Editing Prostate cancer (section)

== Pathophysiology ==

Most prostate tumors begin in the peripheral zone – the outermost part of the prostate.{{sfn|Sandhu|Moore|Chiong|Beltran|2021|loc="The biology of prostate cancer"}} As cells begin to grow out of control, they form a small clump of disregulated cells called a [[prostatic intraepithelial neoplasia]] (PIN).<ref name=ACS-Pins>{{cite web|url=https://www.cancer.org/cancer/diagnosis-staging/tests/understanding-your-pathology-report/prostate-pathology/high-grade-prostatic-intraepithelial-neoplasia.html |access-date=25 May 2023 |title=Understanding Your Pathology Report: Prostatic Intraepithelial Neoplasia (PIN) and Intraductal Carcinoma |publisher=American Cancer Society}}</ref> Some PINs continue to grow, forming layers of tissue that stop expressing genes common to their original tissue location – [[TP63|p63]], [[cytokeratin 5]], and [[cytokeratin 14]] – and instead begin expressing genes typical of cells in the innermost lining of the pancreatic duct – [[cytokeratin 8]] and [[cytokeratin 18]].{{sfn|Sandhu|Moore|Chiong|Beltran|2021|loc="The biology of prostate cancer"}} These multilayered PINs also often overexpress the gene [[AMACR]], which is associated with prostate cancer progression.{{sfn|Sandhu|Moore|Chiong|Beltran|2021|loc="The biology of prostate cancer"}}

Some PINs can eventually grow into tumors.<ref name=ACS-Pins/> This is commonly accompanied by large-scale changes to the [[genome]], with [[chromosome]] sequences being rearranged or copied repeatedly. Some genomic alterations are particularly common in early prostate cancer, namely [[Fusion gene|gene fusion]] between [[TMPRSS2]] and the oncogene [[ERG (gene)|ERG]] (up to 60% of prostate tumors), mutations that disable [[SPOP]] (up to 15% of tumors), and mutations that hyperactivate [[FOXA1]] (up to 5% of tumors).{{sfn|Sandhu|Moore|Chiong|Beltran|2021|loc="The biology of prostate cancer"}}

Metastatic prostate cancer tends to have more genetic mutations than localized disease.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}} Many of these mutations are in genes that protect from DNA damage, such as [[p53]] (mutated in 8% of localized tumors, more than 27% of metastatic ones) and [[Retinoblastoma protein|RB1]] (1% of localized tumors, more than 5% of metastatic ones).{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}} Similarly mutations in the DNA repair-related genes [[BRCA2]] and [[ATM (gene)|ATM]] are rare in localized disease but found in at least 7% and 5% of metastatic disease cases respectively.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}}

The transition from castrate-sensitive to castrate-resistant prostate cancer is also accompanied by the acquisition of various gene mutations. In castrate-resistant disease, more than 70% of tumors have mutations in the [[androgen receptor]] signaling pathway – amplifications and gain-of-function mutations in the receptor gene itself, amplification of its activators (for example, FOXA1), or inactivating mutations in its negative regulators (for example, [[ZBTB16]] and [[NCOR1]]).{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}} These androgen receptor disruptions are only found in up to 6% of biopsies of castrate-sensitive metastatic disease.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}} Similarly, deletions of the tumor suppressor [[PTEN (gene)|PTEN]] are harbored by 12–17% of castrate-sensitive tumors, but over 40% of castrate-resistant tumors.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}} Less commonly, tumors have aberrant activation of the [[Wnt signaling pathway]] via disruption of members [[APC (gene)|APC]] (9% of tumors) or [[CTNNB1]] (4% of tumors); or  dysregulation of the [[Phosphoinositide 3-kinase|PI3K]] pathway via [[PI3KCA]]/[[PI3KCB]] mutations (6% of tumors) or [[AKT1]] (2% of tumors).{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}}