REPRODUCTIVE PATHOPHYS III Cancers of the Reproductive System
Julie Kasperzyk, Sc.D. November 12, 2012
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Acquired capabilities of cancer From: Hanahan D. Weinberg RA.
Hallmarks of cancer: The next generation. Cell.
2011;144:646-674
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Additional characteristics of some cancers From: Hanahan D.
Weinberg RA. Hallmarks of cancer: The next generation. Cell.
2011;144:646-674
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Tumor development occurs in stages (1) Weinberg RA. How cancer
arises. Sci Am. 1996 Sep;275(3):62-70.
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Tumor development occurs in stages (2) Weinberg RA. How cancer
arises. Sci Am. 1996 Sep;275(3):62-70.
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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
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DNA Mutation Additions Deletions Normal gene Single base change
DNA C T AGCGAACTAC AGGCGCTAACACT AGCTAACTAC AGAACTAC
http://www.cancer.gov/cancertopics/understandingcancer/cancer
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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.
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A) Oncogene example: HER2+ breast cancer
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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)
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Normal cellCell 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
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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
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Cancer can spread to other sites (1) Ruoslahti E. How cancer
spreads. Sci Am. 1996 Sep;275(3):72-7.
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Cancer can spread to other sites (2) Ruoslahti E. How cancer
spreads. Sci Am. 1996 Sep;275(3):72-7.
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New cases of cancer in the US American Cancer Society. Cancer
Facts & Figures 2012. Atlanta: American Cancer Society.
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Cancer deaths among US men
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Cancer deaths among US women (includes cervix)
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MALE CANCERS
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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
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Testicular cancer risk factors a)Northern European residence
b)Family history c)Race/ethnicity: rates are 6x higher in
Caucasians than African americans d)Testicular dysgenesis syndrome
e)Carcinoma in situ can sometimes progress to invasive cancer f)HIV
infection (debatable) g)Body size: taller and leaner men show
highest risk
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Height (per 5cm) & testicular cancer risk British Journal
of Cancer (2010) 103, 1467 1474
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BMI (per kg/m 2 ) & testicular cancer risk British Journal
of Cancer (2010) 103, 1467 1474
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Family history & prostate cancer risk Bratt et al. J Urol
2002;168:906-13
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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.
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8q24 Gene Desert Region and Associations with Various Cancers
26 J Natl Cancer Inst 2008;100: 962 966 PROSTATE COLORECTAL OVARIAN
BREAST PROSTATE
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Prostate cancer incidence & mortality rates by race World J
Urol (2012) 30:195200
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Diet & prostate cancer risk Dietary factorDirection 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, 15711578 (2007) Wilson et al. J Natl Cancer
Inst. 2011;103(11):876-84. Chan et al. J Clin Oncol
23:8152-8160
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Other risk factors for prostate cancer Risk factorDirection of
effect Accumulating 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)
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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
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Role of energy balance in cancer development Exp Diabetes Res.
2012;2012:789174
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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
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FEMALE CANCERS
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http://seer.cancer.gov/ faststats/index.php
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American Cancer Society. Global Cancer Facts & Figures 2nd
Edition. Atlanta: American Cancer Society; 2011.
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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)
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Breast Disease 24 (2005,2006) 1735 Risk factors for
postmenopausal breast cancer across the life course
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Race/Ethnicity and Breast Cancer American Cancer Society.
Breast Cancer Facts & Figures 2011-2012. Atlanta: American
Cancer Society.
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Heredity and Breast Cancer Inherited factor(s) All Breast
Cancer Patients Other factor(s)
http://www.cancer.gov/cancertopics/understandingcancer/cancer
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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
American Cancer Society. Global Cancer Facts & Figures 2nd
Edition. Atlanta: American Cancer Society; 2011.
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Cervical cancer risk factors Virtually all cervical cancers are
caused by HPV infections Other risk factors: Sexual behavior: 1 st
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
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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
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Prevalence of HPV-16 in serum Infect Dis Obstet Gynecol.
2006;2006 Suppl:40470.
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Cumulative incidence of CIN after HPV infection Infect Dis
Obstet Gynecol. 2006;2006 Suppl:40470. Cervical Intraepithelial
Neoplasia (CIN): precancerous lesion
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Endometrial cancer Most common gynecological cancer in the
US
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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)
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Ovarian cancer Rare, occurs mainly in older women Rapidly fatal
because difficult to detect in early stages
http://www.medinfographics.com/c ancer-statistics/ovarian-
cancer/ovarian-cancer-survival-by- stage-at-diagnosis/
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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
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BURDEN OF OBESITY IN THE UNITED STATES
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Obesity Trends* Among U.S. Adults BRFSS, 1985 (*BMI 30, or ~ 30
lbs. overweight for 5 4 person) No Data
