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The Genomic Structure Of Human Papillomavirus(HPV) And It’s Association To Cervical Cancer Presented by Fadi Alanazi A laboratory Specialist AUD (KSA), BSc in Biomedical Science(Essex University, UK) Virology Section Laboratory and Blood Bank Department Arar Central Hospital 1

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Page 1: Human papiloma virus

The Genomic Structure Of Human Papillomavirus(HPV) And It’s

Association To Cervical Cancer

Presented by Fadi AlanaziA laboratory Specialist

AUD (KSA), BSc in Biomedical Science(Essex University, UK)

Virology SectionLaboratory and Blood Bank DepartmentArar Central Hospital

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Papillomavirus particle

Small, non-enveloped icosahedral particles made up of 360 copies of L1 protein, and 12 copies of L2. Virion is 55nm in diameter. 2

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Taxonomy

Family: Papillomaviridae

• 16 genera • Human ones in Alpha, Beta, Gamma, Mu and Nu

• Alpha is the largest and main group but also contains cutaneous viruses(Warts).

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Papillomaviridae taxonomy

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Cervical Cancer: Worldwide Prevalence, Incidence, and Mortality Estimates

Cervical cancer is the 2nd most common cancer among women worldwide.

Estimated 530,000 new cases Estimated 274,000 deaths

More than 85% of the global problem occurs in developing countries .

Source: GLOBOCAN 20085

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Human papillomavirus (HPV)• Over 100 different HPVs characterised: Classified into

genital/mucosal and cutaneous and designated high-risk or low-risk.

HPV Types Lead to:

Low-Risk

High-Risk

HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81

HPV 16, 18,31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82

Benign cervical changes

Genital warts

Precancer cervical changes

Cervical cancer

Anal and other cancers

1. Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1.2. Munoz et al. N Engl J Med. 2003;348:518.

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Genome organisation

of HPV16

Doorbar (2006) Clinical Science 110, 525–541

• LCR = Contains the origin of replication and regulatory sites

• PAE, PAL= early and late polyadenylation sites

• Transcription is driven by P97 and P670 promoters

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Doorbar (2006) Clinical Science 110, 525–541

Stimulation of cell proliferation(E6/E7)

• Increased proliferation

• Drive cells into S-phase, as this is needed for virus genome replication.

• E7 associates with pRb and related proteins.

• E7 also associates with other proteins involved in proliferation e.g. p21, p27.

As cells differentiate, levels of p21 and p27 increase and this overcomes the effect of E7.

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Stimulation of cell proliferation• E6 associates with p53 and causes, in high risk HPVs, ubiquitin

modification and degradation.

• E7 /E6 Prevents growth arrest and apoptosis(Bax and Bak).

• E5 obstructs growth suppression mechanisms.

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Molecular mechanisms of oncogenic HPV infection

Communicating Current Research and Educational Topics and Trends in Applied Microbiology A. Méndez-Vilas (Ed.)

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Co-factors for HPV Infection

•Smoking•HIV infection •Other immune system defect•Pregnancy(?)•Oral contraceptive use

Ferris et al, 200412

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The American Cancer Society reported ‘Women who have had 3 or 4 full‑term pregnancies have an increased risk of CC’.

American Cancer Society

Co-factors for HPV Infection

Which means, (2.6 times) the risk of developing CC compared to women who hadn’t given birth.

These women may have had more exposureto HPV infection because of having unprotected intercourse to get pregnant.

Due hormonal changes during pregnancy, as it makes women more susceptible to HPV infection or cancer growth.

THEORIES:

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Source: http://www.ndhealthfacts.org/wiki/Oncology_%28Cancer%29

Carcinoma in Situ and Invasive Carcinoma

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• Early Signs-No Early Warning Signs

• Irregular Bleeding-May occur between menstrual periods or after sex.

• Vaginal Discharge-Pale-Watery-Brown-Tinged with blood

• Advanced Symptoms-Back or pelvic pain-Difficulty urinating or defecating due to obstruction-Swelling of one or both legs-Fatigue-Weight loss

Signs and Symptoms

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The screening Test for cervical cancer

• PAP Smear

• VIA= Visual inspection with acetic acid

• HPV testing

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PAP Smear

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Cytology

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Dysplasia on a Pap Smear

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• Subjective

• Require regular training and monitoring.

• Requires high quality control.

• Multiple visits with cytology based are required!.

• Even with the best quality control ,cytology has low sensitivity

(Sensitivity of PAP 53 % )

Cuzick et al, 2006

Limitations of Cytology

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• VIA: Visual inspection with Acetic Acid

• VILI: Visual inspection with Lugols Iodine

- Both Low tech can be done by nurses

- May need to utilize colposcopy to triage post positive test to rule out cancer

Visual Inspection with Ascetic Acid(VIA) for Biopsy

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Monsel’s solutionis a chemical cautery agent made of ferric sub-sulphate. It should have a consistency of mustard, and is applied to bleeding sites by transferring it on a cotton swab. It is caustic, more effective than silver nitrate.

Lugol’s is a strong iodine solution that stains normal epithelium dark brown, useful for outlining normal from abnormal epithelium, for defining the borders of a lesion, and for finding vaginal lesions.

Silver nitrate sticks These provide a useful cautery agent that is applied with pressure to bleeding biopsy sites.

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After the procedure this material

will be expelled naturally: patients

can expect to have a thin coffee-

ground like discharge for up to

several days after the procedure.

Monsel’s solution

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Visual Inspection with Ascetic Acid(VIA)

Wright et al 2004

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• More sensitive than pap smear

• Negative PV testing provides reassurance of not developing Cervical

Intraepithelial Neoplasia grade 3(CIN3), over the next 5-10 years.

• HPV test is ideally suited to reassure the negative HPV individual and to

increase interval between two subsequent screens.

HPV testing in Primary Screening

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Cytology vs HPV testing :variability of cytological diagnosis

Wright et al 200430

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Saudi Arabia has a population of 9.29 millions women ages 15 years and older who are at risk of developing cervical cancer.

Information Centre on HPV and Cancer, Feb 2016

Cervical screening practices and recommendations

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Jeddah Cervical Cancer Screening Program(JCSP)

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A bivalent (Cervarix) vaccine that protect against HPV-16 and -18.

A quadrivalent (Gardasil) that is effective against HPV-6, -11, -16, and -18 are being widely introduced in western countries.

Should be administered in 3 times over a 6-month period:1st Dose: Now.2nd Dose: 2 months after the first dose. 3rd Dose: 6 months after the first dose.

HPV VACCINES

Two types,

Centers for Disease Control and Prevention, 2014

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Reactions where the shot was given:

• Pain (about 9 people in 10)

• Redness or swelling (about 1 person in 2)

Other mild reactions:

• Fever of 37.5°C or higher (about 1 person in 8)

• Headache or fatigue (about 1 person in 2)

• Nausea, vomiting, diarrhea, or abdominal pain (about 1 person in 4)

• Muscle or joint pain (up to 1 person in 2).

Centers for Disease Control and Prevention, 2014

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Is there any treatment for cervical cancer?

There are many options on treating cervical cancer.

1. Surgery

2. Chemotherapy

3. Radiotherapy

4. Or a combination of chemotherapy and radiotherapy

The treatment mainly depends on the size of the tumor or weather the cancer

has spread.

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Is the thirteenth most frequent cancer in Saudi women(All Ages).

Cervical cancer is the sixth on the list of the most widespread cancers inSaudi Arabia (15y-44y)

Cervical cancer in Saudi Arabia

El.Mahalli, 2015

99% of Cervical cancer patients would be associated with Human Papilloma Virus (HPV)

Current estimates indicate that every year 152 women are diagnosed with Cervical Cancer and 55 die from the disease.

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Cervical cancer in Saudi Arabia

Total of 504 patients

74% present with advanced disease

The overall 3, 5 and 10 years survival patients was 64%, 55% and 40%, respectively

Improvement in overall outcomes will require earlier diagnosis, achievable only through an effective screening program

Manji et al, 199937

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Cervical Cancer in Saudi Arabia

Incidence of cervical cancer is low in Saudi Arabia

Rank number 11 between all cancers in female

Every year, 152 women are diagnosed with cervical cancer and 55 die

from the disease. new cervical cancer cases and deaths in 2025 are 309

Account only 2.4 % of all cases

SCR Report 2009 38

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Age specific incidence rate for cancer cervix in SA

SCR Report 200939

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Cervical cancer in Saudi Arabia One hundred specimensThe mean age 56 ±3.32 y (range20-94 years).

The rate of HPV genotype detection among cervical cancer samples was 95.5%.

HPV-16(63.4%)HPV-18(11.1%)HPV-45 (4.5%)HPV-33 (3.3%)HPV-31, HPV-52, HPV-53, HPV-58, HPV-59, and HPV-66 (2.2%)

Albadawi et al, 2011 40

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Cervical cancer in Saudi ArabiaOne hundred ( 82%) were positive for HPV

sequences.

Most common genotypes were HPV-16(71%),

31(7%), and 18, 45, 73 (4% each).

Alsebeih et al, 2013

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Cervical cancer in Saudi ArabiaA total of 40 cervical samples

HPV infections were found in 43% .

The most prevalent genotypes were HPV 16(30%) HPV 18(8.0%) followed by type HPV 45 (5%)

Turki et al, 2013 42

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What should we do to our society?

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Further Reading:• Doorbar (2006) Clinical Science 110, 525–541• Galloway (2009) Genes and Development 23, 138-142• http://www.microbiologybytes.com/virology/

Papillomaviruses.html• Strauss and Strauss (2008) pp308-314• Zur Hausen (2002) Nature Reviews Cancer 2, 342-350

Thanks 44

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References

El.Mahalli, A. (2015). Incidence And Risk Factors Of Abnormal Cervical Cytology In A University Hospital ‑ Saudi Arabia. Saudi Journal for Health Sciences, 4 (2), 104-110.

American Cancer Society. American Cancer Society Prevention, EarlyDetection, and Survivorship Guidelines. Available online from: http://www.cancer.org/healthy/informationforhealthcareprofessionals/acsguidelines/index [Last accessed on 2016 Feb 21].

Harper D M .Currently approved prophylactic HPV vaccines. Expert Rev Vaccines (2009) 8(12):1663–79.doi:10.1586/erv.09.123

Mahdavi A, MonkB J.Vaccines against human papilloma virus and cervical cancer: promises and challenges. Oncologist (2005) 10(7):528–38.doi:10.1634/ theoncologist.10-7-528