REPRODUCTIVE PATHOPHYS IIICancers of the Reproductive System

Julie Kasperzyk, Sc.D.November 12, 2012

Acquired capabilities of cancer

From: Hanahan D. Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:646-674

Additional characteristics of some cancers

From: Hanahan D. Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:646-674

Tumor development occurs in stages (1)

Weinberg RA. How cancer arises. Sci Am. 1996 Sep;275(3):62-70.

Tumor development occurs in stages (2)

Weinberg RA. How cancer arises. Sci Am. 1996 Sep;275(3):62-70.

Malignant versus Benign Tumors

Malignant (cancer) cells invade neighboring tissues, enter blood vessels, and metastasize to different sites

Time

Benign (not cancer) tumor cells grow only locally and cannot spread by invasion or metastasis

http://www.cancer.gov/cancertopics/understandingcancer/cancer

DNA Mutation

Additions

Deletions

Normal gene

Single base change

DNA

CT

A G C G A A C TAC

A G G C G C T AAC A C T

A G C T A A C TAC

A G A A C TAC

http://www.cancer.gov/cancertopics/understandingcancer/cancer

General genetic abnormalities in cancer cells (1)

A. Oncogenes get activated or become expressed more than normal

– Oncogene: a gene that, when mutated or dysregulated, participates in the onset and development of cancer

– The protein may be• expressed at a greater level (more protein in the cell)• become more active• lose its potential to be regulated• increase its stability (hang around in the cell longer)

– These changes can cause the cell to be hyper-responsive to growth signals, grow in the absence of proper growth signals, evade apoptosis, etc.

A) Oncogene example: HER2+ breast cancer

B. Tumor suppressor genes stop working

– Tumor suppressor gene: a gene that protects a cell from one step in the cancer pathogenesis process

– The gene product may be a protein that maintains the normal cell cycle, inhibits an oncogene, inhibits cell division, etc.

– When a tumor suppressor gene is mutated or dysregulated, the cell can progress to cancer if other aberrations are also present

General genetic abnormalities in cancer cells (2)

Normal cell Cell suicide(Apoptosis)

p53 protein

Excessive DNA damage

B) Tumor suppressor example: p53 loss

• In normal cells, p53 protein triggers apoptosis

http://www.cancer.gov/cancertopics/understandingcancer/cancer

A. Viruses– DNA (ex: HPV)– RNA retroviruses (ex: HIV)

B. Chemical carcinogens– Can cause chemical changes in DNA, DNA

breaks, and/or inflammation– Ex: asbestos, benzene, diesel exhaust

C. UV and ionizing radiation– Causes chromosomal breaks and

translocations, and can interfere with DNA repair

Environmental carcinogens

Cancer can spread to other sites (1)

Ruoslahti E. How cancer spreads. Sci Am. 1996 Sep;275(3):72-7.

Cancer can spread to other sites (2)

Ruoslahti E. How cancer spreads. Sci Am. 1996 Sep;275(3):72-7.

New cases of cancer in the US

American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society.

Cancer deaths among US men

Cancer deaths among US women

(includes cervix)

MALE CANCERS

Testicular cancer

• Very rare: 8,590 new cases and 360 deaths annually in US

• Most common form of cancer in men 16-34• Median age at diagnosis is 33• Most (90%) of cases arise from germ cells in the

testes

Testicular cancer risk factors

a) Northern European residenceb) Family historyc) Race/ethnicity: rates are 6x higher in

Caucasians than African americansd) Testicular dysgenesis syndromee) Carcinoma in situ can sometimes progress to

invasive cancerf) HIV infection (debatable)g) Body size: taller and leaner men show highest

risk

Height (per 5cm) & testicular cancer risk

British Journal of Cancer (2010) 103, 1467 – 1474

BMI (per kg/m2) & testicular cancer risk

British Journal of Cancer (2010) 103, 1467 – 1474

Family history & prostate cancer risk

Bratt et al. J Urol 2002;168:906-13

Genetics & prostate cancer: 8q24

• Multiple genetic variants in this region found to increase PCa risk in variety of racial/ethnic groups

• Not in a coding region • Closest gene is MYC, a transcription

factor and oncogene• Not clear how/if risk variants in 8q24

regulate MYC function or expression

Amundadottir et al. Nat Genet. 2006 Jun;38(6):652-8.Freedman et al. Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14068-73.

26

8q24 “Gene Desert” Region and Associations with Various Cancers

J Natl Cancer Inst 2008;100: 962 – 966

PROSTATE

PROSTATECOLORECTALOVARIAN

BREASTPROSTATE

Prostate cancer incidence & mortality rates by race

World J Urol (2012) 30:195–200

Diet & prostate cancer risk

Dietary factor Direction of effect Calcium (fatal & adv disease) Processed meat intake () Fish intake (fatal disease) Vitamin D () Tomatoes/tomato based products “Mediterranean diet” Coffee

(adv disease)

Giovannucci et al. Int. J. Cancer: 121, 1571–1578 (2007)Wilson et al. J Natl Cancer Inst. 2011;103(11):876-84.Chan et al. J Clin Oncol 23:8152-8160

Other risk factors for prostate cancer

Risk factor Direction of effectAccumulating evidence Growth Factors (IGF-I)

Genetic factors or Height (fatal disease) BMI (adv/fatal disease)

Possible factors Physical activity - vigorous (fatal disease) Long-term smoking Inflammation/Infections

(fatal disease)

Height & BMI: potential mechanisms

• Height– Proxy for nutritional status in early life– Growth factors and hormones

• Obesity– Increased total energy intake– Metabolic syndrome & poor insulin

control increased cell proliferation

Role of energy balance in cancer development

Exp Diabetes Res. 2012;2012:789174

Infection & prostate cancer: T. vaginalis• Parasitic protozoan

• Infection affects 5-20% of U.S. young adults, typically asymptomatic in males

• Causes inflammation and may induce anti-apoptosis genes

• Preliminary data suggest that infection is linked to higher risk of aggressive prostate cancer

FEMALE CANCERS

http://seer.cancer.gov/faststats/index.php

American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011.

American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011.

Breast cancer risk factors: high estrogen exposure

• Reproductive factors that increase level or duration of exposure to estrogen increase risk– Nulliparity– Early menarche– Late menopause– Postmenopausal hormone use– Older forms of birth control pills (high estrogen)– Postmenopausal obesity (fat cells produce estrogen)– Alcohol use (increases conversion of testosterone to

estrogen)

Breast Disease 24 (2005,2006) 17–35

Risk factors for postmenopausal breast cancer across the life course

Race/Ethnicity and Breast Cancer

American Cancer Society. Breast Cancer Facts & Figures 2011-2012. Atlanta: American Cancer Society.

Heredity and Breast Cancer

Inherited factor(s)

All Breast Cancer Patients

Other factor(s)

http://www.cancer.gov/cancertopics/understandingcancer/cancer

BRCA1 & BRCA2 mutations

• Tumor suppressor genes• Normally, BRCA1 and BRCA2 help to stabilize

DNA and prevent uncontrolled cellular proliferation

• Prevalence of BRCA1 mutations in the general population is estimated between 1/500 to 1/1000

• Prevalence of BRCA2 mutations is lower, but not known precisely

BRCA mechanism

Hum Mol Genet. 2001;10:705-13

43Am.J. Hum. Genet. 52:678-701, 1993

BRCA1 & breast-ovarian cancer risk

http://seer.cancer.gov/faststats/index.php

American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011.

American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011.

Cervical cancer risk factors

• Virtually all cervical cancers are caused by HPV infections

• Other risk factors:– Sexual behavior: 1st intercourse at early age; multiple

partners– Family history– Poor diet and overweight– HIV infection (weakens immune system)– Oral contraceptives– Multiple pregnancies May reflect sexual behaviors

HPV infection• DNA virus• Viral proteins (E6 & E7)

disrupt tumor suppressor genes in infected cells

• 100+ subtypes, but only some (mainly HPV-16 and HPV-18) can cause cervical cancer

• Most infections cleared by the immune system without any clinical symptoms

Gynecologic Oncology Volume 107, Issue 2, Supplement 2007 S2 - S5

Prevalence of HPV-16 in serum

Infect Dis Obstet Gynecol. 2006;2006 Suppl:40470.

Cumulative incidence of CIN after HPV infection

Infect Dis Obstet Gynecol. 2006;2006 Suppl:40470.

Cervical Intraepithelial Neoplasia (CIN): precancerous lesion

Endometrial cancer

• Most common gynecological cancer in the US

Endometrial cancer risk factors• Reproductive factors that increase exposure to estrogen

increase risk (similar to breast cancer)– Nulliparity, early menarche, late menopause– Postmenopausal hormone use with estrogen and not

progesterone (progesterone lowers risk by reducing growth of the endometrium)

– Older forms of birth control pills with high estrogen– Obesity– Alcohol use– Prior breast cancer treatment with tamoxifen (acts as

estrogen receptor antagonist in breast, but agonist in ovary)

– Polycystic ovarian syndrome (PCOS)

Ovarian cancer • Rare, occurs mainly in older women• Rapidly fatal because difficult to detect in early

stages

http://www.medinfographics.com/cancer-statistics/ovarian-cancer/ovarian-cancer-survival-by-stage-at-diagnosis/

Ovarian cancer risk factors

• Prolonged exposure to high FSH & LH– Nulliparity – Oral contraceptive use decreases risk (reduced # of

ovulations and lower FSH/LH)– Depletion of oocytes with age (less inhibin and

estrogen reduces negative feedback on FSH & LH)– Fertility drugs (stimulate FSH & LH release)

• BRCA1 & BRCA2 mutations• Obesity• Androgen use

BURDEN OF OBESITY IN THE UNITED STATES

Obesity Trends* Among U.S. AdultsBRFSS, 1985

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14%

Obesity Trends* Among U.S. AdultsBRFSS, 1990

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14%

Obesity Trends* Among U.S. AdultsBRFSS, 1995

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. AdultsBRFSS, 2000

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends* Among U.S. AdultsBRFSS, 2005

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Obesity Trends* Among U.S. AdultsBRFSS, 2010

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Major obstacles to obesity control• Genetic programming to store energy• Abundance of energy-dense foods• Poor adherence to calorie restriction• Poor sleep• Sedentary lifestyle• Inadequate built environment to promote

physical activity• Cost of exercise programs/equipment• No effective drugs to combat obesity• High cost and risks of bariatric surgery

Cancer Prev Res; 5(11); 1260–72.