перспективные биомаркеры для диагноза и

ОБЗОРЫ
Ã. Ñàðäàíà1,2, Á. Äîóýëë3, Ý. Ï. Äèàìàíäèñ1,2,4
ПЕРСПЕКТИВНЫЕ БИОМАРКЕРЫ ДЛЯ ДИАГНОЗА
И ПРОГНОЗА РАКА ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫ (ОБЗОР)
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…/L ,“2%#…,* " ›3!…= &Clinical Chemistry[.
4
Emerging Biomarkers for the Diagnosis and Prognosis of Prostate Cancer
Girish Sardana1,2, Barry Dowell3, and Eleftherios P. Diamandis1,2,4
1
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada,
2
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada,
3
Abbott Laboratories, Abbott Park, IL;
Department of Clinical Biochemistry, University Health Network and Toronto Medical Laboratories, Toronto, Ontario, Canada
This article has been translated with the permission of AACC. AACC is not responsible for the accuracy of the translation.
The views presented are those of the authors and not necessarily those of AACC or the journal.
Reprinted from Clin. Chem. 2008. Vol. 52. P. 1951$1960, by permission of the publisher.
Original Copyright I 2008 American Association of Clinical Chemistry, Inc
When citing this article, please refer to the original publication source in the journal, Clinical Chemistry.
q.*0 9%-(?: ÐÏÆ – ðàê ïðåäñòàòåëüíîé æåëåçû (ïðîñòàòû); ÄÃÏ – äîáðîêà÷åñòâåííàÿ ãèïåðïëàçèÿ ïðîñòàòû;
fPSA– ñâîáîäíûé ñïåöèôè÷åñêèé äëÿ ïðîñòàòû àíòèãåí; KLK2 – ðîäñòâåííàÿ êàëëèêðåèíó ïåïòèäàçà 2; PSMA –
ñïåöèôè÷åñêèé äëÿ ïðîñòàòû ìåìáðàííûé àíòèãåí; PCA3 – àíòèãåí ðàêà ïðîñòàòû; EPCA – ðàííèé àíòèãåí ðàêà
ïðîñòàòû; AMACR – α-ìåòèë-ÊîÀ-ðàöåìàçà; uPA – àêòèâàòîð óðîêèíàçû è ïëàçìèíîãåíà, uPAR – ðåöåïòîð uPa; IGF –
èíñóëèíîïîäîáíûé ðîñòîâûé ôàêòîð; IGFBP – áåëîê ñâÿçûâàíèÿ IGF; TGF – òðàíñôîðìèðóþùèé ðîñòîâûé ôàêòîð;
PSP94 – ñåêðåòîðíûé áåëîê-94 ïðîñòàòû; CRISP-3 – áîãàòûé öèñòåèíîì ñåêðåòîðíûé áåëîê-3; ANXA3 – àííåêñèí À3;
PSCA – àíòèãåí ñòâîëîâûõ êëåòîê ïðîñòàòû; IL-6 – èíòåðëåéêèí 6
Ðàê ïðåäñòàòåëüíîé æåëåçû (ÐÏÆ) ÿâëÿåòñÿ ñà- øèì èç áèîìàðêåðîâ, èçâåñòíûõ â îíêîëîãèè, íî ïðè
ìûì ðàñïðîñòðàíåííûì ðàêîâûì çàáîëåâàíèåì ó ýòîì èìååò ìíîæåñòâî íåäîñòàòêîâ. Èñõîäíî PSA
ìóæ÷èí è âòîðîé ïî çíà÷èìîñòè ïðè÷èíîé ñìåðòè â èñïîëüçîâàëè äëÿ ìîíèòîðèíãà áîëüíûõ ÐÏÆ, è
Ñåâåðíîé Àìåðèêå. Êàæäûé øåñòîé ìóæ÷èíà íàõî- òîëüêî ïîçæå åãî ïðèìåíåíèå áûëî ðàñïðîñòðàíåíî
äèòñÿ â ãðóïïå ðèñêà ïî ÐÏÆ íà ïðîòÿæåíèè æèçíè, íà ñêðèíèíã. Îòêðûòèå PSA è åãî âíåäðåíèå â êëèíèà âåðîÿòíîñòü ñìåðòè îò ýòîãî çàáîëåâàíèÿ ñîñòàâëÿ- êó â íà÷àëå 1990-õ ãã. XX â. îêàçàëî îãðîìíîå âëèÿåò 3,4 %.  íàñòîÿùåå âðåìÿ äèàãíîç â áîëüøèíñòâå íèå íà ðàííþþ äèàãíîñòèêó ÐÏÆ è ñòàëî ïðè÷èíîé
ñëó÷àåâ ñòàâèòñÿ ó áîëüíûõ íà ðàííåé áåññèìïòîìíîé óâåëè÷åíèÿ äîêóìåíòèðîâàííîé çàáîëåâàåìîñòè ÐÏÆ.
ñòàäèè çàáîëåâàíèÿ. Âñëåäñòâèå òàêîãî äèàãíîñòè÷å-  íàñòîÿùåå âðåìÿ PSA èñïîëüçóþò êàê äèàãíîñòèñêîãî ñäâèãà êëàññè÷åñêèå ïîäõîäû ê ïðîãíîçó, òàêèå ÷åñêèé ìàðêåð, íî åãî óðîâíè âñå áîëüøå ïðèçíàþòêàê òàáëèöû Ïàðòýíà (Partin) è íîìîãðàììû Êàòòàíà ñÿ îòðàæàþùèìè ðèñê ÐÏÆ. Âåðõíèé ïðåäåë íîðìû
(Kattan), óæå íå ñòîëü ýôôåêòèâíû, êàê â ïðîøëîì. óñòàíîâëåí íà óðîâíå 4 ìêã/ë, ÷òî íå ïîçâîëÿåò âûÿâÂíèìàíèå ñåé÷àñ ñìåñòèëîñü îò ðàííåãî âûÿâëåíèÿ ëÿòü ìíîãèå ñëó÷àè ðàêà, è â ïðîåêòå «Èñïûòàíèå ïðîê îïðåäåëåíèþ êëèíè÷åñêîãî çíà÷åíèÿ îïóõîëåé íà ôèëàêòèêè ðàêà ïðîñòàòû» áûë ñäåëàí âûâîä î òîì,
ðàííåé ñòàäèè. Îäíà èç çàäà÷ ïðè ýòîì ñîñòîèò â îòûñ- ÷òî íèêàêàÿ êîíöåíòðàöèÿ PSA íå èñêëþ÷àåò íàëè÷èÿ
êàíèè ïóòåé âûÿâëåíèÿ êëèíè÷åñêè çíà÷èìûõ îïóõî- ðàêà. Îïðåäåëåíèå îáùåãî PSA îêàçàëîñü ïîëåçíûì
ëåé, ñïîñîáíûõ ê ìåòàñòàçèðîâàíèþ.  íàñòîÿùåå ïðîãíîñòè÷åñêèì ñðåäñòâîì, ïðè÷åì âûñîêèå äîîïåâðåìÿ 30 % îïóõîëåé, óäàëÿåìûõ ïðè ðàäèêàëüíîé ðàöèîííûå óðîâíè ñâÿçàíû ñ äàëåêî çàøåäøèì çàáîïðîñòàòýêòîìèè, ïðèçíàþòñÿ êëèíè÷åñêè íåçíà÷èìû- ëåâàíèåì è ïëîõèì ïðîãíîçîì. Ïðîòèâîðå÷èÿ âîêðóã
ìè è íå òðåáóþùèìè âìåøàòåëüñòâà òàêîãî îáúåìà. PSA ñåé÷àñ àêòèâíî îáñóæäàþòñÿ, ïîñêîëüêó íåÿñíî,
 áîëüøèíñòâå ñëó÷àåâ âûÿâëÿåòñÿ ëàòåíòíûé íå- ïðèâåë ëè ñêðèíèíã íà PSA ê ñíèæåíèþ ñìåðòíîñòè
àãðåññèâíûé ÐÏÆ, ïîýòîìó âàæíî íå ïîäâåðãàòü ýòèõ îò ÐÏÆ. Îòâåò íà âîïðîñ, ñíèæàåò ëè ñêðèíèíã íà
áîëüíûõ ðàäèêàëüíîìó ëå÷åíèþ. Ñäåðæèâàíèå ÐÏÆ PSA ñìåðòíîñòü, äîëæåí áûòü ïîëó÷åí ïî ðåçóëüòàòàì
âîçìîæíî ïðè ðàííåé äèàãíîñòèêå è äîëæíîì ëå÷å- ïðîâåäåííûõ â 2008–2009 ãã. äâóõ êðóïíûõ ðàíäîìèíèè, îäíàêî ñîîòâåòñòâóþùèé óðîâåíü äèàãíîñòè÷å- çèðîâàííûõ ïðîñïåêòèâíûõ êëèíè÷åñêèõ èññëåäîâàñêîé èçîùðåííîñòè ïîêà åùå íå äîñòèãíóò.
íèé «Åâðîïåéñêîå ðàíäîìèçèðîâàííîå èññëåäîâàíèå
Áèîìàðêåðîì, èñïîëüçóåìûì â íàñòîÿùåå âðåìÿ ñêðèíèíãà íà ðàê ïðîñòàòû» è «Èçó÷åíèå ñêðèíèíãà
äëÿ ðàííåé äèàãíîñòèêè ÐÏÆ, ÿâëÿåòñÿ ñïåöèôè÷å- íà ðàê ïðîñòàòû, ëåãêèõ, ïðÿìîé è îáîäî÷íîé êèøêè
ñêèé äëÿ ïðîñòàòû àíòèãåí (PSA). Îí ñ÷èòàåòñÿ ëó÷- è ÿè÷íèêîâ». Ñîîòíîøåíèå ìåæäó PSA è ñòàäèåé îïó-
ПОДПИСНОЙ ИНДЕКС 72075
3
ОБЗОРЫ
õîëè òàêæå íåÿñíî. Óðîâåíü PSA â òêàíè ñíèæàåòñÿ ïî ñûâîðîòêå ñëåäóåò, ÷òî äèàãíîç ÐÏÆ óëó÷øàåòñÿ
ñ óâåëè÷åíèåì êîýôôèöèåíòà Ãëèñîíà, íî êîíöåíòðà- ïðè èñïîëüçîâàíèè KLR2 â ñî÷åòàíèè ñ îáùèì PSA
öèè PSA â ñûâîðîòêå ïðè ýòîì ðàñòóò èç-çà ðàçðûâîâ è fPSA, îñîáåííî â òîì, ÷òî êàñàåòñÿ ýêñòðàêàïñóáàçàëüíîé ìåìáðàíû âîêðóã ýïèòåëèàëüíûõ êëåòîê ëÿðíîãî ðàñïðîñòðàíåíèÿ è îáúåìà îïóõîëè. Òàêæå
ïðîñòàòû è íàðóøåíèÿ îáùåãî ñòðîåíèÿ òêàíè ïðîñòà- KLK2, ïðè ñðàâíåíèè ñ PSA, äàåò âàæíóþ íåçàâèñèòû. PSA íåñïåöèôè÷åí â îòíîøåíèè ÐÏÆ è ìîæåò ñëó- ìóþ ïðîãíîñòè÷åñêóþ èíôîðìàöèþ î ðèñêå ðåöèäèæèòü ìàðêåðîì äîáðîêà÷åñòâåííîé ãèïåðïëàçèè ïðåä- âîâ ÐÏÆ ïðè óðîâíå PSA <
–10 ìêã/ë. Äëÿ âûÿñíåíèÿ
ñòàòåëüíîé æåëåçû (ÄÃÏÆ) è óâåëè÷åíèÿ åå îáúåìà. ïðîãíîñòè÷åñêîãî ïîòåíöèàëà KLK2 íåîáõîäèìà äîÎäíàêî êëþ÷åâûå ñòàòèñòè÷åñêèå îöåíêè åãî àäåêâàò- ïîëíèòåëüíàÿ àïðîáàöèÿ ýòîãî ìàðêåðà.
íîñòè îêàçàëèñü íåïîêàçàòåëüíûìè: ïðè ïîçèòèâíûõ
ïðåäñêàçàòåëüíûõ âåëè÷èíàõ, ïîëó÷àåìûõ â 37 % ñëóСпецифический для предстательной
÷àåâ, äëÿ áîëüíûõ â «ñåðîé» çîíå 4–10 ìêã/ë âåжелезы мембранный антиген
ðîÿòíîñòü ñêðûòîãî ÐÏÆ ñîñòàâëÿåò 25 %, è ÐÏÆ
Ñïåöèôè÷åñêèé äëÿ ïðîñòàòû ìåìáðàííûé àíòèâûÿâëÿåòñÿ ó 15% áîëüíûõ ñ êîíöåíòðàöèåé PSA
<4 ìêã/ë. Íåàäåêâàòíîñòü PSA â êà÷åñòâå ìàðêåðà ãåí (prostate-specific membrane antigen, PSMA) ÿââûçâàëà íåîáõîäèìîñòü â íîâûõ ìàðêåðàõ ÐÏÆ äëÿ ëÿåòñÿ ìåìáðàííûì ãëèêîïðîòåèíîì, êîòîðûé îáïðåäîòâðàùåíèÿ ÷ðåçìåðíûõ òåðàïåâòè÷åñêèõ ìåð ðàçóåòñÿ â âûñîêèõ êîíöåíòðàöèÿõ â ýïèòåëèàëüíûõ
â îòíîøåíèè âÿëîòåêóùåãî çàáîëåâàíèÿ. Âäîáàâîê êëåòêàõ çäîðîâûõ ëèö è áîëüíûõ ÐÏÆ. Îêàçàëîñü,
ê äèàãíîñòè÷åñêèì ìàðêåðàì, íóæíû ïðîãíîñòè÷å- ÷òî îòíîñèòåëüíàÿ ïðîäóêöèÿ PSMA ïîâûøåíà â ýïèñêèå, ïðåäñêàçàòåëüíûå è òåðàïåâòè÷åñêèå ìàðêåðû òåëèàëüíûõ êëåòêàõ òêàíè ÐÏÆ. Ôèðìà «Cytogen»
â êà÷åñòâå ñóððîãàòíûõ êîíå÷íûõ ïîêàçàòåëåé äëÿ ðàçðàáîòàëà êîììåð÷åñêèé òåñò äëÿ âèçóàëèçàöèè
ïðåäñêàçàíèÿ òÿæåñòè çàáîëåâàíèÿ, âûáîðà ëå÷åíèÿ PSMA (ProstaScint) ðàäèîèììóíîñöèíòèãðàôèåé. Íàè ìîíèòîðèíãà îòâåòà íà òåðàïèþ, ñîîòâåòñòâåííî. êîíåö, PSMA èññëåäîâàí â êà÷åñòâå òåðàïåâòè÷åñêîé
 ýòîì îáçîðå îñíîâíîå âíèìàíèå áóäåò íàïðàâëåíî ìèøåíè àíòèòåë, êîíúþãèðîâàííûõ ñ ðàäèîèçîòîíà íîâûå ìàðêåðû, êîòîðûå âûãëÿäÿò ïåðñïåêòèâíûìè
ïàìè èëè îêñèíàìè, èëè àêòèâèðîâàííûìè äåíäðèòäëÿ ðàííåãî âûÿâëåíèÿ è ëå÷åíèÿ ÐÏÆ (2=K. 1).
íûìè êëåòêàìè ïðîòèâ PSMA. Èñïîëüçîâàíèå PSMA
åùå íå ñòàëî ïðèíÿòûì â êëèíè÷åñêîé ïðàêòèêå,
Производные от уровня PSA
è åãî âîçìîæíîñòè äëÿ äèàãíîñòèêè è òåðàïèè âñå
Ñòàëî ÿñíî, ÷òî ðàáî÷èå õàðàêòåðèñòèêè PSA òðå- åùå íàõîäÿòñÿ â ðàçðàáîòêå.
áóþò óëó÷øåíèÿ. Îäèí èç ïîäõîäîâ äëÿ äîñòèæåíèÿ
ýòîé öåëè ñîñòîèò â îïðåäåëåíèè ïðîèçâîäíûõ îò
Другие тканевые калликреины
óðîâíåé PSA, â òîì ÷èñëå ñêîðîñòè èçìåíåíèÿ PSA
Äî
íåäàâíåãî âðåìåíè òîëüêî KLK3 (ðîäñòâåíñî âðåìåíåì, ñîîòíîøåíèÿ êîíöåíòðàöèè è îáúåìà
íàÿ
êàëëèêðåèíó
ïåïòèäàçà-3, ïðè÷åì èìåííî îíà
ïðîñòàòû («ïëîòíîñòü» PSA) è èíòåðâàëîâ óðîâíåé
ïðåæäå
áûëà
èçâåñòíà
êàê PSA), KLK2 (ðîäñòâåíPSA, ñïåöèôè÷íûõ äëÿ ðàçíûõ âîçðàñòíûõ ãðóïï.
íàÿ
êàëëèêðåèíó
ïåïòèäàçà-2)
è KLK1 (êàëëèêðåèí-1,
Âäîáàâîê, óñïåõè â îïðåäåëåíèè PSA è ðîäñòâåííûõ
òàêæå èçâåñòíûé êàê ïàíêðåàòè÷åñêèé/ïî÷å÷íûé
åìó áåëêîâ ñäåëàëè âîçìîæíûì îïðåäåëåíèå äîëè
êàëëèêðåèí) áûëè ãåíàìè, èäåíòèôèöèðîâàííûìè
ñâîáîäíîãî PSA (fPSA), ïðåäñòàâëÿþùåãî ñîáîé
â êàëëèêðåèíîâîì ëîêóñå íà õðîìîñîìå 19. Èçñîîòíîøåíèå ñâîáîäíîãî è îáùåãî PSA.  ÷àñòíîâåñòíî, ÷òî ýòîò ëîêóñ ïðîñòèðàåòñÿ íà 300 òûñ.
ñòè, áûëî ïðîäåìîíñòðèðîâàíî çíà÷åíèå äîëè fPSA ïàð íóêëåîòèäîâ è ñîñòîèò èç 15 ãåíîâ, èìåþùèõ
â êà÷åñòâå ïðåäñêàçàòåëüíîãî ïðèçíàêà ïîçäíèõ çíà÷èòåëüíóþ ãîìîëîãèþ è ñõîäñòâî íóêëåîòèäíûõ
ñòàäèé ÐÏÆ. Äðóãèå âàðèàíòû âêëþ÷àþò îïðåäåëå- è àìèíîêèñëîòíûõ ïîñëåäîâàòåëüíîñòåé. Âäîáàâîê
íèå êîìïëåêñîâ PSA ñ α2-ìàêðîãëîáóëèíîì, α1-àíòè- ê KLK2, äðóãèå êàëëèêðåèíû îêàçàëèñü ïîëåçíûìè
õèìîòðèïñèíîì, à òàêæå ðàçíûõ ïðîäóêòîâ ðàñùå- â êà÷åñòâå áèîìàðêåðîâ ÐÏÆ è äðóãèõ çàáîëåâàíèé.
ïëåíèÿ PSA, òàêèõ êàê [-2]proPSA è bPSA.
Âîñåìü êàëëèêðåèíîâ îáðàçóþòñÿ â îòíîñèòåëüíî
âûñîêèõ êîíöåíòðàöèÿõ â òêàíÿõ ïðîñòàòû: KLK 2-4,
10-13
è 15. Èç èõ ÷èñëà KLK11 â ñî÷åòàíèè ñ PSA
Человеческая родственная
è
äîëåé
fPSA ïðîäåìîíñòðèðîâàë ñïîñîáíîñòü íåкалликреину пептидаза-2
ñêîëüêî óëó÷øàòü ïðåäñêàçóåìîñòü ÐÏÆ.
×åëîâå÷åñêàÿ ðîäñòâåííàÿ êàëëèêðåèíó ïåïòèäàçà-2 (KLK2, ïðåæäå èçâåñòíàÿ êàê hK2) ÿâëÿåòñÿ
Антиген рака предстательной железы 3
ñåêðåòèðóåìîé ñåðèíîâîé ïðîòåèíàçîé, ãåí êîòîÀíòèãåí ðàêà ïðîñòàòû 3 (PCA3), òàêæå èçâåñòðîé îòíîñèòñÿ ê òîìó æå ñåìåéñòâó, ÷òî è ãåí PSA.
Èç äàííûõ ïî òêàíÿì ÐÏÆ ñëåäóåò, ÷òî KLK2 ïîâû- íûé êàê DD3, ÿâëÿåòñÿ íåêîäèðóþùåé ÐÍÊ, îáðàøàåòñÿ ïî ìåðå åãî ïðîãðåññèðîâàíèÿ è ïîýòîìó ìî- çóþùåéñÿ èñêëþ÷èòåëüíî â ïðîñòàòå. Ñèëüíî ïîâûæåò ñëóæèòü â êà÷åñòâå áèîìàðêåðà ÐÏÆ. Èç äàííûõ øåííûå óðîâíè PCA3 ïðèñóòñòâóþò â òêàíÿõ ÐÏÆ,
4
WWW.TERRAMEDIСA.SPB.RU
ОБЗОРЫ
Таблица 1
Список кандидатов в биомаркеры рака предстательной железы и их возможное клиническое применение
Êàíäèäàò
â áèîìàðêåðû
Ïðîâåðåííàÿ êëèíè÷åñêàÿ ïðèìåíèìîñòü
KLK2
Äèàãíîñòè÷åñêîå è ïðîãíîñòè÷åñêîå ïðåäñêàçàíèå ýêñòðàêàïñóëÿðíîãî ðàñïðîñòðàíåíèÿ îïóõîëè, îáúåìà îïóõîëè è ðåöèäèâîâ ïî áèîõèìè÷åñêèì ïðèçíàêàì
PSMA
Âèçóàëèçàöèÿ, òåðàïåâòè÷åñêàÿ ìèøåíü
KLK11
Ðàííèé ñûâîðîòî÷íûé ïðåäñêàçàòåëüíûé ïðèçíàê ÐÏÆ
PCA3
Áèîìàðêåð ÐÏÆ, îïðåäåëÿåìûé â ìî÷å
EPCA/EPCA-2
Èììóíîãèñòîõèìè÷åñêîå âûÿâëåíèå ÐÏÆ, ñûâîðîòî÷íûé ìàðêåð
äëÿ äèôôåðåíöèàöèè ëîêàëüíîãî è ìåòàñòàòè÷åñêîãî ÐÏÆ
AMACR
Âûÿâëåíèå ÐÏÆ ïî àóòîàíòèòåëàì, èììóíîãèñòîõèìè÷åñêîå âûÿâëåíèå,
ïðîãíîñòè÷åñêèé ïðèçíàê ñìåðòíîñòè è ðåöèäèâîâ ïî áèîõèìè÷åñêèì ïðèçíàêàì
uPA/uPAR
Ïîâûøåííûå êîíöåíòðàöèè â òêàíÿõ è ñûâîðîòêå ïðåäñêàçûâàþò áèîõèìè÷åñêèå
ðåöèäèâû è ìåòàñòàçû
IGF/IGFBP
IGF-1 ñëåãêà ïîâûøåí â ñûâîðîòêå ïðè ÐÏÆ, êîíöåíòðàöèè IGFBP íàõîäÿòñÿ
â îáðàòíîé êîððåëÿöèè ñ ïðîãðåññèåé ÐÏÆ
TMPRSS2:ERG/
ETV1
TGFβ- 1
EZY2
GSTP1
PSP94
CRISP-3
Õðîìîãðàíèí `
Ïåïòèäíûé ôàêòîð
âûñâîáîæäåíèÿ
ïðîãàñòðèíà
e-êàäõåðèí
Àííåêñèí `3
PSCA
Ãåïñèí
Èíòåðëåéêèí 6
ПОДПИСНОЙ ИНДЕКС 72075
Âûÿâëÿþòñÿ íà ïîâûøåííûõ óðîâíÿõ â ìî÷å ó áîëüíûõ ÐÏÆ è èíòðàýïèòåëèàëüíîé íåîïëàçèåé in situ, ñëèÿíèå ãåíîâ âûÿâëÿåòñÿ â òêàíÿõ ÐÏÆ ôëþîðåñöåíòíîé
ãèáðèäèçàöèåé in situ
Ïîâûøåíèå èììóíîãèñòîõèìè÷åñêîãî îêðàøèâàíèÿ è óðîâíÿ â ñûâîðîòêå êðîâè
ïî ìåðå ïðîãðåññèè ÐÏÆ è ðåöèäèâîâ ïî áèîõèìè÷åñêèì ïðèçíàêàì
Ýêñïðåññèÿ ãåíà â òêàíÿõ ÐÏÆ ÿâëÿåòñÿ ïðåäñêàçàòåëüíûì ïðèçíàêîì ïðîãðåññèè
Âûÿâëåíèå ãèïåðìåòèëèðîâàíèÿ ïðîìîòîðà ýòîãî ãåíà äëÿ îöåíêè
öåëåñîîáðàçíîñòè áèîïñèè
Ïðåäñêàçàòåëüíûé ïðèçíàê èíäåêñà Ãëèñîíà è ðåöèäèâîâ ïî áèîõèìè÷åñêèì
ïðèçíàêàì ïîñëå ëîêàëüíîé îïåðàöèè
Ïîâûøåííàÿ ãèñòîõèìè÷åñêàÿ îêðàøèâàåìîñòü òêàíè ïðîñòàòû ó ìóæ÷èí ñ ñèëüíî
òðàíñôîðìèðîâàííîé èíòðàýïèòåëèàëüíîé íåîïëàçèåé, íåçàâèñèìûé ïðåäñêàçàòåëüíûé ïðèçíàê ðåöèäèâîâ ÐÏÆ
Ìîíèòîðèíã áîëüíûõ ñ íåçàâèñèìûì îò àíäðîãåíîâ ÐÏÆ ñ íåéðîýíäîêðèííîé
äèôôåðåíöèàöèåé íà ïîçäíèõ ñòàäèÿõ
Ìîíèòîðèíã áîëüíûõ ñ ìåòàñòàòè÷åñêèì ÐÏÆ, èìåþùèì íåéðîýíäîêðèííûå
è íåçàâèñèìûå îò àíäðîãåíîâ ôåíîòèïû
Ñíèæåííàÿ èììóíîãèñòîõèìè÷åñêàÿ ýêñïðåññèÿ ïðè ÐÏÆ êîððåëèðóåò ñî ñòàäèåé
ñíèæåííîé âûæèâàåìîñòè
Ñíèæåííîå îáðàçîâàíèå â òêàíÿõ ÐÏÆ ïî ðåçóëüòàòàì èììóíîãèñòîõèìèè,
ïðîãíîñòè÷åñêèé ïðèçíàê ðèñêà
Èììóíîãèñòîõèìè÷åñêèé ìàðêåð, êîððåëèðóþùèé ñ èíäåêñîì Ãëèñîíà è ñòàäèåé,
òåðàïåâòè÷åñêàÿ ìèøåíü
Èììóíîãèñòîõèìè÷åñêîå âûÿâëåíèå èíòðàýïèòåëèàëüíîé íåîïëàçèè è ÐÏÆ
â îòëè÷èå îò ÄÃÏÆ
Ïîâûøåííûå êîíöåíòðàöèè â ñûâîðîòêå íà ïîçäíèõ ñòàäèÿõ ÐÏÆ
5
ОБЗОРЫ
â òîì ÷èñëå â ìåòàñòàçàõ, ïðè ñðàâíåíèè ñ òêàíÿìè
ÄÃÏÆ. Ñóùåñòâóåò íåñêîëüêî ñïîñîáîâ îïðåäåëåíèÿ
PCA3 â ìî÷å. Åäèíñòâåííûì èìåþùèìñÿ â ïðîäàæå
òåñòîì ÿâëÿåòñÿ APTIMA® (Gene-Probe), îñíîâàííûé
íà ÏÖÐ. Ðåçóëüòàòû îïðåäåëåíèÿ PCA3 íîðìàëèçóþò
îòíîñèòåëüíî êîíöåíòðàöèè PSA.  íåäàâíåì èññëåäîâàíèè ñ ó÷àñòèåì íåñêîëüêèõ ó÷ðåæäåíèé íà ïàöèåíòàõ, ïîäâåðãàåìûõ áèîïñèè, êîòîðîå âêëþ÷àëî
àíàëèç PCA3 â ìî÷å ïîñëå ìàññàæà ïðîñòàòû, óðîâíåì îòñå÷åíèÿ áûëî îòíîøåíèå 58, ïðè ýòîì ïëîùàäü
ïîä êðèâîé ñîîòíîøåíèÿ èñòèííîïîëîæèòåëüíûõ è
ëîæíîïîëîæèòåëüíûõ ðåçóëüòàòîâ (receiver operating
characteristic curve, ROC curve) áûëà 0,66 ïðîòèâ 0,57
äëÿ PSA. Â èññëåäîâàíèè 223 áîëüíûõ, ïîäâåðãíóòûõ
ïîâòîðíûì áèîïñèÿì ïîñëå ïîëó÷åíèÿ îòðèöàòåëüíîãî ðåçóëüòàòà áèîïñèè, äëÿ PCA3 áûëà îïðåäåëåíà
ïëîùàäü ïîä êðèâîé ROC 0,68, à äèàãíîñòè÷åñêàÿ
÷óâñòâèòåëüíîñòü è ñïåöèôè÷íîñòü îïðåäåëåíû êàê
58 è 72%, ñîîòâåòñòâåííî. Ýòîò òåñò ìîæåò îêàçàòüñÿ
ïîëåçíûì â óëó÷øåíèè äèàãíîñòè÷åñêîé ñïåöèôè÷íîñòè PSA. Ñî÷åòàíèå PCA3 åùå ñ òðåìÿ áèîìàðêåðàìè
â ìî÷å (GPLDPH2, SPINK1 è ïðîäóêò ñëèòíîãî ãåíà
TMPRSS2:EGR ) óëó÷øàåò äèàãíîñòè÷åñêóþ ñïåöèôè÷íîñòü è ÷óâñòâèòåëüíîñòü â ñðàâíåíèè òîëüêî ñ
PCA3.
Ранние антигены РПЖ
Ñ êàíöåðîãåíåçîì ñâÿçàíû èçìåíåíèÿ â áåëêàõ
ÿäåðíîãî ìàòðèêñà. Ðàííèé àíòèãåí ðàêà ïðîñòàòû
(EPCA) ÿâëÿåòñÿ áåëêîì ÿäåðíîãî ìàòðèêñà, êîòîðûé
èñõîäíî áûë âûÿâëåí ïðè ïîñòðîåíèè ïðîòåîìíîãî
ïðîôèëÿ òêàíè ïðîñòàòû êðûñû. Ïîçæå îí îêàçàëñÿ ïåðñïåêòèâíûì â ïëàíå äèàãíîñòè÷åñêîãî ìàðêåðà
ÐÏÆ. Èììóíîãèñòîõèìè÷åñêèå èññëåäîâàíèÿ áèîïñèé
òêàíè ÐÏÆ ïðè èñïîëüçîâàíèè àóòîàíòèòåë ê EPCA
ïîêàçàëè ïîâûøåíèå îêðàøèâàåìîñòè îòíîñèòåëüíî
íåïîðàæåííûõ ó÷àñòêîâ. Òàêîé ýôôåêò íàáëþäàëñÿ
è â íåïîðàæåííûõ ó÷àñòêàõ, ïðèëåãàþùèõ ê îïóõîëåâîé òêàíè, è â 86% ïðîá òêàíè ÐÏÆ. EPCA ïîìîãàåò â èäåíòèôèêàöèè áîëüíûõ ñ ðèñêîì ÐÏÆ ïðè
îòðèöàòåëüíûõ ðåçóëüòàòàõ áèîïñèè. Íåäàâíî ðàçðàáîòàííûé àíàëèç êðîâè íà EPCA ïðîäåìîíñòðèðîâàë
äèàãíîñòè÷åñêóþ ÷óâñòâèòåëüíîñòü 92% è òî÷íîñòü
94% â íåáîëüøîé êîãîðòå èç 12 áîëüíûõ ÐÏÆ è 34
çäîðîâûõ ëèö. Â äðóãîì èññëåäîâàíèè, ãäå áåëîê
EPCA-2 îïðåäåëÿëñÿ â ñûâîðîòêå, ÷óâñòâèòåëüíîñòü
è ñïåöèôè÷íîñòü ïî âûÿâëåíèþ ÐÏÆ îïðåäåëåíû
â 92 è 94%, ñîîòâåòñòâåííî, ïðè÷åì EPCA-2 îêàçàëñÿ ñïîñîáíûì äèôôåðåíöèðîâàòü ëîêàëèçîâàííûé è
ìåòàñòàòè÷åñêèé ÐÏÆ, â êàêîâîì ñëó÷àå ïëîùàäü ïîä
êðèâîé ROC îïðåäåëåíà êàê 0,89. Ýòè ìíîãîîáåùàþùèå ðåçóëüòàòû íàäî ïîäòâåðäèòü áîëåå êðóïíûìè íåçàâèñèìûìè èññëåäîâàíèÿìè, îäíàêî âûÿâëåíû è äèàãíîñòè÷åñêèå íåäîñòàòêè ýòèõ ìàðêåðîâ, çàñòàâëÿþùèå ñîìíåâàòüñÿ â èõ öåííîñòè.
6
α-Метилацил-КоА-рацемаза
α-Ìåòèëàöèë-ÊîÀ-ðàöåìàçà (AMACR ) ÿâëÿåòñÿ ôåðìåíòîì, ó÷àñòâóþùèì â îêèñëèòåëüíîì ìåòàáîëèçìå
è ñèíòåçå æèðíûõ êèñëîò ñ ðàçâåòâëåííîé öåïüþ, êîòîðûå îáíàðóæèâàþòñÿ â ìîëî÷íûõ ïðîäóêòàõ è ìÿñå.
Êðîìå òîãî, ÷òî ýòîò ôåðìåíò îáðàçóåòñÿ â áîëüøèõ êîëè÷åñòâàõ â òêàíè ÐÏÆ, îí åùå è êîäèðóåòñÿ
ãåíîì, êîòîðûé ëîêàëèçîâàí â îáëàñòè 5p13.3, êîòîðàÿ ñîäåðæèò ïîëèìîðôèçìû, ñâÿçàííûå ñ ÐÏÆ.
Ìåòààíàëèç äàííûõ ïî îäíîâðåìåííîìó îïðåäåëåíèþ ýêñïðåññèè áîëüøîãî ÷èñëà ãåíîâ îïðåäåëåííî
ïîêàçàë, ÷òî ýêñïðåññèÿ AMACR ïîâûøåíà â ÐÏÆ.
Ñîâìåñòíî ïðîâåäåííîå â íåñêîëüêèõ ó÷ðåæäåíèÿõ
èññëåäîâàíèå ïîêàçàëî, ÷òî èììóíîãèñòîõèìè÷åñêîå
îêðàøèâàíèå íà AMAP ìîæåò ïîìîãàòü â ðàçëè÷åíèè ìåæäó çëîêà÷åñòâåííîé è äîáðîêà÷åñòâåííîé
òêàíÿìè ðàêà ïðîñòàòû ñ äèàãíîñòè÷åñêîé ÷óâñòâèòåëüíîñòüþ 97% è ñïåöèôè÷íîñòüþ 92%. Ñíèæåííàÿ
ïðîäóêöèÿ AMACR èìååò ïðîãíîñòè÷åñêóþ öåííîñòü
äëÿ ïðåäñêàçàíèÿ áèîõèìè÷åñêèõ ðåöèäèâîâ ÐÏÆ è
ñìåðòè îò ïîñëåäíåãî. Êîíöåíòðàöèè ìÐÍÊ è AMACR
â ñûâîðîòêå êðîâè è ìî÷å îïðåäåëÿþò îáðàòíîòðàíñêðèïòàçíîé ÏÖÐ. Êîíöåíòðàöèÿ áåëêà AMACR â ñûâîðîòêå íèçêàÿ, íî îí áûë âûÿâëåí â ìî÷å Âåñòåðíáëîòòèíãîì. Ïîâûøåííûå êîíöåíòðàöèè àóòîàíòèòåë
ê AMACR ïîìîãàþò â ðàçëè÷åíèè áîëüíûõ ÐÏÆ è
çäîðîâûõ ëèö â èíòåðâàëå PSA 4–10 ìêã/ë. Ó ýòîãî òåñòà äèàãíîñòè÷åñêàÿ ÷óâñòâèòåëüíîñòü îêàçàëàñü
62%, à ñïåöèôè÷íîñòü 72%. Äëÿ ïîëíîãî âûÿñíåíèÿ
ïîòåíöèàëà AMACR â êà÷åñòâå áèîìàðêåðà ÐÏÆ ïðîâîäÿòñÿ äîïîëíèòåëüíûå èññëåäîâàíèÿ.
Активатор и рецептор
урокиназы и плазминогена
Ñ ïðîãðåññèåé ðàêà ñâÿçàíà äåãðàäàöèÿ âíåêëåòî÷íîãî ìàòðèêñà, â ýòîì ïðîöåññå ïðèíèìàåò ó÷àñòèå êàñêàä ðåàêöèé, âêëþ÷àþùèé àêòèâàöèþ óðîêèíàçû è ïëàçìèíîãåíà. Ïëàçìèíîãåí ïðåâðàùàåòñÿ â
àêòèâíóþ ôîðìó ïëàçìèíà ÷åðåç àêòèâàöèþ ñåðèíîâîé ïðîòåèíàçû, èçâåñòíîé êàê àêòèâàòîð óðîêèíàçû
è ïëàçìèíîãåí (uPA), è åå ñâÿçûâàíèå ñ ðåöåïòîðîì
(uPAR ). Ïðîäåìîíñòðèðîâàíî ïîâûøåíèå êîíöåíòðàöèè uPA ó áîëüíûõ ÐÏÆ è ÄÃÏÆ â ñðàâíåíèè ñî
çäîðîâûìè ëèöàìè, õîòÿ ñòàòèñòè÷åñêè äîñòîâåðíàÿ
ñâÿçü ñ ÐÏÆ îòñóòñòâîâàëà. Êîìáèíàöèè âûÿâëåíèÿ
èçîôîðì uPAR ñ âûÿâëåíèåì KLK2 è èçîôîðì PSA
óëó÷øèëè, ïî ðåçóëüòàòàì àíàëèçà ñ èñïîëüçîâàíèåì îäíîïàðàìåòðè÷åñêèõ è ìíîãîïàðàìåòðè÷åñêèõ
ìîäåëåé, ñïîñîáíîñòü ïðåäñêàçûâàòü ðåçóëüòàòû
áèîïñèè ó áîëüíûõ ñ ïîâûøåííûìè êîíöåíòðàöèÿìè PSA. Ïîâûøåííûå êîíöåíòðàöèè uPAR â òêàíè
ÐÏÆ àññîöèèðîâàíû ñ îñòåîáëàñòíûìè ìåòàñòàçàìè, à òàêæå ñ äàëåêî çàøåäøåé ïðîãðåññèé ÐÏÆ.
Ïîâûøåíû êîíöåíòðàöèè uPa è uPAR â ñûâîðîòêå
WWW.TERRAMEDIСA.SPB.RU
ОБЗОРЫ
êðîâè áîëüíûõ ÐÏÆ ñ ìåòàñòàçàìè â êîñòü. Â ýòèõ
èññëåäîâàíèÿõ ñîîáùàåòñÿ, ÷òî ïðåäîïåðàöèîííûå
óðîâíè uPA â ïëàçìå ÿâëÿþòñÿ ïðåäñêàçàòåëüíûì
ïðèçíàêîì ðåöèäèâîâ ïî áèîõèìè÷åñêèì ïðèçíàêàì
è ìåòàñòàçèðîâàíèÿ è óêàçûâàþò íà íàëè÷èå îòäàëåííûõ ìåòàñòàçîâ íà ìîìåíò ëîêàëüíîé òåðàïèè.
Äëÿ âûÿñíåíèÿ ïðîãíîñòè÷åñêîãî ïîòåíöèàëà uPa è
uPAR íóæíû êðóïíûå ïðîñïåêòèâíûå èññëåäîâàíèÿ
ïðîãðåññèè è ìåòàñòàçèðîâàíèÿ ÐÏÆ ïîñëå ïðåäîïåðàöèîííîãî îáñëåäîâàíèÿ.
Инсулиноподобные факторы
роста и связывающие их белки
Èìååòñÿ ñâÿçü ìåæäó ÐÏÆ è ñûâîðîòî÷íûìè
êîíöåíòðàöèÿìè èíñóëèíîïîäîáíûõ ôàêòîðîâ ðîñòà
(IGF) è áåëêîâ, êîòîðûå èõ ñâÿçûâàþò (IGFBP). Ñåìåéñòâî IGF ñîñòîèò èç äâóõ áåëêîâ (IGF-1 , IGF-2),
êîòîðûå ìîãóò ñâÿçûâàòüñÿ ñ äâóìÿ ðåöåïòîðàìè
(IGFR1 è IGFR-2) è øåñòüþ ñâÿçûâàþùèìè áåëêàìè
(IFFBP 1-6). Ïîâûøåííûå êîíöåíòðàöèè IGF-1 è ñíèæåííûå êîíöåíòðàöèè IGFBP-3 êîððåëèðóþò ñ ïîâûøåííûì ðèñêîì ðàçâèòèÿ ÐÏÆ. Êîíöåíòðàöèè IGF-1
âîçðàñòàþò ñ ïîâûøåíèåì ðèñêà ÐÏÆ íåçíà÷èòåëüíî, è â ýòîì îòíîøåíèè íå ïðåâîñõîäÿò PSA â êà÷åñòâå ìàðêåðà, îäíàêî ýòè ðåçóëüòàòû íå ïîëó÷èëè
ïîäòâåðæäåíèÿ â äðóãèõ èññëåäîâàíèÿõ. Îñíîâíûì
IGFBP, ïðîäóöèðóåìûì ïðîñòàòîé, ÿâëÿåòñÿ IGFBP-2,
è îí òîæå ïîâûøàåòñÿ ïðè ÐÏÆ, õîòÿ â ëîêàëèçîâàííûõ îïóõîëÿõ åãî óðîâíè îáðàòíî êîððåëèðóþò ñ
èõ ðàçìåðîì è ïðîãðåññèåé. Êîíöåíòðàöèÿ IGFBP-3
â ñûâîðîòêå îáðàòíî êîððåëèðóåò ñ íàëè÷èåì ìåòàñòàçîâ â êîñòü, íî ïðè ýòîì íåò ðàçíèöû ìåæäó áîëüíûìè ñ ëîêàëèçîâàííûì ÐÏÆ è çäîðîâûìè ëèöàìè.
Слитные гены TMPRSS2:ERG
и TMPRSS2:ETV1
 ðàçâèòèè ðàêîâûõ çàáîëåâàíèé, îñîáåííî ãåìàòîëîãè÷åñêèõ, ïðèíèìàþò ó÷àñòèå ãåííûå ïåðåñòðîéêè. Îäíà òàêàÿ ïåðåñòðîéêà çàòðàãèâàåò ãåíû òðàíñêðèïöèîííûõ ôàêòîðîâ ERG (ãîìîëîã îíêîãåíà v-ets
âèðóñà E26 ýðèòðîáëàñòîçà ó ïòèö) (ëîêóñ 21q22.2),
ETV1 (âàðèàíò 1 ets) (ëîêóñ 7p21.1) è ãåí, êîäèðóþùèé çàÿêîðåííóþ â ìåìáðàíå ñåðèíîâóþ ïðîòåèíàçó
TMPRSS2, êîòîðûé ëîêàëèçîâàí â ëîêóñå 21q22.3.
Ïî ðåçóëüòàòàì àíàëèçà ïðîôèëÿ âûïàäàþùèõ öèòîãåíåòè÷åñêèõ ðåçóëüòàòîâ, ñâÿçàííûõ ñ ðàêîì (cancer
outlier profile analysis, COPA ), ýòà ïåðåñòðîéêà ïðîèñõîäèò â 80% ñëó÷àåâ ÐÏÆ. Ñëèòíûé ïðîäóêò ýòèõ ãåíîâ âûÿâëÿåòñÿ ó 42% áîëüíûõ ÐÏÆ, ó 20% áîëüíûõ
ñ èíòðàýïèòåëèàëüíîé íåîïëàçèåé ïðîñòàòû è ðåäêî –
ïðè ÄÃÏÆ. Â ïðîñïåêòèâíîì èññëåäîâàíèè, â êîòîðîì 252 áîëüíûõ ÐÏÆ íà ñòàäèè T1a/b íàáëþäàëè
â òå÷åíèå 9 ëåò, ñëèòíûé ïðîäóêò TMPRSS2:ERG áûë
áîëåå ñèëüíî, ÷åì TMPRSS2:ETV1, ñâÿçàí ñ èíäåêñîì
ПОДПИСНОЙ ИНДЕКС 72075
Ãëèñîíà âûøå 7, ñ ìåòàñòàçàìè è ñî ñìåðòüþ îò ÐÏÆ.
Èçîôîðìà TMPRSS2:ERG áûëà ïðîäåìîíñòðèðîâàíà
ôëþîðåñöåíòíîé ãèáðèäèçàöèåé in situ â 80–95%
îáðàçöîâ òêàíè ÐÏÆ è ìîæåò áûòü ïîòåíöèàëüíîé
òåðàïåâòè÷åñêîé ìèøåíüþ. Âäîáàâîê, ñ íåáëàãîïðèÿòíûì ïðîãíîçîì ñâÿçàííîé îêàçàëàñü ïîâûøåííàÿ
ïðîäóêöèÿ SPINK1, ñåðèíîâîé ïðîòåèíàçû, ìîãóùåé
ñïîñîáñòâîâàòü èíâàçèè îïóõîëè ó áîëüíûõ, íåãàòèâíûõ ïî TMPRSS2:ETV1.
Трансформирующий ростовый фактор-β1
Òðàíñôîðìèðóþùèé ðîñòîâûé ôàêòîð-β1 (TGF-β1)
ÿâëÿåòñÿ ðîñòîâûì ôàêòîðîì øèðîêîãî äåéñòâèÿ, ó÷àñòâóþùèì âî ìíîæåñòâå ìîëåêóëÿðíûõ ïðîöåññîâ, òàêèõ êàê êëåòî÷íàÿ äèôôåðåíöèàöèÿ, èììóííûé îòâåò,
àíãèîãåíåç è ïðîëèôåðàöèÿ. Èññëåäîâàíèÿ íà ìîäåëÿõ ÐÏÆ ïðîäåìîíñòðèðîâàëè ðîëü TGF-β1 â ïðîãðåññèè ÐÏÆ. Ïîâûøåííûå êîíöåíòðàöèè TGF-β1
â òêàíÿõ ÐÏÆ êîððåëèðóþò ñî ñòàäèåé è ñòåïåíüþ
òðàíñôîðìàöèè è ñ ìåòàñòàçàìè â ëèìôàòè÷åñêèå
óçëû. Ñ ïîìîùüþ èììóíîôåðìåíòíîãî àíàëèçà äëÿ
îïðåäåëåíèÿ ïðåäîïåðàöèîííûõ êîíöåíòðàöèé TGF-β1
â ïëàçìå ïîêàçàíî, ÷òî óðîâåíü ýòîãî ôàêòîðà ïîâûøåí ó áîëüíûõ ÐÏÆ è êîððåëèðóåò ñ ýêñòðàêàïñóëÿðíûì ðàñïðîñòðàíåíèåì, èíâàçèåé â ñåìåííûå ïóçûðüêè, ìåòàñòàçàìè è áèîõèìè÷åñêèìè ðåöèäèâàìè.
Òàêèì îáðàçîì, TGF-β1 ìîæåò áûòü ïîëåçíûì ïðîãíîñòè÷åñêèì ìàðêåðîì ÐÏÆ.
Энхансер гомолога-2 белка Zeste
EZH2 (ýíõàíñåð ãîìîëîãà-2 áåëêà Zeste äðîçîôèë)
êîäèðóåò áåëîê, îòíîñÿùèéñÿ ê ñåìåéñòâó polycomb,
ó÷àñòâóþùåìó â ðåãóëÿöèè ýêñïðåññèè ãåíîâ. Îïðåäåëåíèå ïðîôèëÿ ýêñïðåññèè áåëêîâ â òêàíÿõ ÐÏÆ, ïîëó÷åííûõ àóòîïñèåé, ïîêàçàëî, ÷òî ó áîëüíûõ, óìåðøèõ îò ìåòàñòàòè÷åñêîãî ÐÏÆ, EZH2 îáíàðóæèâàëè
â ìåòàñòàçàõ ÐÏÆ â áî'ëüøèõ êîëè÷åñòâàõ, ÷åì â ëîêàëèçîâàííîì ÐÏÆ è ÄÃÏÆ. Ýòîò ìàðêåð ïðåâîñõîäèò
ïðåäîïåðàöèîííûå êîíöåíòðàöèè PSA è ïîêàçàòåëü
Ãëèñîíà â îïðåäåëåíèè ïðîãðåññèè ÐÏÆ. Ïðèìåíåíèå
ýòîãî ìàðêåðà â ñî÷åòàíèè ñ e-êàäõåðèíîì ïðåäñêàçûâàåò ðåöèäèâû ÐÏÆ ïîñëå ìåñòíîé òåðàïèè. Ðàçðàáîòêà ñïîñîáîâ åãî îïðåäåëåíèÿ â ñûâîðîòêå äîëæíà
ïîìî÷ü ïðè îöåíêå ýòîãî êàíäèäàòà â ìàðêåðû äëÿ
èäåíòèôèêàöèè ïàöèåíòîâ ñ ðèñêîì ðàçâèòèÿ ìåòàñòàòè÷åñêîãî çàáîëåâàíèÿ.
Гиперметилирование гена
глутатион-S-трансферазы
Ê ðàçâèòèþ ÐÏÆ ïðè÷àñòíî ãèïåðìåòèëèðîâàíèå
ãåíîâ-ñóïðåññîðîâ îïóõîëåé ïî íóêëåîòèäíûì êëàñòåðàì CpG â èõ ïðîìîòîðàõ. Ôåðìåíò ãëóòàòèîí-Sòðàíñôåðàçà π çàùèùàåò ÄÍÊ îò ñâîáîäíîðàäèêàëüíîãî ïîâðåæäåíèÿ. Ñíèæåííàÿ ýêñïðåññèÿ ãåíà GSTP1 ïî
7
ОБЗОРЫ
ïðè÷èíå ãèïåðìåòèëèðîâàíèÿ åãî ïðîìîòîðà íåèçìåí- è àññîöèèðîâàíû ñ ïðîãðåññèåé ÐÏÆ. Îíè ïðåäñêàíî îáíàðóæèâàåòñÿ ïðè ÐÏÆ, åå îïðåäåëåíèå â îñàä- çûâàþò íåçàâèñèìûé îò àíäðîãåíîâ ôåíîòèï ÐÏÆ.
êå ìî÷è ìîæåò óêàçûâàòü íà íåîáõîäèìîñòü â áèîïñèè. Òàêèì îáðàçîì, êàê õðîìîãðàíèí `, òàê è ïåïòèäíûé
Ýòîò àíàëèç óñîâåðøåíñòâîâàí äîáàâëåíèåì ìàññàæà ôàêòîð âûñâîáîæäåíèÿ ïðîãàñòðèíà ìîæíî èñïîëüïðîñòàòû ïåðåä ñáîðîì ìî÷è. Òàêèì æå îáðàçîì èç- çîâàòü äëÿ ìîíèòîðèíãà áîëüíûõ íà ïîçäíèõ ñòàäèÿõ
íå÷óâñòâèòåëüíîãî ê ãîðìîíàì ÐÏÆ ñ ïðèçíàêàìè
ó÷åíû öåëûå íàáîðû ãåíîâ, âêëþ÷àþùèå GSTP1.
íåéðîýíäîêðèííîé äèôôåðåíöèàöèè.
Секреторный белок 94 простаты
и связывающий его белок
Å-кадхерин
Ìåæêëåòî÷íàÿ àäãåçèÿ èãðàåò âàæíóþ ðîëü â íîðÑåêðåòîðíûé áåëîê 94 ïðîñòàòû (PSP94 ), òàêæå
èçâåñòíûé êàê β-ìèêðîñåìèíîïðîòåèí, ïðèñóòñòâóåò ìàëüíîì ïîñòðîåíèè òêàíè è ïðè êàíöåðîãåíåçå.
â áîëüøèõ êîëè÷åñòâàõ â ñïåðìå è èãðàåò ðîëü â êëå- e-êàäõåðèí ÿâëÿåòñÿ ìîëåêóëîé êëåòî÷íîé àäãåçèè,
òî÷íîé ïðîëèôåðàöèè è àïîïòîçå.  ñâÿçàííîì âèäå ïðîäóöèðóåìîé â ýïèòåëèàëüíûõ êëåòêàõ, åãî ïðîPSP94 ñóùåñòâóåò â âèäå êîìïëåêñà ñ PSP94-ñâÿçû- äóêöèÿ ýòèìè êëåòêàìè ÿâëÿåòñÿ ïðåäñêàçàòåëüíûì
âàþùèì áåëêîì. Ñîîòíîøåíèå îáùåãî è ñâîáîäíîãî ïðèçíàêîì äëÿ ïðîãíîçà ÐÏÆ.
 èììóíîãèñòîõèìè÷åñêîì èññëåäîâàíèè ïðîäåPSP94 è êîíöåíòðàöèÿ PSP94-ñâÿçûâàþùåãî áåëêà â
ñûâîðîòêå ó áîëüíûõ ÐÏÆ ïîñëå ëîêàëüíîé îïåðàöèè ìîíñòðèðîâàíî, ÷òî ïðîäóêöèÿ e-êàäõåðèíà ñíèæåíà
êîððåëèðóþò ñ ïîêàçàòåëåì Ãëèñîíà, áèîõèìè÷åñêèìè â 50% îïóõîëåé ÐÏÆ, òîãäà êàê â íîðìàëüíîé òêàïðèçíàêàìè ðåöèäèâîâ. Äëÿ îöåíêè ýòîò êàíäèäàòà â íè ïðîñòàòû ïðîäóêöèÿ e-êàäõåðèíà ðàñïðåäåëåíà
áèîìàðêåðû âñå åùå òðåáóþòñÿ áîëüøèå ïðîñïåêòèâ- ðàâíîìåðíî. Â äàëüíåéøèõ èññëåäîâàíèÿõ ïðîäóêöèÿ e-êàäõåðèíà áûëà àññîöèèðîâàíà ñî ñòåïåíüþ
íûå èññëåäîâàíèÿ.
òðàíñôîðìàöèè, ñòàäèåé îïóõîëè è âûæèâàåìîñòüþ
Богатый цистеином секреторный белок 3 áîëüíûõ. Åãî ñíèæåííàÿ ïðîäóêöèÿ, ïî äàííûì èììóíîãèñòîõèìè÷åñêîãî àíàëèçà, ñâÿçàíà ñ ñîêðàùåÁîãàòûé öèñòåèíîì ñåêðåòîðíûé áåëîê 3 (CRISP-3) íèåì æèçíè áîëüíûõ ÐÏÆ.
îáðàçóåòñÿ â ìóæñêèõ ïîëîâûõ ïóòÿõ, ãäå ó÷àñòâóåò â
ñîçðåâàíèè ñïåðìû. Åãî áîëüøèå êîëè÷åñòâà âûÿâëåАннексин А3
íû â ïëàçìå ñïåðìû. Âäîáàâîê, îêðàøèâàíèå òêàíè
Àííåêñèí
3
(ANXA3
), ÷ëåí áåëêîâîãî ñåìåéñòâà
ïðîñòàòû íà CRISP-3 ïîêàçàëî âîçðàñòàíèå åãî óðîâàííåêñèíîâ,
ÿâëÿåòñÿ
ñâÿçûâàþùèì
êàëüöèé áåëêîì.
íÿ ïðè ñèëüíî òðàíñôîðìèðîâàííûõ èíòðàýïèòåëèANXA3
ó÷àñòâóåò
â
àêòèâàöèè
èììóííîãî
îòâåòà, à òàêàëüíûõ íåîïëàçèÿõ â íåñêîëüêèõ ïðîáàõ òêàíè ÐÏÆ.
æå
â
ðåãóëÿöèè
ïðîíèöàåìîñòè
ìåìáðàí
è ìèãðàöèè
Àññîöèàöèÿ ìåæäó CRISP-3 è ÐÏÆ áûëà ïðîâåðåíà â
ëèìôîöèòîâ.
Íåäàâíî
ANXA3
áûë
èññëåäîâàí
èììóñâÿçè ñ îïðåäåëåíèåì β-ìèêðîñåìèíîïðîòåèíà â òêàíîãèñòîõèìè÷åñêèìè
ìåòîäàìè
â
êà÷åñòâå
ïåðñïåêòèâíÿõ, ïîëó÷åííûõ ïðè ðàäèêàëüíîé ïðîñòàòýêòîìèè.
Îêàçàëîñü, ÷òî CRISP-3 ÿâëÿåòñÿ íåçàâèñèìûì ïðåä- íîãî òêàíåâîãî ìàðêåðà äëÿ ïðîãíîçà ÐÏÆ. Áûëà âûñêàçàòåëüíûì ïðèçíàêîì ðåöèäèâîâ ÐÏÆ. Òàêèì îá- ÿâëåíà åãî ñíèæåííàÿ ïðîäóêöèÿ â ÐÏÆ â ñðàâíåíèè
ðàçîì, ýòîò áåëîê ìîæíî ñ÷èòàòü íîâûì òêàíåâûì ÄÃÏÆ, èíòðàýïèòåëèàëüíîé íåîïëàçèåé è çäîðîâûìè
òêàíÿìè. Ñ ïîìîùüþ îïðåäåëåíèÿ ANXA3 ìîæíî ñòðàìàðêåðîì äëÿ ïðîãíîçà ÐÏÆ.
òèôèöèðîâàòü áîëüøóþ ãðóïïó áîëüíûõ ïðîìåæóòî÷íîãî ðèñêà íà ïîäãðóïïû âûñîêîãî è íèçêîãî ðèñêà.
Маркеры нейроэндокринной
дифференциации
Ïåïòèä õðîìîãðàíèí `, êîòîðûé ïðîäóöèðóåòñÿ
íåéðîýíäîêðèííûìè êëåòêàìè ïðîñòàòû, â íàñòîÿùåå âðåìÿ èñïîëüçóþò â äèàãíîñòèêå ÐÏÆ è ïðîãíîçèðîâàíèè â ñëó÷àÿõ îïóõîëåé ïðîñòàòû, èìåþùèõ
ïðèçíàêè íåéðîýíäîêðèííîé äèôôåðåíöèàöèè. Ïîâûøåíèå êîíöåíòðàöèè õðîìîãðàíèíà ` â ñûâîðîòêå
êîððåëèðóåò ñ ïðîãðåññèåé ÐÏÆ, íåçàâèñèìîãî îò
àíäðîãåíîâ, è ïëîõîãî ïðîãíîçà. Îíî ïðåäøåñòâóåò
ïîâûøåíèþ PSA è óëó÷øàåò äèàãíîñòè÷åñêóþ ñïåöèôè÷íîñòü â ñðàâíåíèè ñ fPSA.
Ïåïòèäíûé ôàêòîð âûñâîáîæäåíèÿ ïðîãàñòðèíà
ÿâëÿåòñÿ ðîñòîâûì ôàêòîðîì, êîòîðûé îáðàçóåòñÿ
â íåéðîýíäîêðèííûõ òèïàõ ÐÏÆ. Åãî ïîâûøåííûå
êîíöåíòðàöèè âûÿâëåíû ïðè ìåòàñòàòè÷åñêîì ÐÏÆ
8
Антиген стволовых клеток
предстательной железы
Àíòèãåí ñòâîëîâûõ êëåòîê ïðîñòàòû (PSCA) ÿâëÿåòñÿ ìåìáðàííûì ãëèêîïðîòåèíîì, âåñüìà ñïåöèôè÷åñêè ïðîäóöèðóåìûì â ïðîñòàòå. PSCA âûÿâëåí â
òêàíÿõ ÐÏÆ èììóíîãèñòîõèìè÷åñêèìè ìåòîäàìè, à
åãî ÐÍÊ íàéäåíà â îáðàçöàõ êðîâè. Ïîâûøåííàÿ
ïðîäóêöèÿ PSCA êîððåëèðóåò ñ ïîâûøåííûì ðèñêîì
ÐÏÆ, áîëåå âûñîêèì êîýôôèöèåíòîì Ãëèñîíà, áîëåå âûñîêîé ñòàäèåé è íàëè÷èåì ìåòàñòàçîâ. PSCA
òàêæå èññëåäîâàí â êà÷åñòâå òåðàïåâòè÷åñêîé ìèøåíè, îäíàêî äëÿ ïîäòâåðæäåíèÿ êëèíè÷åñêîé ïðèìåíèìîñòè ýòîãî ìàðêåðà òðåáóþòñÿ áîëåå îáøèðíûå
àïðîáàöèîííûå èññëåäîâàíèÿ.
WWW.TERRAMEDIСA.SPB.RU
ОБЗОРЫ
Гепсин
Ãåïñèí ÿâëÿåòñÿ ìåìáðàííîé ñåðèíîâîé ïðîòåàçîé, âïåðâûå èäåíòèôèöèðîâàííîé â áèáëèîòåêàõ
êÄÍÊ ïå÷åíè.  áîëüøèõ êîëè÷åñòâàõ îí îáðàçóåòñÿ
â òêàíÿõ ïðîñòàòû. Èññëåäîâàíèÿ ïðîôèëÿ ýêñïðåññèè ìÐÍÊ ãåïñèíà ïðîäåìîíñòðèðîâàëè ïîâûøåííóþ ýêñïðåññèþ åãî ãåíà â 90 % ÐÏÆ. Íàáëþäàåòñÿ
ñèëüíîå èììóíîãèñòîõèìè÷åñêîå îêðàøèâàíèå íà
ãåïñèí â èíòðàýïèòåëèàëüíûõ êàðöèíîìàõ ïðîñòàòû
è åãî ïðåèìóùåñòâåííîå îáðàçîâàíèå ïðè ÐÏÆ, à
íå ÄÃÏÆ. Äëÿ ïîëíîãî âûÿñíåíèÿ äèàãíîñòè÷åñêîãî
ïîòåíöèàëà ãåïñèíà òðåáóþòñÿ äàëüíåéøèå èññëåäîâàíèÿ íà îáðàçöàõ êðîâè è ìî÷è.
Интерлейкин 6 и его рецептор
Èíòåðëåéêèí 6 (IL-6 ) ÿâëÿåòñÿ öèòîêèíîì, êîòîðûé ïðîäóöèðóåò êëåòêè ìíîãèõ òèïîâ, îí ó÷àñòâóåò
â èììóííîì îòâåòå è â ðåàêöèè îñòðîé ôàçû. Ïîâûøåííûå êîíöåíòðàöèè IL-6 è åãî ðåöåïòîðîâ ïðîäåìîíñòðèðîâàíû ïðè ìåòàñòàòè÷åñêîì è íåçàâèñèìîì
îò àíäðîãåíîâ ÐÏÆ, îí ïðåäëîæåí â êà÷åñòâå êàíäèäàòà â ìàðêåðû ïðîãðåññèðîâàíèÿ ÐÏÆ. Ìíîãîîáåùàþùèå ðåçóëüòàòû äàëè èññëåäîâàíèÿ IL-6 â êîìáèíàöèè ñ TGF-β1 äëÿ äèàãíîñòèêè ÐÏÆ.
Циркулирующая опухолевая ДНК
Äèññåìèíàöèÿ îïóõîëåâûõ êëåòîê ÿâëÿåòñÿ íåîáõîäèìûì óñëîâèåì ìåòàñòàçèðîâàíèÿ, è ðàííåå âûÿâëåíèå òàêèõ êëåòîê â öèðêóëèðóþùåé êðîâè ìîæåò
áûòü ïîëåçíûì äëÿ ïðîãíîçà áîëüíûõ ÐÏÆ. Îïóõîëåâûå êëåòêè ìîæíî âûÿâëÿòü â îáðàòíîòðàíñêðèïòàçíîé ÏÖÐ, êîòîðàÿ îêàçàëàñü äîñòàòî÷íî ÷óâñòâèòåëüíîé äëÿ ïîâûøåíèÿ äèàãíîñòè÷åñêîé òî÷íîñòè
îïðåäåëåíèÿ ñòàäèè ÐÏÆ, ïðåäñêàçàíèÿ ðåöèäèâîâ
ñ ïîìîùüþ ìàðêåðîâ, ñïåöèôè÷íûõ äëÿ ïðîñòàòû.
Аутоантитела
Èçâåñòíî, ÷òî èììóííàÿ ñèñòåìà îòâå÷àåò íà íåêîòîðûå îïóõîëåâûå àíòèãåíû óñèëåíèåì ïðîäóêöèè
àóòîàíòèòåë. Ñîîáùàåòñÿ î ãóìîðàëüíûõ îòâåòàõ íà
áåëîê-1, âçàèìîäåéñòâóþùèé ñ õàíòèíãòèíîì, íà
ïðîñòàñîìå è íà AMACR. Ñ èñïîëüçîâàíèåì ôàãîâîãî äèñïëåÿ è áåëêîâûõ ìèêðî÷èïîâ â ðàìêàõ íîâîãî
ïîäõîäà «èììóíîìèêà ðàêà» óäàëîñü èäåíòèôèöèðîâàòü àóòîàíòèòåëà ê ïåïòèäàì, ïðîèñõîäÿùèì èç
òêàíåé ÐÏÆ. Áûë ñîçäàí 22-ïåïòèäíûé ôàãîâûé äèñïëåé, ïîçâîëèâøèé îòëè÷èòü 69 îáðàçöîâ ñûâîðîòêè
êðîâè áîëüíûõ ÐÏÆ îò 66% êîíòðîëåé ïðè äèàãíîñòè÷åñêîé ñïåöèôè÷íîñòè 88,2% è ÷óâñòâèòåëüíîñòè
81% ñ ïëîùàäüþ ïîä êðèâîé ROC 0,93, ÷òî ëó÷øå,
÷åì ïðè èñïîëüçîâàíèè PSA (0,80). Ïðîâîäÿòñÿ èññëåäîâàíèÿ ïî äàëüíåéøåé àïðîáàöèè ýòîãî ìåòîäà
íà áîëåå ìíîãî÷èñëåííîé êîãîðòå.  íåäàâíåì èññëåäîâàíèè ïðèìåíåí òàêîé æå ïîäõîä, çàòåì ïðîâåäåí
ПОДПИСНОЙ ИНДЕКС 72075
àíàëèç áèîëîãè÷åñêèõ ïóòåé âçàèìîäåéñòâèÿ ñîîòâåòñòâóþùèõ ôàêòîðîâ äëÿ îïðåäåëåíèÿ ìåõàíèçìîâ
ïðîãðåññèè ÐÏÆ. Îäíîé èç ïðîáëåì çäåñü ÿâëÿåòñÿ
íåîáõîäèìîñòü ïóíêöèîííîé áèîïñèè, êîòîðàÿ ñàìà
ïî ñåáå ìîæåò âûçûâàòü èììóííûé îòâåò.
Номограммы
Íîìîãðàììû ÿâëÿþòñÿ ñðåäñòâîì ìíîãîôàêòîðíîãî àíàëèçà ñî÷åòàíèé òàêèõ ïðèçíàêîâ, êàê ñòåïåíü
òðàíñôîðìàöèè/ñòàäèÿ îïóõîëè è óðîâíè áèîìàðêåðîâ äëÿ îáåñïå÷åíèÿ ñòàíäàðòèçàöèè ñïîñîáîâ âûðàáîòêè ëå÷åáíîé òàêòèêè. Îíè îñíîâàíû íà ïðèíöèïàõ
äîêàçàòåëüíîé ìåäèöèíû äëÿ ïðèíÿòèÿ ðåøåíèé íà
êàæäîé ñòàäèè ëå÷åíèÿ áîëåçíè. Öåííîñòü íîìîãðàìì îïðåäåëÿåòñÿ ýôôåêòèâíîñòüþ è ðàçâåðíóòîñòüþ. Äëÿ ÐÏÆ ðàçðàáîòàíû ìíîãî÷èñëåííûå íîìîãðàììû, â òîì ÷èñëå ó÷èòûâàþùèå TGF-β1 è IL-6 äëÿ
ðåöèäèâîâ ïî áèîõèìè÷åñêèì ïðèçíàêàì, à òàêæå íîìîãðàììû äëÿ ïðåäñêàçàíèÿ ðåçóëüòàòîâ áèîïñèè.
Многопараметрические тесты/
нейрональные сети
Äëÿ óëó÷øåíèÿ ïðåäñêàçàíèÿ ïðè ìíîãèõ çàáîëåâàíèÿõ øèðîêî èñïîëüçóþò êîìáèíàöèè áèîìàðêåðîâ.
Âñå ëþäè ðàçíûå, è áîëåçíåííûå ñîñòîÿíèÿ ó íèõ
òàêæå ðàçëè÷íû. Òàêèì îáðàçîì, ìíîãîïàðàìåòðè÷åñêèå òåñòû äîëæíû áûòü áîëåå àäåêâàòíûìè äëÿ
ïîïóëÿöèîííîãî ñêðèíèíãà, ÷åì îòäåëüíûé ìàðêåð.
Íåäàâíî áûëà ïðîâåðåíà ïàíåëü èç 45 áèîìàðêåðîâ, âêëþ÷àþùàÿ àäèïîêèíû, ìåòàëëîïðîòåèíàçû,
ìîëåêóëû àäãåçèè è ðîñòîâûå ôàêòîðû. Ïîêàçàòåëè
â ñûâîðîòêå îïðåäåëÿëè äî ïîñòàíîâêè äèàãíîçà ó
ëèö îäíîé âîçðàñòíîé ãðóïïû è ñðàâíèâàëè ìåæäó
ñëó÷àÿìè, êîãäà â äàëüíåéøåì äèàãíîç ÐÏÆ áûë èëè
íå áûë ïîñòàâëåí. Ïðè ýòîì íå óäàëîñü ïîêàçàòü, ÷òî
òàêàÿ ïàíåëü ïðåâîñõîäèò «êàëüêóëÿòîð» ôàêòîðîâ
ðèñêà, ðàçðàáîòàííûé â ðàìêàõ ïðîåêòà «Èçó÷åíèå
ïðîôèëàêòèêè ðàêà ïðîñòàòû». Äëÿ ìîäåëèðîâàíèÿ
ñëîæíûõ îòíîøåíèé ìåæäó ðàçíûìè ôàêòîðàìè è
èäåíòèôèêàöèè ðàçíûõ ïàòòåðíîâ äàííûõ èñïîëüçîâàëè ìåòîä íåéðîííûõ ñåòåé. Íàïðèìåð, äëÿ ÐÏÆ
îöåíèâàëè ðàçíûå êîìáèíàöèè êàëëèêðåèíîâûõ áèîìàðêåðîâ.
Протеомные паттерны
Ñ íåäàâíèõ ïîð ïîïóëÿðíûì ïîäõîäîì ê èäåíòèôèêàöèè íîâûõ áèîìàðêåðîâ ñòàë âûñîêîïðîèçâîäèòåëüíûé ïðîòåîìíûé àíàëèç áèîëîãè÷åñêèõ æèäêîñòåé. Ñ ýòîé öåëüþ èñïîëüçîâàëè ìàññ-ñïåêòðîìåòðèþ
ñ ïîâåðõíîñòíûì óñèëåíèåì ïðè èîíèçàöèè ëàçåðíûì èçëó÷åíèåì â ñî÷åòàíèè ñ ãàçîõðîìàòîãðàôè÷åñêèì îïðåäåëåíèåì âðåìåíè ïðîëåòà èîíîâ (surfaceenhanced laser desorption/ionization time-of-flight
mass spectrometry, SELDI-TOF-MS).  ñëó÷àå ÐÏÆ
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ОБЗОРЫ
èñïîëüçîâàëè åùå è àëãîðèòì äåðåâà ðåøåíèé äëÿ
èäåíòèôèêàöèè ñî÷åòàíèé ïèêîâ, ñïîñîáíûõ äèôôåðåíöèðîâàòü áîëüíûõ è çäîðîâûõ ëèö ïðè äèàãíîñòè÷åñêîé ÷óâñòâèòåëüíîñòè è ñïåöèôè÷íîñòè 83
è 97%, ñîîòâåòñòâåííî. Ïðè èññëåäîâàíèè 266 îáðàçöîâ ñûâîðîòêè ó áîëüíûõ ÐÏÆ è çäîðîâûõ, áûëà
äîñòèãíóòà äèàãíîñòè÷åñêàÿ ÷óâñòâèòåëüíîñòü 95 % è
ñïåöèôè÷íîñòü 78%. Ïðè èñïîëüçîâàíèè óñîâåðøåíñòâîâàííîãî àëãîðèòìà äåðåâà ðåøåíèé íà äðóãîì
ìàññèâå äàííûõ áûëà äîñòèãíóòà äèàãíîñòè÷åñêàÿ
÷óâñòâèòåëüíîñòü 97% è ñïåöèôè÷íîñòü 97%. Ïîëåçíîñòü òàêîãî ïîäõîäà ïðîäåìîíñòðèðîâàíà è äðóãèìè
èññëåäîâàíèÿìè. Îäíàêî îí ïîïàë ïîä ñêðóïóëåçíóþ
ïðîâåðêó Íàöèîíàëüíîãî ïðîòèâîðàêîâîãî èíñòèòóòà
ÑØÀ, ãäå áûëà ó÷ðåæäåíà Èññëåäîâàòåëüñêàÿ ñåòü
ïî ðàííåìó âûÿâëåíèþ ÐÏÆ, êîòîðàÿ ïðîâåëà èññëåäîâàíèå ñ ó÷àñòèåì ìíîãèõ ó÷ðåæäåíèé, ðåçóëüòàòû êîòîðîãî áûëè íåäàâíî îïóáëèêîâàíû. Õîòÿ
íà I ñòàäèè áûëà ïîäòâåðæäåíà àíàëèòè÷åñêàÿ âîñïðîèçâîäèìîñòü òàêîãî ïîäõîäà, íà II ñòàäèè, ïðîâåäåííîé ïî ñõåìå «ñëó÷àé-êîíòðîëü», íå óäàëîñü
ïîêàçàòü, ÷òî îí îáåñïå÷èâàåò ïðåäñêàçàíèå ÐÏÆ âî
âñåõ ó÷ðåæäåíèÿõ. Ýòó íåóäà÷ó îòíåñëè ê ïðåàíàëèòè÷åñêèì, àíàëèòè÷åñêèì è áèîèíôîðìàöèîííûì èñêàæåíèÿì, óæå îïèñàííûì â ëèòåðàòóðå.
Òàêèì îáðàçîì, ìîæíî çàêëþ÷èòü, ÷òî âíåäðåíèå
àíàëèçîâ êðîâè íà PSA ðåâîëþöèîíèçèðîâàëî äèàãíîñòèêó è ëå÷åíèå ÐÏÆ. Îäíàêî âñå åùå ñóùåñòâóþò ïðîòèâîðå÷èÿ ïî âîïðîñó, ñíèæàåò ëè ñêðèíèíã
íà PSA ñìåðòíîñòü îò ÐÏÆ è ðèñêè, ñâÿçàííûå ñ èçáûòî÷íûì ÷èñëîì ïîëîæèòåëüíûõ äèàãíîçîâ. Ñóùåñòâóþò ñâèäåòåëüñòâà ïðèìåíèìîñòè ìíîæåñòâåííûõ
ìàðêåðîâ äëÿ áîëåå ïîëíîé õàðàêòåðèçàöèè ôåíîòèïîâ îïóõîëåé ïðîñòàòû âî âñåé ìóæñêîé ïîïóëÿöèè.
Ïðèìåíåíèå ìíîãî÷èñëåííûõ ìàðêåðîâ â ñî÷åòàíèè
ñ êëèíè÷åñêèìè è äåìîãðàôè÷åñêèìè äàííûìè äîëæíî ïîìî÷ü â ïðåäñêàçàíèè òîãî, êàêèå ïàöèåíòû íàõîäÿòñÿ ïîä ðèñêîì ðàçâèòèÿ ÐÏÆ, è â îöåíêå ïðîãíîçîâ äëÿ íèõ. Íîâûå èññëåäîâàòåëüñêèå âîçìîæíîñòè
äîëæíû ïîìî÷ü â âûÿâëåíèè íîâûõ ìàðêåðîâ, îäíàêî êëþ÷åâûì äëÿ ïîëó÷åíèÿ âîñïðîèçâîäèìûõ è íåèñêàæåííûõ ðåçóëüòàòîâ îñòàåòñÿ ïðèìåíåíèå íàäëåæàùèõ ñõåì èññëåäîâàíèÿ è àíàëèçà êëèíè÷åñêèõ
äàííûõ.
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10
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