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| Epidemiology[https://pubmed.ncbi.nlm.nih.gov/33538338][https://seer.cancer.gov/statfacts/html/prost.html][https://www.ncbi.nlm.nih.gov/pubmed/32122974] | | == Epidemiology[https://pubmed.ncbi.nlm.nih.gov/33538338][https://seer.cancer.gov/statfacts/html/prost.html][https://www.ncbi.nlm.nih.gov/pubmed/32122974] == |
| <li><strong>Incidence</strong>
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| <ul>
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| <li><strong>Highest in countries with the highest rates of screening</strong></li>
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| <li><strong>Worldwide</strong>
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| <ul>
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| <li>2nd most common visceral malignancy in men</li>
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| <li><strong>Estimated incidence 2020: 1,414,259</strong></li>
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| </ul>
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| </li>
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| <li><strong>US</strong>
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| <ul>
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| <li><strong><span class="red">Most common visceral malignancy in men</span></strong></li>
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| <li><strong>Estimated incidence 2021: 248,530</strong>
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| <ul>
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| <li><strong>≈1/8 males are diagnosed with prostate cancer during their lifetime</strong></li>
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| </ul>
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| </li>
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| </ul>
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| </li>
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| <li>Canada Statistics
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| <ul>
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| <li>Most common malignancy in males <ul>
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| <li>Followed by lung and bronchus (13.2%) and colorectal (12.9%)</li>
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|
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| <li>In females, most common cancers are breast (25%), lung and bronchus (13.5%), and colorectal (10.9%)</li>
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| </ul>
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| </li>
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| <li>Estimated cancer incidence 2020: 220,400 </li>
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| <li>Estimated prostate cancer incidence 2020: 23,300
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| <ul>
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| <li>11.3% (≈1/9 men) lifetime probability of prostate cancer diagnosis in males </li>
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| </ul>
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| </li>
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| </ul>
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| </li>
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| <li><strong>Trends in incidence</strong>
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| <ul>
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| <li><strong>PSA</strong> was discovered in 1979 and was <strong>licensed as a test by the FDA in 1986. </strong>Thereafter, the <strong>incidence of prostate cancer increased significantly, peaking in 1992, </strong>≈5 years after the introduction of the PSA test<strong>. </strong></li>
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| <li><strong>Incidence then declined until 1995 (screening responsible for decrease i.e. there were now fewer people with prostate cancer in the source population as they had been screen-detected)</strong></li>
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| <li><strong>Since 1995, incidence increased at a rate similar to pre-PSA screening era, and fluctuated year-to-year since 2001 until 2011 when the draft of the 2012 <a href="../../CNotes/Prostate Cancer/pcascreening.html#uspstf">US Preventative Services Task Force recommendations</a> came out recommending against PSA screening in all males (grade D).</strong></li>
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| </ul>
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| </li>
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| <li><strong>Median age at diagnosis: 67</strong>
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| <ul>
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| <li><strong>Incidence has increased in younger males and decreased in older males, largely account for by PSA screening</strong></li>
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| <li><strong>Men with prostate cancer younger than 50 years account for 2% of all cases</strong> </li>
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| </ul>
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| </li>
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| </ul>
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| </li>
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| <li><strong><span class="red">Mortality</span></strong>
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| <ul>
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| <li><strong><span class="red">Cause of death in ≈3% of US men</span></strong>
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| <ul>
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| <li><strong>Only ≈16% of males diagnosed with prostate cancer ultimately die of it, </strong>demonstrating the indolent course of most prostate cancers</li>
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| <li><strong>Most common cause of mortality in males with prostate cancer is cardiac disease</strong><a href="https://pubmed.ncbi.nlm.nih.gov/23795786/">§</a></li>
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| </ul>
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| </li>
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|
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| <li><strong><span class="red">2nd leading cause of cancer-related death</span></strong> (lung is 1st); </li>
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| <li><strong>Trends in Mortality</strong>
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| <ul>
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| <li><strong>Decreasing since 2001</strong></li>
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| </ul>
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| </li>
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| <li>Average age of death from prostate cancer is 77 years </li>
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| <li>Mortality in African-Americans 2.4x higher than Caucasians</li>
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| </ul>
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| </li>
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| <li><strong>Trends in stage</strong>
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| <ul>
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| <li>There has been clinical and pathological stage migration over time largely due to PSA screening</li>
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| <li>At the time of diagnosis<a href="https://seer.cancer.gov/archive/csr/1975_2014/browse_csr.php?sectionSEL=23&pageSEL=sect_23_table.08.html#table3">§</a>
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| <ul>
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| <li> ≈<strong>80% present with localized disease</strong></li>
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| <li>≈12% present with regional disease</li>
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| <li>≈ 5% present with metastatic disease</li>
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| </ul>
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| </li>
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| </ul>
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| </li>
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| </ul>
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| <h5><strong><span class="red"><a name="pcriskfactors">Pathogenesis</a></span></strong></h5>
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| <ul>
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| <li><strong><span class="red">Risk factors (5):</span></strong>
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| </li>
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| </ul>
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| <ol>
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| <ol>
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| <li><strong><span class="red">Age</span></strong></li>
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| <li><strong><span class="red">Ethnicity</span></strong>
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| <ul>
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| <li><strong><span class="red">Incidence in African-American > Caucasians ></span> </strong><strong>Hispanic/Latino > Asian-American</strong> </li>
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| <li>Men of Asian descent living in the US have a lower incidence compared to white Americans, but their risk is higher than that of Asians living in Asia, suggesting a dietary, lifestyle, environmental factor</li>
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| </ul>
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| </li>
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| <li><strong><span class="red">Family history</span></strong>
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| <ul>
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| <li>≈15% of prostate cancer patients have the familial or hereditary form</li>
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| <li>Risk varies according to the number of affected family numbers, their degree of relatedness, and the age at which they were affected
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| <ul>
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| <li>Father affected: relative risk (RR) 2.2x</li>
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| <li>Brother affected: RR 3.4x</li>
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| <li>First-degree family member affected, age <65 at diagnosis: RR 3.3x</li>
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| <li>>2 first-degree relatives affected: RR 5.1x</li>
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| <li>Second-degree relative affected: RR 1.7x </li>
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| </ul>
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| </li>
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| </ul>
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| </li>
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| <li><strong><span class="red">Germline mutations</span></strong>
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| <ul>
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| <li><strong><span class="red">Genes that substantially increase risk: </span></strong>
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| <ol>
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| <li><strong><span class="red">HOXB13 </span></strong></li>
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| <li><strong><span class="red"> BRCA </span></strong>
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| </li>
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| </ol>
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| <ul>
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| <ul>
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| <li><strong><span class="red">BRCA-associated, especially BRCA2, cancers are more aggressive</span></strong>
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| <ul>
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| <li>More likely to present with higher grade, locally advanced, and metastatic disease, and have worse cancer-specific survival and metastasis-free survival after prostatectomy</li>
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| <li>2-6x increased lifetime risk (BRCA2 > BRCA1)</li>
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| <li>Increased risk of metastatsis and prostate cancer-specific mortality<a href="https://pubmed.ncbi.nlm.nih.gov/25454609/">§</a></li>
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| </ul>
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| </li>
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| <li><strong name="brcacancers"><span class="red"><a name="brcacancers">BRCA-cancers: breast, ovarian, pancreatic, prostate, melanoma</a></span> </strong></li>
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| </ul>
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| </ul>
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| </li>
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| <li><strong name="pritchard2016"><span class="purple"><a name="pritchard2016">Incidence of germline mutations in genes mediating DNA-repair processes in prostate cancer (2016)</a></span></strong>
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| <ul>
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| <li>Population: 692 men</li>
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| <li><strong>Results:</strong>
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| <ul>
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| <li><strong>Incidence of <span class="red">germline mutations in genes mediating DNA-repair </span>processes was significantly higher in males with <span class="red">metastatic prostate cancer (11.8%)</span> compared to males with localized prostate cancer (4.6%) and the <span class="red">general population (2.7%)</span> </strong></li>
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| </ul>
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| </li>
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| <li><a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1603144">Pritchard et al. NEJM 2016</a></li>
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| </ul>
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| </li>
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| <li><strong><span class="red">Lynch syndrome<a href="https://cebp.aacrjournals.org/content/23/3/437 ">§</a></span></strong><u> </u>
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| <ul>
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| <li>Due to mutation in mismatch repair genes</li>
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| <li><strong>Associated cancers: (8) colonic (most common), endometrial (second most common), prostate, urothelial, adrenal, gastric, pancreatic, uterine, ovarian, and sebaceous carcinomas</strong></li>
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| </ul>
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| </li>
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| </ul>
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| </li>
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| <li><strong><span class="red">Inflammation</span></strong>
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| <ul>
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| <li>Likely contributes to development and progression of early-stage disease</li>
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| <li>Potential triggers for inflammation include dietary carcinogens (especially from cooked meats), <strong>estrogens</strong>, and infectious agents</li>
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| <li>Studies assessing the association between infection and prostate cancer have shown mixed results; some data suggest that history of STIs and prostatitis is associated with increased risk of prostate cancer</li>
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| </ul>
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| </li>
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| </ol>
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| <ul>
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| <li><strong>Polymorphisms</strong> in both synthetic and metabolic genes, including the <strong>androgen receptor (AR), the 5-alpha reductase type 2 isoenzyme</strong>, and genes involved in testosterone biosynthesis, have been reported to affect risk</li>
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| <li><strong>Insulin-like growth factor </strong>axis is important in prostate cancer risk and progression</li>
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| <li><strong>Polymorphisms conferring lower vitamin D receptor activity</strong> are associated with increased risk for prostate cancer; vitamin D and its interaction with its receptor modulates disease aggressiveness</li>
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| <li><strong>Smoking increases risk and is associated with worse biochemical recurrence, metastasis, and cancer-specific mortality</strong></li>
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| <li>Mixed results with alcohol</li>
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| </ul>
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| </ol>
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| <h5><strong>Molecular Genetics</strong></h5>
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| <ul>
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| <li>Biologic functions of known prostate cancer susceptibility genes include:
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| <ol>
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| <li>Control of the inflammatory response</li>
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| <li>Homeobox genes</li>
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| <li>DNA repair mechanisms</li>
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| <li>Susceptibility to infection </li>
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| </ol>
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| </li>
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| <li><strong><span class="red">Most common gene fusion identified in localized prostate cancer involves TMPRSS2</span></strong> or other promoters (SLC45A3, HERPUD1, or NDRG) <strong><span class="red">fused to ERG (ETS-related gene)</span></strong></li>
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| <ul>
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| <li><strong>The TMPRSS2 gene is prostate specific, and is expressed in both benign and malignant prostatic epithelium; </strong></li>
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| <li><strong>TMPRSS2:ERG fusion gene is detected in ≈50% of prostate cancers</strong></li>
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| <li><strong> TMPRSS2-ERG fusion gene is present in prostate stem cells</strong></li>
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| <li><strong>TMPRSS2 expression has been shown to be induced by androgens</strong></li>
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| <li><strong>TRMPSS2-related gene fusions are highly specific for the presence of prostate cancer</strong></li>
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| </ul>
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| <li>Most common point mutations in prostate cancer are mutations in SPOP, which encodes a subunit of ubiquitin ligase</li>
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| <li>Current evidence suggests that most prostate cancer is polygenic in origin. GWAS studies have identified more than 70 risk alleles and chromosomal loci, many of which occur in non-coding areas of the genome. A variety of genes implicated in prostate cancer initiation and progression include</li>
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| <ul>
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| <li>Hypermethylation of</li>
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| <ul>
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| <li>Hormonal response genes (ERαA, ERβ, and RARβ)</li>
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| <li>Genes controlling the cell cycle (CyclinD2 and 14-3-3σ)</li>
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| <li>Tumor cell invasion/tumor architecture genes (CD44)</li>
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| <li>DNA repair genes (GSTpi, GPX3, and GSTM1)</li>
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| <li>Tumor suppressor genes (APC, RASSF1α, DKK3, p16INK4?−α, E-cadherin, and p57WAF1)</li>
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| <li>Signal transduction genes (EDNRB and SFRP1)</li>
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| <li>Inflammatory response genes (PTGS/COX2)</li>
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| </ul>
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| <li>Hypomethylation of CAGE, HPSE, and PLAU</li>
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| <li>Histone hypoacetylation of CAR, CPA3, RARB, and VDR</li>
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| <li>Histone methylation of GSTP1 and PSA</li>
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| </ul>
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| <li>Epigenetic mechanisms active in prostate cancer include:
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| <ol>
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| <li>Chromatin remodeling</li>
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| <li>Promoter hypomethylation and hypermethylation</li>
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| <li>MicroRNAs that lead to gene silencing</li>
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| <li>Long non-coding RNAs </li>
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| </ol>
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| </li>
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| </ul>
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| <h5><strong><span class="red">Questions</span></strong></h5>
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| <ol>
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| <li>What proportion of US males are diagnosed with prostate cancer during their lifetime? </li>
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| <li>Which germline mutations are associated with increased risk of prostate cancer? </li>
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| <li>What are the BRCA2 related cancers? </li>
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| <li>Which 5 ARI subtype (type 1 vs 2) is predominantly in the prostate? Also found in the brain? </li>
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| <li>What is the most common gene fusion identified in localized prostate cancer? </li>
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| </ol>
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| <p> </p>
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| <h5><strong><span class="red">Answers</span></strong></h5>
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| <ol>
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| <li>What proportion of US males are diagnosed with prostate cancer during their lifetime?
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| <ul>
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| <li>≈1/7-1/9</li>
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| </ul>
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| </li>
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| <li>Which germline mutations are associated with increased risk of prostate cancer?
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| <ul>
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| <li>HOXB13 and BRCA2</li>
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| </ul>
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| </li>
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| <li>What are the BRCA2 related cancers?
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| <ul>
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| <li>Breast, ovarian, prostate, pancreatic, melanoma</li>
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| </ul>
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| </li>
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| <li>Which 5 ARI subtype (type 1 vs 2) is predominantly in the prostate? Also found in the brain?
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| <ul>
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| <li>Type 2 is primarily in the prostate and other genital tissues such as the epididymis, genitalia, seminal vesicle, testis, but also in liver, uterus, breast, hair follicles, and placenta</li>
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| <li>Type 1 is primarily in the non-genital skin and liver, and also found in the prostate, testis, and brain </li>
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| </ul>
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| </li>
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| <li>What is the most common gene fusion identified in localized prostate cancer? </li>
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| <ul>
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| <li>TMPRSS2 fused to ERG </li></ul></ol>
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| <h5><span class="teal">Next Chapter: </span><a href="pcaprevention.html">Prevention</a> </h5>
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| <h5>References</h5>
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| <ul>
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| <li>Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 107</li>
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| </ul>
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| <p> </p>
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