb tumor suppressor degradation HPV E6 and E7 Oncogenes Physically Disrupt Activities of Tumor Suppressor Proteins DNA damage P53 Apoptosis activated HPV E6 E6 oncoprotein binds to P53 and promotes its destruction Growth factor Cdk cyclin restriction point E7 oncoprotein binds to Rb and disrupts its ability to halt cells at the restriction point HPV E6 protein targets P53 HPV E7 protein targets pRB HPV Hijacks Epithelial Cells Once Integrated into host DNA then Cancer is Likely Infection by HPV HPV infects epithelial cells in the cervical mucous membrane HPV DNA integrates into the cellular genome when causing cancer Infection by HPV Infected basal cell weeks Viral replication HPV in epithelial cells 90 heal within two years 2 4 months Establishment of latency 10 30 years HPV DNA integrated into tumor cell DNA invasive cancer 0 8 develop cancer HPV hides from the immune system by inserting into host DNA persistent infection This leads to over expression of E6 and E7 and Cancer Infection and Progression to Cervical Cancer With 1 year Initial HPV infection Can Take Decades High grade changes cancer 1 5 years Persistent HPV infection low grade changes Most cleared HPV infection Prevalence of HPV Infection Currently there are around 20 million people infected with the various types of HPV in the U S states along Approximately 6 2 million new cases of HPV infection occurring annually Between 75 and 80 of sexually active individuals will become infected with Each year more than 20 000 HPV associated cancers occur in women cervical About 12 000 HPV associated cancers occur each year in men oropharyngeal HPV within their lifetime cancer is the most common cancers are the most common Prevalence of HPV Infection HPV is a virus that is very common In fact most men and women are infected with HPV at sometime in their lives A recent study showed that women who have had at least three sexual partners 81 of them had HPV Risk Factors of Cervical Cancer HPV infection Multiple sex partners Started having sex before age 18 Other STIs HIV syphilis Chlamydia Smoking Multiple pregnancies Oral contraceptives Diet Family history Low socioeconomic status Molecular genetic factors P53 Rb Pap Test and Cervical Cancer The pap test was developed in 1943 by Dr George Papanicolaou Since then early detection of cervical cancer has greatly improved As a result cervical cancer dropped from the second leading cause of cancer deaths among American women to the 13th in the US This is the most successful screening test reducing cervical cancer mortality by 70 in the U S New guidelines suggest that women should have their first Pap Smear by the age of 21 or within 3 years of first sexual intercourse Pap Smear Morphology Dysplasia A higher nuclear to cytoplasmic ratio This means the nucleus is larger than it should be for the size of the cell Mild Dysplasia The nucleus is about 3 4 times larger than it should be Moderate Dysplasia The nucleus is 5 6 times larger than it should be Severe Dysplasia The nucleus is taking up most of the cell Colonoscopy and Cervical Exam Pap smear Cells are scraped from the cervix and examined under a microscope to Cervical Biopsy Small tissue samples are taken from the cervix and examined for check for disease or other problems disease or other problems Treating Cervical Cancer Early stage treatments Compressed nitrogen gas flows through a cryo probe making the metal cold enough to freeze and destroy the abnormal cervical tissue Advanced stages Hysterectomy Recurrent Pelvic exteneration Surgical Treatment Hysterectomy A hysterectomy removes the uterus and may also remove the cervix total and the vagina radical Pelvic Extenteration When cervical cancer is Stage 4 recurrent or Stage 4B then a surgery called a pelvic exenteration may be performed Since the bladder and rectum are removed the surgeon will utilize a segment of the intestine to form a new bladder that can be drained with a catheter and she will fix what is left of the large intestine to the wall of the abdomen so that waste matter can pass through an opening in the abdomen and into a special bag HPV Also Causes Oral and Throat Cancer In men oral sex may cause more throat cancer than smoking A 20 year study of throat tumors found that the percentage of oral cancer linked to HPV surged from 16 to 72 By 2020 It is estimated that throat cancer from HPV will become more common than HPV caused cervical cancer Rise in Throat Cancer Driven by HPV Infections BUT differences in nature of the disease more preventable and responds better to treatment
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