Breast cancer--Æý´â¤Î¿ÇÃǤȼ£ÎÅ

 

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Æý¤¬¤ó¤Ïɬ¤º¤·¤â¶Ñ°ì¤Ç¤Ï¤Ê¤¯, heterogenous¤Ê¼À´µÃ±°Ì¤Ç¤¢¤ë¤¬, ´ðËÜŪ¤Ë¤ÏÅÀÊѰÛ, À÷¿§ÂÎÁý¿£, ·ç¼º, ºÆ¹½À®, žºÂ, ½ÅÊ£¤Ê¤É¤Î°äÅÁŪ°Û¾ï¤¬½ù¡¹¤ËÃßÀѤ¹¤ë¤³¤È¤¬¸¶°ø¤È¤Ê¤ë.*1*2

À¸¿£ºÙ˦·ÏÎóÊѰۤÏÁ´Æý¤¬¤ó¤Î¤ª¤è¤½10%¤Ë¤ß¤é¤ì, ÂçÉôʬ¤Ï»¶È¯À­¤Ç, ÂκÙ˦¤Î°äÅÁ»Ò°Û¾ï¤Ëµ¯°ø¤¹¤ë¤È¹Í¤¨¤é¤ì¤ë.

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Æý¤¬¤ó¤Î¥ê¥¹¥¯°ø»Ò¤ÇºÇ¤â½ÅÍפʤâ¤Î¤Î¤Ò¤È¤Ä¤Ï²È²Îò¤Ç¤¢¤ë. ²È²À­Æý¤¬¤ó¤ÏÁ´Æý¤¬¤ó¤ÎÁ´ÂΤÎ20%¤òÀê¤á¤ë¤¬, ¤½¤Î¸¶°ø°äÅÁ»Ò¤Î¿¤¯¤ÏƱÄꤵ¤ì¤Æ¤¤¤Ê¤¤.

Æý¤¬¤ó´¶¼õÀ­°äÅÁ»Ò(±¦¿Þ*3)¤Ï, ÉÑÅÙ¤Èȯ¾É¤Î²ÄǽÀ­¤Ë¤è¤ê

  • 1. ÄãÉÑÅ٤ǹ⿻ƩΨ¡Ê=ȯ¾É²ÄǽÀ­Âç); ''BRCA1/2, TP53, PTEN, CDH1, STK11/LKB1
     
  • 2. ÄãÉÑÅÙ¤ÇÃæ¿»Æ©Î¨; CHEK2, BRIP1, ATM, PALB2
     
  • 3. ¹âÉÑÅÙ¤ÇÄ㿻ƩΨ; FGFR2, TOX3, LSP1, TGFB1, MAP3K1, CASP8, 6q22.33, 2q35, 8q24, 5p12.
    ¤Î3¼ïÎà¤ËʬÎव¤ì¤ë.*4

²È²À­Æý¤¬¤ó¤ÏÁ´Æý¤¬¤ó¤Î20-30%¤òÀê¤á¤ë. BRCA1¤ÈBRCA2¤Ï°äÅÁÀ­Æý¤¬¤ó¤ª¤è¤ÓÍñÁã´â¾É¸õ·²¤Ë´ØÏ¢¤¹¤ë¼çÍפʹ⿻ƩΨ°äÅÁ»Ò¤Ç¤¢¤ê,¹ç¤ï¤»¤ë¤È°äÅÁÀ­Æý¤¬¤ó¤ÎȾʬ¶á¤¯¤òÀê¤á¤ë.
¤Þ¤¿CHEK2, TP53, PTEN, STK11¤Ê¤É¤Î, ¤Þ¤ì¤ÊÆý¤¬¤ó´¶¼õÀ­°äÅÁ»Ò¤¬Æ±Äꤵ¤ì¤Æ¤¤¤ë.

¥²¥Î¥à¥ï¥¤¥É´ØÏ¢²òÀϤˤè¤êƱÄꤵ¤ì¤¿¤¤¤¯¤Ä¤«¤ÎÄ㿻ƩΨ°äÅÁ»Ò¤äºÂ°Ì¤¬²È²À­Æý¤¬¤ó¤Î°ìÉô(5%̤Ëþ)¤Ëǧ¤á¤é¤ì¤ë.

²È²À­Æý¤¬¤ó¤ÎÌó50%¤Ï¤Þ¤À¸¶°ø¤¬ÌÀ¤é¤«¤Ë¤µ¤ì¤Æ¤¤¤Ê¤¤¤¬, ¤Þ¤ÀƱÄꤵ¤ì¤Æ¤¤¤Ê¤¤°äÅÁ»Ò¤¢¤ë¤¤¤Ï¿°ø»Ò´¶¼õÀ­¤Ë¤è¤êȯ¾É¤¹¤ë¤È¿ä»¡¤µ¤ì¤Æ¤¤¤ë.

 

mark-R.jpg ¤½¤Î¾¤Î¹â¥ê¥¹¥¯, ÄãÉÑÅÙ¤ÎÆý¤¬¤ó´¶¼õÀ­°äÅÁ»Ò¤È¤·¤ÆTP53, PTEN, STK11/LKB1, CHD1¤¬Ç§¤á¤é¤ì¤Æ¤¤¤ë.

  • ¤³¤ì¤é¤Î¹â¿»Æ©Î¨°äÅÁ»Ò¤Ë¤è¤êÆý¤¬¤óȯ¾ÉΨ¤Ï 8¡Á10Çܤ˾徺¤¹¤ë¤¬, ¹ç·×¤ÇÆý¤¬¤ó¤Î1%̤Ëþ¤Ë¤ß¤é¤ì¤ëÄøÅÙ.
  • ¾ïÀ÷¿§ÂÎÍ¥À­°äÅÁ¤·, ¤¬¤óÍÞÀ©°äÅÁ»Ò¤È¤·¤Æµ¡Ç½¤·¤Æ¤¤¤ë.
  • ¤½¤ì¤¾¤ì¤Î°äÅÁ»Ò¤¬¤«¤«¤ï¤ë°äÅÁÀ­¤¬¤ó¾É¸õ·²¤ÏÄ̾ï¤ÏÆý¤¬¤ó¤À¤±¤Ç¤Ê¤¯, ¤¬¤ó¤Î¿ȯ¤òÆÃħ¤È¤·¤Æ¤¤¤ë.
     

mark-Or.jpg Ãæ¿»Æ©Î¨, ÄãÉÑÅÙ¤ÎÆý¤¬¤óÁǰø°äÅÁ»Ò

  • CHEK2, ATM, BRIP1, PALB2¤Î4°äÅÁ»Ò¤¬ÃΤé¤ì, Æý¤¬¤ó¤Îȯ¾É¥ê¥¹¥¯¤òÃæÅùÅ٤˾徺¤µ¤»¤ë.
  • ³Æ¡¹¤ÎÊÑ°Û¤ÏÆý¤¬¤óȯ¾ÉΨ¥ê¥¹¥¯¤ò2¡Á3ÇÜÄøÅ٤˾徺¤µ¤»¤ë. Î×¾²¾ò·ï¤Ë¤è¤Ã¤Æ¤Ï¤µ¤é¤Ë¹â¤¤²ÄǽÀ­¤â¤¢¤ë
  • °ìÈ̽¸ÃĤÎÉÑÅÙ¤Ï0.1¡Á1%¤ÈÄ㤤. ¤¤¤¯¤Ä¤«¤ÎÁϻϼÔÊѰۤâÃΤé¤ì¤Æ¤ª¤ê, ¹ç·×¤¹¤ë¤È°äÅÁÀ­Æý¤¬¤ó¤Î2.3%¤òÀê¤á¤ë.
  • ¤³¤ì¤é¤Î°äÅÁ»Ò¤Ï¥·¥°¥Ê¥ëÅÁã¤Ç¤ÎÌò³ä¤ä, DNA½¤Éü¤Ë¤ª¤±¤ëBRCA1/BRCA2¤È¤Î¶¯¤¤´ØÏ¢¤¬ÃΤé¤ì, Æý¤¬¤ó°äÅÁ»Ò¸õÊä¤È¤·¤ÆÆÃ¤ËÁªÂòŪ¤Ë¸¦µæ¤µ¤ì¤¿.
     

mark-B.jpg¡¡Ä㿻ƩΨ, ¹âÉÑÅÙ¤ÎÆý¤¬¤óÁǰø°äÅÁ»Ò

  • genomewide association study(GWAS)¤Ë¤è¤ê, Æý¤¬¤ó½÷À­¤Î15¡Á40%¤Ë¤ª¤è¤½10¸Ä¤ÎÄã¥ê¥¹¥¯¥¢¥ì¥ë¤¢¤ë¤¤¤ÏºÂ°Ì¤¬³Îǧ¤µ¤ì¤¿.*5
  • ¹âÉÑÅ٤Ǥ¢¤ë¤¬, ¤½¤ì¤¾¤ì¤Î°äÅÁ»ÒÊѰÛñÆÈ¤ÎÁêÂХꥹ¥¯¤Ï¾®¤µ¤¯, 1.5̤Ëþ¤Ç¤¢¤ë.*6
  • ¾¤Î¹â, Ãæ, Äã¥ê¥¹¥¯°äÅÁ»Ò¤È¤ÎÁê¸ßºîÍѤ¬¤¢¤ë¾ì¹ç¤Ï, Î×¾²Åª¤Ë½ÅÍפʰÕÌ£¤ò¤â¤Á, Áê²ÃŪÁê¾èŪ¸ú²Ì¤¬Â¬Äê²Äǽ¤Ê¥ê¥¹¥¯¤È¤Ê¤ê¤¦¤ë.
  • BRCA²È·Ï¤Ë¤ª¤±¤ëFGFR2¤ÈMAP3K1¤Î´ØÏ¢¸¦µæ¤Ç¤Ï¤³¤ì¤é¤ÎSNP¤ÏBRCA2ÊѰÛ¸ºß²¼¤ÇÆý¤¬¤ó¥ê¥¹¥¯¤ò¾å¾º¤µ¤»¤ë²ÄǽÀ­¤¬¤¢¤ë¤³¤È¤Ï¾åµ­¤ÎÎã¤È¤Ê¤ë.

mark-B.jpg¡¡¥Þ¥¤¥¯¥í¥µ¥Æ¥é¥¤¥ÈÉÔ°ÂÄêÀ­¤ÈÆý¤¬¤ó

  • Lynch¾É¸õ·²¤Ï, MLH1, MSH2, MSH6, PMS2¤Ê¤É¤ÎDNA¥ß¥¹¥Þ¥Ã¥Á½¤Éü(mismatch repair;MMR)°äÅÁ»Ò¤ÎÀ¸¿£ºÙ˦·ÏÎóÊѰۤˤè¤ëȯ¤¬¤ó´¶¼õÀ­¤Î¾ïÀ÷¿§Âθ²À­(Í¥À­)°äÅÁÀ­¼À´µ--->Lynch¾É¸õ·².
    Æý¤¬¤ó¤Î¥ê¥¹¥¯¤â¹â¤¤¤³¤È¤¬ÌÀ¤é¤«¤Ë¤Ê¤Ã¤Æ¤­¤Æ¤¤¤ë.*7
  • ÊѰۥ­¥ã¥ê¥¢¤ÏÂçIJ´â¤Ë´Ø¤·¤Æ¤Ï¥ê¥¹¥¯¤¬ÁýÂ礹¤ë¤¬, Æý´â¤Ë¤Ä¤¤¤Æ¤Ïcontrovertial¤Ê¾õÂÖ.
  • MMRÊѰÛÊÝÍ­¼Ô¤ÈÈóÊÝÍ­¼Ô´Ö¤Ç¤¬¤ó¥ê¥¹¥¯É¾²Á¤¬¹Ô¤ï¤ì, ÊѰÛÊÝÍ­¼Ô¤Ï°ìÈ̽¸ÃĤÈÈæ¤ÙÆý´â¥ê¥¹¥¯¤¬4ÇܤȿäÄꤵ¤ì¤¿.*8
  • Lynch¾É¸õ·²ÊѰÛÊÝÍ­¼Ô¤ÎÆý´â¥ê¥¹¥¯¤ÎÂηÏŪÁíÀâ¤Ç¤Ï*9.
    Lynch¾É¸õ·²¤ÎÆý´â¥ê¥¹¥¯É¾²Á¤Ë¤Ï, ¤è¤êĹ´ü¤Î´Ñ»¡´ü´Ö¤Ë¤ï¤¿¤ë¸¦µæ¤òɬÍפȤ·¤Æ¤¤¤ë.

mark-B.jpg¡¡¥Þ¥¤¥¯¥íRNA(miRNA)¤ÈÆý¤¬¤ó¤Îȯ¤¬¤ó´¶¼õÀ­

  • ºÇ¶á¤Î¸¦µæ¤Ë¤è¤êmiRNA¤ÎSNP¤¬Æý¤¬¤ó´¶¼õÀ­¤Ë´Ø·¸¤¹¤ë¤³¤È¤¬¼¨º¶¤µ¤ì¤Æ¤¤¤ë.
  • miRNA¤ÏɸŪ¤ÎmRNA¤òʬ²ò¤·¤¿¤ê, ¤½¤ÎËÝÌõ¤òÍÞÀ©¤·¤¿¤ê¤¹¤ë¤³¤È¤Ç¿¤¯¤Î¤¬¤óÍÞÀ©°äÅÁ»Ò¤ä¤¬¤ó°äÅÁ»Ò¤òÀ©¸æ¤·¤Æ¤¤¤ë¤È¹Í¤¨¤é¤ìmiRNA¤ämiRNA·ë¹çÇÛÎó¤Î¿ÍÍÀ­¤Ë¤è¤ê, ¤¬¤óÍÞÀ©°äÅÁ»Ò¤ä¤¬¤ó°äÅÁ»Ò¤Îȯ¸½, ¤Ò¤¤¤Æ¤Ï¤¬¤ó´¶¼õÀ­¤¬±Æ¶Á¤ò¼õ¤±¤ë¤È¿ä»¡¤µ¤ì¤ë.
  • Æý¤¬¤ó¤Ë´ØÍ¿¤¹¤ë¤â¤Î¤È¤·¤Æ, pre-miR-27a¤Èpre-miR-196a-2°äÅÁ»ÒÆâ¤ÎÆÃÄê¤ÎSNP¤ÏÆý¤¬¤óȯ¾É¥ê¥¹¥¯¤ÎÄã²¼¤Ë¤«¤«¤ï¤ë¤³¤È¤¬ºÇ¶á¤Î¥á¥¿²òÀϤˤè¤ê³Îǧ¤µ¤ì¤Æ¤¤¤ë. *10*11
 
 

BRCA1 and BRCA2

BRCA1, BRCA2--¹â¿»Æ©Î¨, ÄãÉÑÅÙ¤ÎÆý¤¬¤ó¤ÎÁǰø¤È¤Ê¤ë°äÅÁ»Ò.

BRCA1¤ÈBRCA2¤ÎÊѰۤÏ, ¸²À­(Í¥À­)°äÅÁ¤¹¤ë°äÅÁÀ­Æý¤¬¤ó¤ÎÌó50%¤Ëǧ¤á¤é¤ì¤ë.¡¡ÊѰÛÊÝÍ­¼Ô¤Ï°ìÈ̽¸ÃĤǤϤޤì¤À¤¬, ÆÃÄê¤Î½¸ÃÄ(i.e. ¥¢¥·¥å¥±¥Ê¡¼¥¸·Ï¥æ¥À¥ä¿Í)¤Ç¤ÏÉÑÅÙ¤¬¹â¤¤¤³¤È¤¬¤¢¤ë.

ÊѰۤˤè¤êÆý¤¬¤óÁêÂХꥹ¥¯¤Ï°ìÈ̽¸ÃĤÎ10¡Á30ÇܤȤʤê, Æý¤¬¤ó¤ÎÀ¸³¶¥ê¥¹¥¯¤Ï¤Û¤Ü85%¤È¤Ê¤ë.*12

BRCA1¤ÈBRCA2¤ÎÀ¸¿£ºÙ˦·ÏÎóÊѰۤˤÏ1000°Ê¾å¤ÎÊѰۤ¬Æ±Äꤵ¤ì¤Æ¤¤¤ë. ¸¶°ø¤È¤Ê¤ëÊѰۤˤè¤ê¿¤¯¤Î¾ì¹çû¤¤¥¿¥ó¥Ñ¥¯¼Á¤¬À¸À®¤µ¤ì¤ë¤¬, ¥¿¥ó¥Ñ¥¯¼Áµ¡Ç½ÁÓ¼º¤ò¤­¤¿¤¹ÊѰۤâǧ¤á¤é¤ì¤ë.*6*5

BRCA1¤ÈBRCA2ÊѰۤο»Æ©Î¨¤È¤¬¤óȯ¾ÉǯÎð¤Ï, ²È²Æâ, ²È²´Ö¤Ç¿ÍÍ. BCRA¤ÎÆÃÄê¤ÎÊѰۤ˲䨤Æ, °äÅÁ»Ò´ÖÁê¸ßºîÍѤä°äÅÁ»Ò-´Ä¶­´Ö¤ÎÁê¸ßºîÍѤ¬BRCA¤Ë¤è¤ë¤¬¤ó¥ê¥¹¥¯¤ò¤É¤Î¤è¤¦¤ËÊѲ½¤µ¤»¤ë¤«À¹¤ó¤Ë¸¦µæ¤µ¤ì¤Æ¤¤¤ë.*13*14

  • BRCA1ÊѰÛÊÝÍ­¼Ô¤ÈBRCA2ÊѰÛÊÝÍ­¼Ô¤Ç¤Ï, °Û¤Ê¤ë½¤¾þ°äÅÁ»Ò(genetic modifiers)¤Ë¤è¤ê¥ê¥¹¥¯¤Î¿ÍÍÀ­¤¬À¸¤¸¤Æ¤¤¤ë²ÄǽÀ­¤¬¤¢¤ë.
  • °ì±ö´ð¿·¿¤¬BRCA1/BRCA2¤Î½¤¾þ°ø»Ò¤È¤·¤Æ¤è¤¯¤ß¤é¤ì, ¤³¤ì¤é¤Î½¤¾þSNP¤¬Áê¾èŪ¤ËºîÍѤ·, risk allele¤Î¿ô¤Ë±þ¤¸¤ÆÊѰÛÊÝÍ­¼Ô¤Î¥ê¥¹¥¯¤òÍ­°Õ¤ËÊѲ½¤µ¤»¤Æ¤¤¤ë²ÄǽÀ­¤¬Êó¹ð¤µ¤ì¤Æ¤¤¤ë.
  • ÉÑÅ٤ι⤤Æý¤¬¤ó´¶¼õÀ­¥¢¥ì¥ë¤¬BRCA1/BRCA2ÊѰÛÊÝÍ­¼Ô¤ËÍ¿¤¨¤ë±Æ¶Á¤òÁ°¸þ¤­¸¦µæ¤Ç¤·¤é¤Ù,
    BRCA2´ØÏ¢Â¿·¿7¤Ä¤È, BRCA1´ØÏ¢Â¿·¿4¤Ä¤¬¥¹¥³¥¢²½¤µ¤ì, 3·²¤ËʬÎव¤ì¤Æ¤¤¤ë.
  • BRCA2ÊѰÛÊÝÍ­¼Ô¤Ç¤Ï3·²´Ö¤ÇÆý¤¬¤ó¥ê¥¹¥¯¤¬Í­°Õ¤Ë°Û¤Ê¤ê, ºÇ¤â¹â¤¤·²¤Ç, 70ºÐ¤Þ¤Ç¤Ë72%¤Îȯ¾ÉΨ¤Ç¤¢¤Ã¤¿¤Î¤ËÂФ·, ºÇ¤âÄ㤤·²¤Ç¤Ï20%¤Ç¤¢¤Ã¤¿.
  • BRCA1ÊѰۥ­¥ã¥ê¥¢¤Ç¤ÏÆý¤¬¤ó¥ê¥¹¥¯¤Ï3·²´Ö¤ÇÍ­°Õ¤Ê°ã¤¤¤Ï¤ß¤é¤ì¤Ê¤«¤Ã¤¿.
     

BRCA1´ØÏ¢Æý¤¬¤ó¤Ï, BRCA2´ØÏ¢Æý¤¬¤ó¤ª¤è¤Ó»¶È¯À­Æý¤¬¤ó¤È¤Ï°Û¤Ê¤ëÆÃħ¤ò¤â¤Ä.

  • ŵ·¿Åª¤Ë¤Ï¼ãǯ¤Çȯ¾É, ¿Ê¹Ô¤¬Áᤤ.
     
  • ÁÈ¿¥³ØÅª¤Ë¹â°­À­ÅÙ¤Ç, Áý¿£Î¨¤¬¹â¤¤. °Û¿ôÂΤǤ¢¤êER-, PgR-, HER2-¤Î¥È¥ê¥×¥ë¥Í¥¬¥Æ¥£¥Ö.
     
  • triple-negative¤Îphenotype¤Ï, ¤µ¤é¤Ë, CK5/6, CK14, CK17, EGF, P-cadherin¤Î´ðÄìºÙ˦ÍÍ(basal-like)°äÅÁ»Òȯ¸½¥×¥í¥Õ¥¡¥¤¥ë¤òÆÃħ¤È¤·¤Æ¤¤¤ë.*15

BRCA1¤ÈBRCA2¤Ï¿µ¡Ç½¤ÎÂ礭¤Ê¥¿¥ó¥Ñ¥¯¼Á¤ò¥³¡¼¥É¤·, ¼ç¤ËÁêÆ±ÁȤߴ¹¤¨¤Ë¤è¤ëDNA¤ÎÆóËܺ¿ÀÚÃǤν¤Éü¤ò¿Ê¤á¤ë¤³¤È¤Ç¥²¥Î¥à°ÂÄêÀ­¤ò°Ý»ý¤·, ¸ÅŵŪ¤Ê¤¬¤óÍÞÀ©°äÅÁ»Ò¤È¤·¤Æµ¡Ç½¤·¤Æ¤¤¤ë (²¼µ­¡Ë*15*16

¤Ç¤Ï¡¢¼ãÇ¯ÉØ¿Í¤Ë¤ª¤¤¤Æ, BRCA°äÅÁ»ÒÊѰۤò»ý¤ÄÆý´â¤Îͽ¸å¤ÏÎɤ¤¤Î¤«°­¤¤¤Î¤«¡©

mark-Or.jpg¡¡BRCAÊѰÛÍÛÀ­Æý´â¤Îͽ¸å¤Ï¡¤BRCA±¢À­¤Î°ìÈÌ¤ÎÆý´â¤ÈÈæ¤Ù¤Æ·è¤·¤Æ°­¤¯¤Ê¤¤¤³¤È¤¬BRCA°äÅÁ»ÒÊѰÛÍÛÀ­¤È±¢À­¤ÎÆý´â¤ÎÊý¤Îͽ¸å¤òÁ°¸þ¤­¤ËĹ´üÄ´ºº¤·¤¿¸¦µæ¤Ë¤è¤ê¼¨¤µ¤ì¤Æ¤¤¤ë. *17

¤³¤Î»î¸³¤Ï¥¤¥®¥ê¥¹¤Ç40ºÐ°Ê²¼¤Ç¿»½áÀ­Æý´â¤È¿ÇÃǤµ¤ì¤¿´µ¼Ô¤µ¤ó¤ÎÀ¸¿£ºÙ˦·Ï¤Ç¤ÎBRCA°äÅÁ»ÒÊѰۤòÄ´¤Ù¤Æ¡¤ÊѰۤò»ý¤Ä¾ÉÎã¤È¡¤»ý¤¿¤Ê¤¤¾ÉÎã¤Îͽ¸å¤òÁ°¸þ¤­¤Ë´Ñ»¡¤¹¤ë¸¦µæ.

  • BRCA¤ÎÀ¸¿£ºÙ˦·Ï¤Ç¤ÎÉÂŪ°äÅÁ»ÒÊѰۤò»ý¤Ã¤¿´µ¼Ô¤µ¤ó¤¬338¿Í¡Ê12¡ó¡Ë¤Ç¡¤201¿Í¤¬BRCA1°äÅÁ»ÒÊѰÛÍÛÀ­¡ÊBRCA1ÍÛÀ­¡Ë¡¤137¿Í¤¬BRCA2°äÅÁ»ÒÊѰÛÍÛÀ­¡ÊBRCA2ÍÛÀ­¡Ë¤Ç¤¢¤Ã¤¿.ÅÐÏ¿¤µ¤ì¤¿´µ¼ÔÇØ·Ê¤Ç¡¤BRCAÍÛÀ­¤È±¢À­¤Î´µ¼Ô¤µ¤ó¤ÎBMI¤ËÍ­°Õº¹¤Ï¤Ê¤¯¡¤¿Í¼ï¤Ëº¹¤Ï¤Ê¤«¤Ã¤¿
     
    ÉÂÍýÁÈ¿¥³ØÅªÇØ·Ê
  • ¼ðáç·Â¤ÏBRCAÍÛÀ­Æý´â¤È±¢À­Æý´â¤ÇÍ­°Õº¹¤Ï¤Ê¤¯¡¤BRCA1ÍÛÀ­Æý´â¡ÊÊ¿¶Ñ21mm¡Ë¤ÏBRCA2ÍÛÀ­Æý´â¡ÊÊ¿¶Ñ25mm¡Ë¤è¤ê¤â¾®¤µ¤¤·¹¸þ¤¬¤¢¤Ã¤¿¡ÊP=0.06¡Ë.
  • ÁÈ¿¥³ØÅª°­À­ÅÙ¤ÏBRCAÍÛÀ­¤ÎÊý¤¬BRCA±¢À­¤è¤ê¤â°­À­ÅÙ¤¬Í­°Õ¤Ë¹â¤¯¡ÊP¡ã0.0001¡Ë¡¤BRCA1ÍÛÀ­¤ÎÊý¡ÊG3¤¬91¡ó¡Ë¤¬BRCA2ÍÛÀ­¤ÎÊý¡ÊG3¤¬69¡ó¡Ë¤è¤ê¤â°­À­ÅÙ¤¬Í­°Õ¤Ë¹â¤«¤Ã¤¿¡ÊP¡ã0.0001).¡¨ (ÁÈ¿¥³ØÅª°­À­ÅÙ¤Ïͽ¸å°ø»Ò¤È¤·¤Æ¹×¸¥¤·¤Æ¤¤¤Ê¤¤¡©¡©)
  • BRCAÍÛÀ­¤ÎÊý¡Ê51¡ó¤¬ER±¢À­¡Ë¤ÏBRCA±¢À­¤ÎÊý¡Ê31¡ó¤¬ER±¢À­¡Ë¤è¤ê¤â¥¨¥¹¥È¥í¥²¥ó¥ì¥»¥×¥¿¡¼¡ÊER¡Ë±¢À­¤¬Í­°Õ¤Ë¿¤¯¡ÊP¡ã0.0001¡Ë¡¤BRCA1ÍÛÀ­¤ÎÊý¡Ê76¡ó¤¬ER±¢À­¡Ë¤ÏBRCA2ÍÛÀ­¤ÎÊý¡Ê15¡ó¤¬ER±¢À­¡Ë¤è¤ê¤âER±¢À­Æý´â¤¬Í­°Õ¤Ë¿¤«¤Ã¤¿¡ÊP¡ã0.0001¡Ë
  • HER2ÍÛÀ­Æý´â¤Ï¡¤BRCAÍÛÀ­Æý´â¤Ç9¡ó¤ËÂФ·¤Æ¡¤BRCA±¢À­Æý´â¤Ç¤Ï30¡ó¤ÈÍ­°Õ¤Ê°ã¤¤¤òǧ¤á¤¿¡ÊP¡ã0.0001¡Ë
  • TN¡Ê¥È¥ê¥×¥ë¥Í¥¬¥Æ¥£¥ÖÆý´â¡Ë¤Î³ä¹ç¤Ï¡¤BRCA1ÍÛÀ­Æý´â¤Ç61¡ó¡¤BRCA2ÍÛÀ­Æý´â¤Ç10¡ó¤ÈÍ­°Õ¤Ë°Û¤Ê¤Ã¤Æ¤¤¤¿¡ÊP¡ã0.0001¡Ë
  • ¥ê¥ó¥ÑÀáž°ÜÍÛÀ­¤ÏBRCAÍÛÀ­Æý´â¤Ç45¡ó¤ËÂФ·¤Æ¡¤BRCA±¢À­Æý´â¤Ç53¡ó¤È±¢À­´µ¼Ô¤ÎÊý¤¬Í­°Õ¤Ë¹â¤«¤Ã¤¿¡ÊP=0.013¡Ë¡¥ BRCA1ÍÛÀ­¤Ç¤Ï36¡ó¤ËÂФ·¤Æ¡¤BRCA2ÍÛÀ­¤Ç¤Ï59¡ó¤ÈBRCA2ÍÛÀ­Æý´â¤ÇÍ­°Õ¤Ë¥ê¥ó¥ÑÀឰܤ¬Â¿¤«¤Ã¤¿¡ÊP¡ã0.0001¡Ë
     
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  • ¼þ½Ñ´ü²½³ØÎÅË¡¡Ê½ÑÁ°¡¦½Ñ¸å¡Ë¤¬»Ü¹Ô¤µ¤ì¤¿³ä¹ç¤Ï¡¤BRCAÍÛÀ­Æý´â¤Ç94¡ó¡¤BRCA±¢À­Æý´â¤Ç88¡ó¤ÈÍ­°Õº¹¤¬¤¢¤Ã¤¿¡ÊP=0.0058¡Ë
    ¼ê½Ñ¤Î½Ñ¼°¤ÏBRCAÍÛÀ­¤È±¢À­¤Çº¹¤Ï¤Ê¤«¤Ã¤¿¤¬¡¤BRCA1ÍÛÀ­Æý´â¡Ê53¡ó¤¬²¹Â¸¡Ë¤ÏBRCA2ÍÛÀ­Æý´â¡Ê31¡ó¤¬²¹Â¸¡Ë¤ÈÈæ¤Ù¤ÆÍ­°Õ¤Ë²¹Â¸¼ê½Ñ¤Î³ä¹ç¤¬¹â¤«¤Ã¤¿¡ÊP=0.0004¡Ë
    ²½³ØÎÅË¡¤Î¥ì¥¸¥á¥ó¤ËÂ礭¤Ê°ã¤¤¤Ï¤Ê¤«¤Ã¤¿¡¥Â¿¤¯¤¬¥¿¥­¥µ¥ó·Ï¹³¤¬¤óºÞ¤Î¤Ê¤¤¡¤¥¢¥ó¥¹¥é¥µ¥¤¥¯¥ê¥ó·Ï¹³¤¬¤óºÞ¤ÎÅêÍ¿¤Ç¤¢¤Ã¤¿.
  • Ê¿¶Ñ´Ñ»¡´ü´Ö8.2ǯ¤Ç¡¤91¿Í¡Ê3¡ó¡Ë¤¬¥í¥¹¥È¥Õ¥©¥í¡¼¥¢¥Ã¥×¤Ç¤¢¤Ã¤¿¡¥ÂЦÆý´â¤¬151¿ÍȯÀ¸¤·¤Æ¡¤BRCA1ÍÛÀ­¤Ç37/201 ¡Ê18¡ó¡Ë¤Ç¡¤BRCA2ÍÛÀ­¤Ç17/137 ¡Ê12¡ó¡Ë¤Ç¤¢¤Ã¤¿¡¥BRCA±¢À­Æý´â¤ÎÊý¤¬¡¤97/2395 ¡Ê4¡ó¡Ë¤Ç¤¢¤ê¡¤BRCAÍÛÀ­Æý´â¤ÎÊý¤¬ÂЦÆý´â¤ÎȯÀ¸¤Î³ä¹ç¤¬¹â¤«¤Ã¤¿¡¥
    ÂЦÆý´â¤ÎȯÀ¸¤Î¥¿¥¤¥ß¥ó¥°¤ÏÊ¿¶Ñ¤Ç3ǯ¤Ç¤¢¤Ã¤¿. Á´ÂΤÎ752¿Í¡Ê28¡ó¡Ë¤¬±ó³Öž°Ü¤ò¤­¤¿¤·¡¤678¿Í¤¬»àË´¤·¤¿¡¥¤½¤Î¤¦¤Á651¿Í¡Ê96¡ó¡Ë¤¬Æý´â¤¬¸¶°ø¤Ç¤Î»àË´¤Ç¤¢¤Ã¤¿¡¥
  • 2¼¡´â¤Ç¤Î»àË´Î㤬BRCA1ÍÛÀ­´µ¼Ô¤Ç6¿Í¡Ê3¡ó¡Ë¡ÊÍñÁã´â3¿Í¡¤Ê¢Ëì´â1̾¡¤¿©Æ»´â1̾¡¤ç¹Â¡´â1̾¡Ë¡¤BRCA2ÍÛÀ­Æý´â¤Ç¤Ï°ì¿Í¤â¤Ê¤¯¡¤BRCA±¢À­Æý´â¤Ç12̾¡Ê<1¡ó¡Ë¤Ç¤¢¤Ã¤¿
     
    BRCA°äÅÁ»ÒÊѰÛÍÛÀ­¤È±¢À­¤ÎÊý¤ÇÀ¸Â¸Î¨¤ËÍ­°Õ¤Ê°ã¤¤¤Ï¤Ê¤¯¡¤
  • 2ǯ¤ÎÀ¸Â¸Î¨¤ÏBRCA°äÅÁ»ÒÊѰÛÍÛÀ­¤¬97¡ó¡¤±¢À­¤Ç96.6¡ó¡¤
  • 5ǯ¤Ç¤Ï83.8¡ó¤È85¡ó¡¤10ǯ¤Ç¤Ï73.4¡ó¤È70.1¡ó¤Ç¤¢¤ê¡¤HR:0.96 ¡Ê95¡ó CI:0.76-1.22; P=0.76¡Ë¤ÇÅý·×³ØÅª¤ÊÍ­°Õº¹¤Ï¤Ê¤«¤Ã¤¿.
  • TNÆý´â¡Ê¥È¥ê¥×¥ë¥Í¥¬¥Æ¥£¥ÖÆý´â¡Ë¤¬558¿Í¤¤¤Æ¡¤''BRCA°äÅÁ»ÒÊѰۤò»ý¤Ã¤¿Êý(136¿Í) ¤Î2ǯ¤Îͽ¸å¤Ï¡¤±¢À­¤ÎÊý¤Îͽ¸å¤è¤ê¤âÎɹ¥¤Ç¤¢¤Ã¤¿¡Ê95¡ó vs 91¡ó : HR 0¡¦59 [95¡ó CI 0¡¦35?0¡¦99]; P=0¡¦047¡Ë¡¥¡¡¤·¤«¤·¡¤5ǯ¡¤10ǯ¤Ç¤Îͽ¸å¤Ë¤ÏÅý·×³ØÅª¤Êº¹¤Ïǧ¤á¤Ê¤«¤Ã¤¿
     
    ¤³¤ÎÁ°¸þ¤­¸¦µæ¤Ç¤Ï, BRCAÍÛÀ­Æý´â¤Îͽ¸å¤Ï¡¤BRCA±¢À­¤Î°ìÈÌ¤ÎÆý´â¤ÈÈæ¤Ù¤Æ·è¤·¤Æ°­¤¯¤Ê¤¤¤³¤È¤¬¼¨¤µ¤ì¤Æ¤¤¤ë¡¥
    BRCAÍÛÀ­¤Îtriple negative Æý´â¤Ç¤Ïû´ü´Ö(2ǯ)¤Îͽ¸å¤Ï°ìÈÌ¤ÎÆý´â¤è¤ê¤âÎɹ¥¤Ê·¹¸þ¤â¼¨¤µ¤ì¤¿¡¥
     

BRCA1/2¤Ï¤¬¤óÍÞÀ©°äÅÁ»Ò¤È¤·¤Æ¤·¤é¤ì¤Æ¤¤¤ë.

TP53¤Î¤è¤¦¤ËºÙ˦¼þ´ü¤òľÀÜÍÞÀ©¤¹¤ëgate keeper¤Ç¤Ï¤Ê¤¯, ¥²¥Î¥à°ÂÄêÀ­¤Ëɬ¿Ü¤Êcare taker·¿¤¬¤óÍÞÀ©°äÅÁ»Ò¤Ç, DNA»½ý½¤Éü, ºÙ˦¼þ´ü¥Á¥§¥Ã¥¯¥Ý¥¤¥ó¥ÈÀ©¸æ, ¥¯¥í¥Þ¥Á¥óºÆ¹½À®remodeling, Ãæ¿´ÂÎÀ©¸æ¤Ê¤É¿ºÌ¤Êµ¡Ç½¤òÍ­¤·¤Æ¤¤¤ë. *18. ¤³¤ì¤é¤Ï¤¹¤Ù¤Æ¥²¥Î¥à°ÂÄêÀ­¤ò°Ý»ý¤¹¤ë¤¿¤á¤Îµ¡Ç½¤Ç¤¢¤ë.

DNA»½ý±þÅú/½¤Éü¤Ï¥Ò¥Èȯ¤¬¤ó¤ÎÍÞÀ©¤Ëµ¡Ç½¤¹¤ë°ìÊý, DNA½¤Éüµ¡Ç½¤¬Ð¶¿Ê¤·¤Æ¤¤¤ë¤¬¤óºÙ˦¤Ç¤Ï¹³¤¬¤óºÞ¤äÊü¼ÍÀþ¤Ë¤è¤ëºÙ˦»à¤¬Í¶Æ³¤µ¤ì¤Ë¤¯¤¯¼£ÎÅÄñ¹³À­¤È¤Ê¤ë.

BRCA1/2¤Îµ¡Ç½¤Î¤¦¤Á, DNAÁêÆ±ÁȤߴ¹¤¨½¤Éü(homologous recombination repair: HRR)¤Ï, ºÇ¤â½ÅÍפÇ, PARP(Poly(ADP-ribose)polymerase)Á˳²ºÞ¤Î´¶¼õÀ­¤òº¸±¦¤¹¤ë.

  • BRCA1 BRest CAncer 1 gene, BRCA1 DNA repair associated., 17q21
     
    BRCA1¤ÏHRR¤Ë¤ª¤¤¤Æ, 1) ÀÚÃÇüºï¤ê¹þ¤ß¤Ë¤è¤ë1Ëܺ¿DNA(ssDNA)¤Î¿­Ä¹, 2) Ãç²ðÌò¤ÎPALB2¤ò²ð¤·¤Æ, BRCA2¤È·ë¹ç¤·, BRCA2¤ò»½ý¶É½ê¤ØÍ¶Æ³¤¹¤ë, 2¤Ä¤Î²áÄø¤Çɬ¿Ü¤Ç¤¢¤ë.*19 *20 1)¤Î½½Ê¬¤ÊŤµ¤ÎssDNA¤¬¤Ê¤¤¤ÈssDNA¤Ï»ÐËåÀ÷¿§Ê¬ÂΤؿ¯Æþ¤Ç¤­¤Ê¤¤.
     
  • BRCA2 BRCA2 DNA repair associated., 13q12.3
     
    BRCA2¤Îµ¡Ç½¤ÏBRCA1¤¬Â¿µ¡Ç½¤òÍ­¤¹¤ë¤Î¤ËÈæ¤Ù, HRR¤Ë¸ÂÄꤷ¤Æ¤¤¤ë. BRC repeat¤È¸Æ¤Ð¤ì¤ë8¤Ä¤Î·«¤êÊÖ¤·ÇÛÎó¤ò¤â¤Á, ¤½¤ì¤¾¤ì¤ÎBRC motif¤ò²ð¤·¤Æ, Ê£¿ô¤ÎRAD51¤È·ë¹ç¤¹¤ë.
     
    BRCA1¤Ë¤è¤êDNA»½ý¶É½ê¤ËͶƳ¤µ¤ì¤¿BRCA2¤Ï¿­Ä¹¤·¤¿ssDNA¤ËRAD51¤ò¶¡µë¤¹¤ë. RAD51¤Ï¥ê¥³¥ó¥Ó¥Ê¡¼¥¼¤È¤¤¤¦¹ÚÁǤǤ¢¤ê, ssDNA¤Ë·ë¹ç¤·¤ÆDNA-RAD51¥Õ¥£¥é¥á¥ó¥È¤ò·ÁÀ®¤·, »ÐËåÀ÷¿§Ê¬ÂΤ˿¯Æþ¤·¤Æ¥Û¥â¥í¥¸¡¼¥µ¡¼¥Á(ÁêÆ±Éô°Ìõº÷)¤ò¹Ô¤¦ÁêÆ±ÁȤߴ¹¤¨½¤Éü¤Î¥¨¥Õ¥§¥¯¥¿¡¼Ê¬»Ò¤È¤·¤ÆÆ¯¤¯.
     
    BRCA2¤ÎºÙ˦¶Éºß¤Ï»þ¶õ´ÖŪ¤Ë°Û¤Ê¤ê, ºÙ˦¼þ´ü´Ö´ü¤Ë¤ÏÃæ¿´ÂΤ˶ɺߤ·, ¤½¤ÎÊ£À½¤ä¥Ý¥¸¥·¥ç¥Ë¥ó¥°¤òÀ©¸æ¤¹¤ë(Ãæ¿´ÂÎ¥À¥¤¥Ê¥ß¥Ã¥¯¥¹À©¸æ)
     
    BRCA2¤ÏʬÎö´ü¤Ë¤ÏÀ÷¿§ÂΤ˷ë¹ç¤·, À÷¿§Âΰݻý¡¦Ê¬Çۤ˴ØÍ¿¤¹¤ë(À÷¿§ÂÎʬÇÛÀ©), ºÙ˦¼ÁʬÎö¤Ç¤Ï2¸Ä¤Î̼ºÙ˦¤ÎÃæ´ÖÂÎÀÚÃǤòÀ©¸æ¤¹¤ë(ºÙ˦¼ÁʬÎöÀ©¸æ)
     
    BRCA1,2¤ÏDNA»½ý½¤Éü¤ò¤Ï¤¸¤á, Ãæ¿´ÂÎ¥À¥¤¥Ê¥ß¥¯¥¹À©¸æ, À÷¿§ÂÎʬÇÛÀ©¸æ, ºÙ˦¼ÁʬÎöÀ©¸æ¤ÈºÙ˦¼þ´ü¤Î³Æ»þ´ü¤ä¾ì½ê¤Ë¤ª¤¤¤Æ¥²¥Î¥à°ÂÄê²½¤Ëµ¡Ç½¤·¤Æ¤¤¤ë.*21

DNAÆóËܺ¿ÀÚÃÇ(double-strand break: DSB)¤òÇÛÎ󥨥顼¤Ê¤¯¸µÄ̤ê¤Ë½¤Éü¤¹¤ëµ¡¹½¤¬HRR. ºÙ˦¤Ë¤È¤Ã¤Æ, DSB¤Ï°ìËܺ¿ÀÚÃÇ(single-strand break: SSB)¤Ë¤¯¤é¤Ù¤è¤êÃ×̿Ū¤Ç¤¢¤ê, ²ÄµÚŪ®¤ä¤«¤Ë½¤Éü¤¹¤ëɬÍפ¬¤¢¤ë.

DSB¤Ï, ¥¢¥ó¥È¥é¥µ¥¤¥¯¥ê¥ó·Ï¤ä²Í¶¶ºÞ¤Ê¤É¤Î²½³ØÎÅË¡Ìô, Êü¼ÍÀþ¤Î¾, DNAÊ£À½¤Ë¤È¤â¤Ê¤Ã¤ÆÈ¯À¸¤¹¤ë.

DSB¤Î½¤Éüµ¡¹½¤Ë¤Ï, ÀÚÃÇü¤òñ½ã¤ËºÆ·ë¹ç¤¹¤ë, ÈóÁêÆ±ËöüºÆ·ë¹ç(non-homologous end-joining: NHEJ)¤È»ÐËåÀ÷¿§Ê¬ÂΤòÃò·¿¤Ë¤·¤ÆÂ»½ýÉô°Ì¤ò¤è¤êÀµ³Î¤Ë½¤Éü¤¹¤ëHRR¤¬¤¢¤ë.*22*23

ºÙ˦¼þ´ü¤Ë¤ª¤¤¤Æ, HRR¤¬²Äǽ¤Ê¤Î¤Ï»ÐËåÀ÷¿§Ê¬ÂΤ¬Â¸ºß¤¹¤ëS´ü¤ª¤è¤ÓG2´ü¤Ë¸Â¤é¤ì¤ë. G1´ü¤ÎºÙ˦¤ÏNHEJ¤Ë¤è¤ê½¤Éü¤µ¤ì¤ë.NHEJ¤ÏÈæ³ÓŪÀµ³Î¤Ç¤¢¤ë¤¬DSB¤ÎÀ¸¤¸Êý¤Ë¤è¤Ã¤Æ¤Ï¥¨¥é¡¼¤òµ¯¤³¤¹²ÄǽÀ­¤¬¤¢¤ë.

 

ÁêÆ±ÁȤߴ¹¤¨½¤Éü¥á¥«¥Ë¥º¥à

ÁêÆ±ÁȤߴ¹¤¨½¤Éü(homologous recombination repair; HR) *24

DNArepair_Kumikae.jpg

DNAÆó½Åº¿ÀÚÃǤÏÀ÷¿§ÂΤη缺¤äžºÂ¤ò¤Ò¤­¤ª¤³¤¹½ÅÆÆ¤ÊDNA»½ý¤Ç, ÅÅÎ¥Êü¼ÍÀþ¤Ë¤è¤êͶȯ¤µ¤ì¤ë¤³¤È¤¬ÃΤé¤ì¤Æ¤¤¤¿.

ºÇ¶á¤Î¸¦µæ¤Ç¤Ï, »½ý±ö´ð¤ÈÊ£À½¥Õ¥©¡¼¥¯¤Î¾×ÆÍ¤Ë¤è¤Ã¤Æ¤â¤Ò¤­¤ª¤³¤µ¤ì¤ë¤³¤È¤¬¼¨¤µ¤ì¤¿.

±ö´ð, ¤ª¤è¤Ó¥Ì¥¯¥ì¥ª¥Á¥É½üµî½¤Éü¤Ç¤Ï, »½ý±ö´ð¤ò½üµî¸å¤Ë̵½ý¤Î°ìËܺ¿DNA¤òÃò·¿¤Ë¤·¤Æ½¤Éü¹çÀ®¤Ç¤­¤ë¤¬, DNAÆó½Åº¿ÀÚÃǤˤϤ³¤ÎÊýË¡¤¬»È¤¨¤Ê¤¤. ½¤Éü¤Ë¤Ï, S´ü¤¢¤ë¤¤¤ÏG2´ü¤Ë¸ºß¤¹¤ë»ÐËåÀ÷¿§ÂÎʬÂΤÎÁêÆ±¤ÊÉô°Ì¤òÃò·¿¤È¤·¤Æ»ÈÍѤ¹¤ë.

1. »½ýÉô¤ËÊ£¹çÂÎMRN(MRE11/RAD50/NBS1), BCRA1, ¤ª¤è¤ÓDNA¥Ì¥¯¥ì¥¢¡¼¥¼CtIP¤È¤ÎÊ£¹çÂΤ¬·ÁÀ®¤µ¤ì¤ë.

2. CtIP¤¬DNAÀÚÃÇü¤«¤é3'¦¤ÎDNA¤òÀÚ½ü¤·¤Æ, °ìËܺ¿DNA¤òÀ¸À®, RPA(Ê£À½¥¿¥ó¥Ñ¥¯¼ÁA)¤È¤Î·ë¹ç¤Ë¤è¤ê°ÂÄê²½¤¹¤ë.

3. ¼¡¤ËBRCA2¤¬RPA¤ÈRAD51¤È¤Î¸ò´¹È¿±þ¤òÂ¥¿Ê, °ìËܺ¿DNA¤ËRAD51¤¬´¬¤­¤Ä¤¤¤¿¥Ì¥¯¥ì¥ª¥Õ¥£¥é¥á¥ó¥È¤ò·ÁÀ®¤¹¤ë.

4. RAD51¥Õ¥£¥é¥á¥ó¥È¤Ï, »ÐËåÀ÷¿§Ê¬ÂΤαö´ðÇÛÎó¤¬ÁêÆ±¤ÊÉô°Ì¤Ë¿¯Æþ¤·, CtIP¤¬Ê¬²ò¤·¤¿°ìËܺ¿¤Î¤½¤ì¤¾¤ì¤¬½¤Éü¹çÀ®¤µ¤ì¤ë. ¤½¤Î¸å, ¥Û¥ê¥Ç¥¤¥¸¥ã¥ó¥¯¥·¥ç¥óÃæ´ÖÂΤò·Ðͳ¤·¤Æ½¤Éü¤¬´°Î»¤¹¤ë.

  • ¥Û¥ê¥Ç¥¤¥¸¥ã¥ó¥¯¥·¥ç¥ó¤ÏHolliday R¤Ë¤è¤ê°äÅÁ»ÒÁȤߴ¹¤¨µ¡¹½¤òÀâÌÀ¤¹¤ë¥â¥Ç¥ë¤È¤·¤ÆÄ󾧤µ¤ì¤¿. ÆóËܤÎDNAÆó½Åº¿¤Î°ìËܺ¿¤Îº¿´Ö¸ò´¹¤Ë¤è¤ê, ¤½¤ì¤¾¤ì¤ÎDNAÆó½Åº¿¤¬º¿¤È¸ò´¹¤·¤Æ¤¤¤Ê¤¤º¿¤«¤é¤Ê¤ê¤¿¤ÄÃæ´ÖÂι½Â¤.

5. MRNÊ£¹çÂΤÎÀ®Ê¬NBS1¤ò·ç¼º¤·¤¿¥Ê¥¤¥ß¡¼¥Ø¥ó¾É¸õ·²(Nijmegen¡¡breakage syndrome: NBS)¤Ç¤Ï¹âÉÑÅ٤˥ê¥ó¥Ñ¼ð¤ÎȯÀ¸¤¬Êó¹ð¤µ¤ì¤Æ¤¤¤ë.

BRCA1, BRCA2¤Ï²È²À­Æý¤¬¤ó¤Î¥¿¥ó¥Ñ¥¯¼Á¤Ç¤¢¤ê¥²¥Î¥à°ÂÄêÀ­¤Ë½ÅÍפʥ¿¥ó¥Ñ¥¯¼Á¤Ç¤¢¤ë.

²È·ÏÆâ½¸ÀÑÀ­Æý¤¬¤ó/ ²È²À­Æý¤¬¤ó¡§¡¡²È·ÏÆâ¤ËÊ£¿ô¤Î´µ¼Ô¤µ¤ó¤¬¤ß¤é¤ì¤ëÆý¤¬¤ó.*21

°äÅÁÀ­Æý´â: ²È·ÏÆâ½¸ÀÑÀ­Æý¤¬¤ó/ ²È²À­Æý¤¬¤ó¤ÎÃæ¤Ç¾ïÀ÷¿§Âθ²À­(Í¥À­)°äÅÁÀ­¤Î°äÅÁ»Ò¤Î¸ºß¤¬¶¯¤¯¼¨º¶¤µ¤ì¤ëÆý´â*21

Á´Æý¤¬¤ó¤Î15-20%¤¬²È²À­Æý¤¬¤ó¤Ç, ¤½¤ÎÌó1/3¤¬°äÅÁÀ­Æý¤¬¤ó¡ÊÁ´Æý¤¬¤ó¤Î5%)

°äÅÁÀ­Æý¤¬¤ó¤Î60-70%¤¬BRCA1/ BRCA2°äÅÁ»Ò¤ÎÊѰۤˤè¤êȯÀ¸¤¹¤ë°äÅÁÀ­Æý¤¬¤ó¡¦ÍñÁ㤬¤ó¾É¸õ·²¡Êhereditary breast and ovarian cancer: HBOC).

 

¹çÀ®Ã×»àÀ­, PARPÁ˳²Ìô¤ÎºîÍѵ¡½ø

¹çÀ®Ã×»àÀ­(Synthetic lethality): ¹ÚÊì°äÅÁ³Ø¤Î¸ÀÍÕ¤Ç, ¤¢¤ë1¤Ä¤Î°äÅÁ»ÒA¤Ë·ç»¤¬¤ª¤³¤Ã¤Æ¤â, ¤½¤Îµ¡Ç½¤¬Â¾¤Î°äÅÁ»ÒB¤Ë¤è¤êÊä´°¤µ¤ì¤ë¤ÈºÙ˦¤Ï²¿¤éÉÔÅԹ礬¤Ê¤¤¤Î¤ËÂФ·,
¤ª¸ß¤¤¤ËÊä´°¤·¤¢¤¦°äÅÁ»ÒA, BξÊý¤Ë·ç»¤¬¤ª¤³¤ë¤ÈºÙ˦¤¬»à¤Ì¸½¾Ý.

PARPÁ˳²Ìô¤ÎºîÍѵ¡½ø¤Ï¹çÀ®Ã×»àÀ­¤Ç¤¢¤ê, ¤³¤Î¾ì¹ç¤Î°äÅÁ»ÒA¤ÏPARP, °äÅÁ»ÒB¤Ï, BRCA1/2¤ò´Þ¤àHRR¤Ëɬ¿Ü¤Ê°äÅÁ»Ò¤È¤Ê¤ë.

PARP¤Îµ¡Ç½

PARP¡Êpoly(ADP-ribose) polymerase)¤Ï, ¥Ý¥êADP¥ê¥Ü¥·¥ë²½¤Ë¤è¤ê¦º¿¤ò¤â¤ÄADP¥ê¥Ü¡¼¥¹º¿¤ò, PARP¼«¿È¤ò´Þ¤àɸŪ¥¿¥ó¥Ñ¥¯¼Á¤ËÉղ乤ë¹ÚÁǤǤ¢¤ë.

ADP¥ê¥Ü¡¼¥¹º¿¤Ï¼ï¡¹¤ÎDNA½¤Éü¥¿¥ó¥Ñ¥¯¼Á¤òDNA»½ýÉô°Ì¤ËͶƳ¤·, DNA°ìËܺ¿Â»½ý½¤Éü(single-strand break repair:SSBR)*25,¤ÈÂåÂØÈóÁêÆ±À­ËöüºÆ·ë¹ç(Alternative non-homologous end-joining: Alt-Ej)¤Ëɬ¿Ü¤ÊÌò³ä¤ò²Ì¤¿¤¹.

¥Ò¥È¤Ç¤ÏPARP¤Ï18¤â¤Î¥á¥ó¥Ð¡¼¤ò¤â¤Ä¥Õ¥¡¥ß¥ê¡¼¤ò·ÁÀ®¤¹¤ë¤¬¤³¤ì¤é¤Îµ¡Ç½¤Ë´Ø¤ï¤ë¤Î¤Ï¼ç¤ËPARP1¤Ç¤¢¤ê, PARP2¤Ï°ìÉôÊ䴰Ū¤ÊÌò³ä¤ò²Ì¤¿¤·¤Æ¤¤¤ë¤È¹Í¤¨¤é¤ì¤Æ¤¤¤ë.

 
  • PARPÁ˳²Ìô¤Ë¤è¤êDNAÊ£À½ÅÓÃæ¤Ê¤É¤ÇÀ¸¤¸¤ë°ìËܺ¿ÀÚÃǤò½¤Éü¤¹¤ëPARP¤òÁ˳²¤¹¤ë¤È±ö´ð½üµî½¤Éü¤¬µ¡Ç½¤·¤Ê¤¤¤¿¤áºÙ˦¤Ï°ìËܺ¿ÀÚÃǤòÆóËܺ¿ÀÚÃǤËÊÑ´¹¤·, ÆóËܺ¿ÀÚÃǽ¤Éüµ¡Ç½¤ò»È¤Ã¤Æ½¤Éü¤ò»î¤ß¤ë.
  • ¤³¤Î¤È¤­BRCAÊѰۤʤɤˤè¤êHR½¤Éüµ¡¹½¤¬¹Ô¤¨¤Ê¤¤¾ì¹ç, ÈóÁêÆ±Ëöü·ë¹ç(NHEJ)¤ä¥Þ¥¤¥¯¥í¥Û¥â¥í¥¸¡¼ÇÞ²ðËöü·ë¹ç(MMEJ)¤Ë¤è¤ë½¤Éü¤¬¹Ô¤ï¤ì¤ë¤«, ¤Þ¤¿¤Ï½¤Éü¤¬¤ª¤³¤Ê¤ï¤ì¤ºÆóËܺ¿ÀÚÃǤ¬»ý³¤¹¤ë.
  • NHEJ¤äMMEJ¤Ê¤É¤Ë¤è¤ë½¤Éü¤ÏÈó¾ï¤Ë¥¨¥é¡¼¤¬Â¿¤¯, ¤³¤ì¤é¤Îµ¡¹½¤Ç½¤Éü¤µ¤ì¤¿ºÙ˦¤Ë¤Ï¥²¥Î¥à¤ÎÊ£»¨¤ÊºÆ¹½À®¤¬À¸¤¸, ºÙ˦»à¤¬Í¶Æ³¤µ¤ì¤ë.

½¾Íè¤Î¹³¤¬¤óºÞ¤Î¼ðáç¸ú²Ì¤ÏDNA¤ò»½ý¤µ¤»ºÙ˦»à¤òͶƳ¤¹¤ë¤â¤Î¤Ç¤¢¤ê, BRCAÊѰۤʤɤˤè¤êDNA»½ý½¤Éüǽ¤¬Ä㤤ºÙ˦¤Ç¤Ï¹çÀ®Ã×»à(synthetic lethality)¤¬Í¶Æ³¤µ¤ì¤ä¤¹¤¤. ¼ÂºÝDNA»½ý½¤Éüǽ¤¬Ä㤤HBCO¤ÏDNA¾ã³²·¿¹³¤¬¤óºÞ(¥«¥ë¥Ü¥×¥é¥Á¥ó¤Ê¤É)¤Ë´¶¼õÀ­¤¬¹â¤¤¤³¤È¤¬ÌÀ¤é¤«¤Ë¤Ê¤Ã¤¿

PARPÁ˳²Ìô¤ÎPARP¤ËÂФ¹¤ëºîÍÑ

  1. PARP¹ÚÁdzèÀ­Á˳²; PARP¤ÎDNA°ìËܺ¿ÀÚÃǽ¤Éü¤òÁ˳²¤¹¤ë.
     
  2. PARP¤ÎDNA¤Ø¤Î¼è¤ê¹þ¤ß(PARP trapping); ½¤Éü¤Î¤¿¤áDNA»½ýÉô¤Ë¥ê¥¯¥ë¡¼¥È¤µ¤ì¤¿PARP¤¬DNA¤«¤éÍ·Î¥¤¹¤ë¤Î¤òÁ˳²¤¹¤ë. DNA-PARPÊ£¹çÂΤ¬Áý²Ã¤·DNA¤ò»½ý¤¹¤ë.
     
  • ­¡­¢¤ÎÁê²ÃŪ¤¢¤ë¤¤¤ÏÁê¾è¸ú²Ì¤Ë¤è¤ë¹³¼ðáç¸ú²Ì¤¬PARPÁ˳²ºÞ¤Î¸ú²Ì¤È¹Í¤¨¤é¤ì¤ë.

Þù±ÕÀ­ÍñÁ㤬¤ó¤Î¹çÀ®Ã×»àÎÅË¡--niraparib

Þù±ÕÀ­ÍñÁ㤬¤ó¤Î¥²¥Î¥à²òÀϤǤÏ, Ìó50%¤ËBRCA1¡¦2°äÅÁ»Ò, FanconiÉÏ·ì´ØÏ¢°äÅÁ»Ò, EMSY°äÅÁ»Ò, PTEN°äÅÁ»Ò¤Ê¤É¤Î°Û¾ï¤¬¤ß¤Ä¤«¤êDNA»½ý¤ÎHR½¤Éüµ¡¹½¤¬Äã²¼¤·¤Æ¤¤¤ë²ÄǽÀ­¤¬¼¨º¶¤µ¤ì, ¤³¤ì¤é¤ÎÍñÁ㤬¤ó¤Ë¤Ï, PARPÁ˳²Ìô, ¤¢¤ë¤¤¤Ï¥«¥ë¥Ü¥×¥é¥Á¥ó¤Ê¤É¤ÎÇò¶âÀ½ºÞ¤Ë¤è¤ë¼£ÎŤ¬Í­¸ú¤È¹Í¤¨¤é¤ì¤¿.

  • ÍñÁ㤬¤ó¤ÇÇò¶âÀ½ºÞ¤Ë´¶¼õÀ­¤ò¼¨¤·¤¿¤¬ºÆÈ¯¤·¤¿¾ÉÎã¤òBRCA°äÅÁ»ÒÊѰÛÍÛÀ­·²¤È±¢À­·²¤Ë¤ï¤±, ³Æ¡¹¤ò¤µ¤é¤Ë̵ºî°Ù²½¤·PARPÁ˳²Ìô niraparib¼£ÎÅ·²¤È¥×¥é¥·¡¼¥Ü·²¤Î̵Áý°­À¸Â¸´ü´Ö¤òÈæ³Ó¤¹¤ë¤ÈBRCA°äÅÁ»ÒÍÛÀ­·²¤Ç¤Îniraparib¼£ÎÅ·²¤¬Í¥°Ì¤Ë¤èÎɤ«¤Ã¤¿¤È¤¹¤ë·ë²Ì¤¬Êó¹ð¤µ¤ì¤¿. *26
  • BRCA°äÅÁ»ÒÊѰ۱¢À­·²¤Ç¤âniraparib¼£ÎÅ·²¤Ç̵Áý°­À¸Â¸´ü´Ö¤¬Îɤ«¤Ã¤¿¤¿¤á¤Ë¥²¥Î¥à¥ï¥¤¥É¤Ê²òÀϾðÊó¤Ç¤¢¤ëhomologous recombination deficiency(HRD)score¤òºîÀ®, ÁȤ߹þ¤ó¤À²òÀϤǤÏ, HRD scoreÍÛÀ­¤¬niraparib¼£ÎŤÎ̵Áý°­À¸Â¸´ü´Ö¤Î¤è¤¤»ØÉ¸¤Ë¤Ê¤ë¤È¼¨¤µ¤ì¤¿.*27
  • BRCA°äÅÁ»ÒÊѰ۱¢À­, HRD score±¢À­¤Ç¤âniraparibÍ­¸úÎ㤬¸ºß¤¹¤ë¤³¤È¤«¤éHRD score¤Ï¤Þ¤À²þÁ±¤Î;ÃϤ¬¤¢¤ë¤È¤µ¤ì¤Æ¤¤¤ë. *26

PARPÁ˳²Ìô¤ÎÂÑÀ­µ¡½ø¤È´¶¼õÀ­¾ÉÎã¤ÎÁªÄê

BRCA1¡¦2°äÅÁ»ÒÊѰۤ¬¤¢¤Ã¤Æ¤â, DNA»½ý½¤Éüµ¡Ç½¤¬Êݤ¿¤ì, PARPÁ˳²Ìô¤ËÄñ¹³À­¤ò¼¨¤¹¾ÉÎ㤬¤¢¤ë¤¿¤á, BRCA1¡¦2°äÅÁ»ÒÊѰÛÍÛÀ­Æý¤¬¤ó/ÍñÁ㤬¤ó¤òÂоݤȤ·¤¿PARPÁ˳²Ìô¤ÎÎ×¾²»î¸³¤Ï´üÂÔ¤·¤¿¤Û¤É¤Î¼£ÎŸú²Ì¤Ï¤¨¤é¤ì¤Ê¤«¤Ã¤¿.

  1. BRCAÊѰۤˤè¤ëµ¡Ç½¾Ã¼º¤ËÂФ·, BRCA¤ÎÆó¼¡ÅªÊѰۤˤè¤êÉôʬŪ¤ËDNA»½ý½¤Éüµ¡Ç½¤¬²óÉü¤·¤Æ¤¤¤ë.
     
  2. BRCAÊѰۤ˲䨤Æ53BP1¤äRNF168¤Î¾ã³²¤Ë¤è¤ëÉôʬŪ¤ËDNA»½ý½¤Éüµ¡Ç½¤¬²óÉü¤·¤Æ¤¤¤ë.
     
  3. PTIP¤Î¾ã³², CDH4, PARP¤Î²á¾êȯ¸½¤Ë¤è¤ëÊ£À½¥Õ¥©¡¼¥¯¤ÎÊݸî
     
    PÅü¥¿¥ó¥Ñ¥¯²á¾êȯ¸½¤Ë¤è¤ëÌôºÞÂÑÀ­¤Ê¤É

PARPÁ˳²Ìô´¶¼õÀ­¾ÉÎã¤ÎÁªÄêÊýË¡

£±¡¥recombination proficiency score(RPS)*28¡§ DNA»½ý½¤Éü¤Ë´Ø¤ï¤ë°äÅÁ»Ò¤ÎÃæ¤«¤é4¼ïÎà¤Î°äÅÁ»Ò(Rif1, PARI, RAD51, ¤ª¤è¤Ó Ku80)¤òÁª¤Ó°äÅÁ»Òȯ¸½Î̤òÍøÍѤ¹¤ë.

¤³¤ì¤é4¼ïÎà¤Î°äÅÁ»Òȯ¸½Î̤¬Â¿¤¤¾ì¹ç¤ò lowRPS¤È¤·, low RPS¼ðáç¤ÏÊѰ۸¶À­¤¬¹â¤¯, Î×¾²¾É¾õ¤¬¹âÅÙ¤ÇÄãÀ¸Â¸Î¨. HR¤ÎÍÞÀ©¤Ï¥²¥Î¥àÉÔ°ÂÄêÀ­¤ò¤è¤ê¶¯¤¯¤·¤Æ°­À­Å٤οʹԤò¤­¤¿¤¹¤È¿ä»¡¤µ¤ì¤ë.

£²¡¥homologous recomibination deficiency score(HRD): PARPÁ˳²Ìô¤Î´¶¼õÀ­Îã¤òÁªÊ̤¹¤ë¤¿¤á¤Ë¤¬¤óÁÈ¿¥¤ÎDNA»½ý½¤Éüµ¡Ç½¤ò¿ôÃͲ½¤·¤¿»ØÉ¸.*27

SNP¥¢¥ì¥¤¤È¥·¡¼¥¯¥¨¥ó¥¹µ»½Ñ¤òÁȤ߹ç¤ï¤»¤¿¾ðÊ󤫤饲¥Î¥à¤ÎºÆ¹½À®¤Î¾õÂÖ¤ò²òÀϤ·¤Æ

  1. loss of heterozygosity(HRD-LOH)¥¹¥³¥¢
  2. telomeric allelic imbalance(HRD-TAI)¥¹¥³¥¢
  3. largescale state transition(HRD-LST)¥¹¥³¥¢ ¤Î3¼ï¤ò»»½ÐÅý¹ç.

HRD¥¹¥³¥¢¤¬¹â¤¤(positive)¾ÉÎã¤ÏDNA½¤Éüǽ¤¬Ä㤯¡Ö´¶¼õÀ­¡×¤Ç¤¢¤ê, ¥¹¥³¥¢¤¬Ä㤤(negative)¾ÉÎã¤ÏDNA½¤Éüǽ¤¬°Ý»ý¤µ¤ì¤Æ¤¤¤ë¤¿¤á¤Ë¡ÖÄñ¹³À­¡×¤Ç¤¢¤ë²ÄǽÀ­¤ò¼¨¤¹.

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Âç¿¿ô¤ÎÆý´â¤Ï»¶È¯À­(>80%)¤Ç¤¢¤ê, ¿¤¯¤ÎÂκÙ˦À­°äÅÁŪÊѰۤÎÃßÀѤˤè¤êȯ¾É¤¹¤ë. ŵ·¿Åª¤ÊÆý´â¤Ï50¡Á80¤Î¼ï¡¹¤ÎÂκÙ˦ÊѰۤò¤â¤Ä¤ÈÊó¹ð¤µ¤ì¤Æ¤¤¤ë.*29*30

¤³¤ì¤Þ¤Ç¤Ë¿ôÉ´¤ÎÂκÙ˦À­Æý´â°äÅÁ»Ò¸õÊ䤬, GWAS¤Ê¤É¤Ë¤è¤êƱÄꤵ¤ì¤Æ¤¤¤ë.°äÅÁ»ÒÊѰۤ¬Æý´âȯ¾É¤Ë¤É¤Î¤è¤¦¤Êµ¡Ç½¤ò¤Ï¤¿¤·¤Æ¤¤¤ë¤«¤ò²òÀϤ¹¤ë¤³¤È¤¬º£¸å¤Î²ÝÂê¤Ç¤¢¤ë¤¬, ¤³¤ì¤Þ¤Ç¤ËƱÄꤵ¤ì¤¿DNAÊѰۤΠ¿¤¯¤Ï¥Ñ¥Ã¥»¥ó¥¸¥ã¡¼(passenger)ÊѰۤǤ¢¤êȯ¤¬¤ó¤Ë±Æ¶Á¤ò¤¢¤¿¤¨¤Æ¤¤¤Ê¤¤.*29*30

ºÙ˦Áý¿£¤òÂ¥¿Ê¤·È¯¤¬¤ó¤Ë´Ø·¸¤¹¤ë¥É¥é¥¤¥Ð¡¼(driver)°äÅÁ»Ò¤ÏÄêµÁ¾å, ¸õÊ䤬¤ó°äÅÁ»Ò(candidate cancer gene;CAN)¤Ë´Þ¤Þ¤ì¤ë.*31

ÂκÙ˦ÊѰۤÈCAN¤ÎÌÖÍåŪÌÜÏ¿¤¬ÃßÀѤµ¤ì¤Æ¤ª¤ê, ÆÃÄê¤Î¥É¥é¥¤¥Ð¡¼ÊѰۤ¬Ê£¿ô¤ÎÆý´â½¸ÃÄÃæ¤ËƱÄꤵ¤ì, ÆóÁØÀ­¤Î°äÅÁ³ØÅªÐíâ׿Þ(genetic landscape)¤¬¼¨¤µ¤ì¤ë.(±¦¿Þ;¿Þ¤Ïcolorectal cancer¤Î¤â¤Î.*30.); ¾¯¿ô¤Î¹âÉÑÅÙÊѰۤ¬¤Ä¤¯¤ë¡Ö»³¡×¤È¿ôÉ´¤Î¤Þ¤ì¤ÊÊѰۤ¬·ÁÀ®¤¹¤ë¡ÖµÖ¡×¤«¤é¹½À®¤µ¤ì¤ë.

Æý´â¤Ç¤Î¡Ö»³¡×¤Ï, TP53, CDH1, PI3K, AKT, cyclinD, PTEN¤Ê¤É¤Î¹âÉÑÅÙÊѰ۰äÅÁ»Ò¤ËÂбþ¤·¤Æ¤¤¤ë. °ìÊý, Æý´â¤Ç¤Î¡ÖµÖ¡×¤Ï, ŵ·¿Åª¤Ë¤ÏÆý´â¤Î5%°Ê²¼¤Ëǧ¤á¤é¤ì¤ë*13.
¤³¤ì¤é¤ÎÆý´â¤ÎDNAÊѰÛ¿ÍÍÀ­¤Ï, ¼ðáç¤ÎÀ­¾õ¤ä¼£ÎÅÈ¿±þÀ­¤Ê¤É¤Îɽ¸½·¿¤Î¿ÍÍÀ­¤Î¸¶°ø¤È¤Ê¤ë²ÄǽÀ­¤¬¤¢¤ë.*32

 

¡ú¡Ö»³¡×¤ËÃíÌܤ·¤¿°äÅÁ»Ò²òÀϤ¬¤ª¤³¤Ê¤ï¤ì¤Æ¤­¤¿¤¬, ºÇ¶á¤Î²òÀÏ·ë²Ì¤Ç¤Ï, Æý´â¤Ç¤è¤ê½ÅÍפÊÌò³ä¤ò²Ì¤¿¤·¤Æ¤¤¤ë¤Î¤Ï¡ÖµÖ¡×¤Î°äÅÁ»Ò¤Ç¤¢¤ê, ¤ï¤º¤«¤ÊÀ¸Â¸Í¥°ÌÀ­¤ò¤â¤Ã¤¿¸Ä¡¹¤ÎÊѰۤò¿¿ô³ÍÆÀ¤¹¤ë¤³¤È¤¬¼ðáç¤Î¿ÊŸ¤òÂ¥¿Ê¤¹¤ë¤È¹Í¤¨¤é¤ì¤ë¤è¤¦¤Ë¤Ê¤Ã¤¿.

¡ÖµÖ¡×¤ò¹½À®¤¹¤ëÄãÉÑÅÙ¤ÎÊѰۤο¤¯¤Ï, Æý´âȯ¾É¤Ë¤«¤«¤ï¤ë¾¯¿ô¤ÎÀ¸Êª³ØÅª¥°¥ë¡¼¥×¤¢¤ë¤¤¤ÏºÙ˦¥·¥°¥Ê¥ëÅÁã·ÐÏ©¤Ø¤È½¸Ìó¤Ç¤­, genetic landscape¤ÎÊ£»¨À­¤ÏÂçÉý¤Ëñ½ã²½¤µ¤ì¤ë¤è¤¦¤Ë¤Ê¤Ã¤¿. ¸Ä¡¹¤ÎÊѰۤè¤ê¶¦Ä̤¹¤ë·ÐÏ©¤¬Æý´â¤ÎȯÀ¸²áÄø¤òÀ©¸æ¤·¤Æ¤¤¤ë¤È¤¤¤¨¤ë.*32

  • ¥¤¥ó¥¿¡¼¥Õ¥§¥í¥ó¥·¥°¥Ê¥ë·ÐÏ©
  • ºÙ˦¼þ´ü¥Á¥§¥Ã¥¯¥Ý¥¤¥ó¥È
  • BRCA1/BRCA2´ØÏ¢DNA½¤Éü
  • p53
  • AKT
  • transforming growth factor receptor-¦Â(TGF-¦Â)¥·¥°¥Ê¥ë·ÐÏ©
  • Notch
  • EGFR
  • FGF
  • ERBB2/ Her2
  • RAS
  • PI3K
     

Æý´â¤Ç¤ÏÈ¿ÉüÀ­¤ÎÅÀÊѰۤϾ¤Î¸Ç·Á¼ðáç¤ÈÈæ¤Ù¤Æ¾¯¤Ê¤¤¤¬, ¥²¥Î¥à¤ÎÆÃÄêÎΰ褬¤·¤Ð¤·¤ÐÁýÉý¤·¤Æ¤ª¤ê, ¤½¤Î¤è¤¦¤ÊÎΰè¤Ç¤Ï¤¬¤ó¤Î¿ÊŸ¤òÂ¥¿Ê¤¹¤ë°äÅÁ»Ò¤¬´Þ¤Þ¤ì¤Æ¤¤¤ë.(ie. HER2¤¬¤ó°äÅÁ»Ò¤ò´Þ¤à17q12 )

HER2¤¬¤ó°äÅÁ»Ò¤ò´Þ¤à17q12;Îΰè¤ÏÁýÉý¤¹¤ë¤È°­À­ÅÙ¤¬¹â¤Þ¤ê¹³ÂÎÎÅË¡¤Ç¤¢¤ëtrastuzmab;Herceptin¤ÎɸŪ¤È¤Ê¤Ã¤Æ¤¤¤ë
17q12Æâ¤Ç°ì½ï¤ËÁýÉý¤µ¤ì¤Æ¤¤¤ë°äÅÁ»Ò¤òRNAi¤Çknockdown¤¹¤ë¤ÈºÙ˦Áý¿£¤ÏÍÞÀ©¤µ¤ì¥¢¥Ý¥È¡¼¥·¥¹¤¬Ð¶¿Ê¤¹¤ë.
17q12ÁýÉýÎΰè¤Ï¤¬¤ó²½¤Ë¤«¤«¤ï¤ë¶¨Ä´Åª¤Ê°äÅÁŪ¥×¥í¥°¥é¥à¤ò¥³¡¼¥É¤·¤Æ¤¤¤ë¤È¹Í¤¨¤é¤ì¤ë.*33

17q12°Ê³°¤Ë, 11q13(CCND1), 8q24(MYC), 20q13¤Ê¤É¤ÎÁýÉýÎΰ褬¤¬¤ó·Á¼Á¤òÂ¥¿Ê¤·Æý´â¤Îͽ¸å¤ò·èÄꤹ¤ë¤È¹Í¤¨¤é¤ì¤ë*34.
¤³¤ì¤é¤ÎÎΰè¤Ë¤Ï, DNAÂå¼Õ¤äÀ÷¿§Âδ°Á´À­(chromosomal integrity)¤Î°Ý»ý¤ËɬÍפʰäÅÁ»Ò¤¬´Þ¤Þ¤ì, ¹³¤¬¤ó¼£ÎŤ˻ÈÍѤµ¤ì¤ëDNA¾ã³²À­Ìôʪ¤Ø¤Î±þÅúÀ­¤¬ÆÃÄê¤ÎÁýÉýÎΰè¤Ë¤è¤ê±Æ¶Á¤µ¤ì¤Æ¤¤¤ë²ÄǽÀ­¤¬¤¢¤ë.*35*36

  • ¤³¤ì¤é¤ÎÁýÉýÎΰè¤ÏHER2¤ÎÁýÉý¤·¤¿¼ðáç¤ÇÉÑÅÙ¤¬¹â¤¯¼ðáçÀ­¾õ¤È´µ¼Ô¤µ¤ó¤Îͽ¸å¤Ë±Æ¶Á¤·¤Æ¤¤¤ë¤«¤â¤·¤ì¤Ê¤¤.
  • ¤³¤ì¤é¤Î°äÅÁŪ°Û¾ï¤Îµ¡Ç½Åª±Æ¶Á¤Ï¸Ä¡¹¤Î°äÅÁ»Ò¤Îȯ¸½²á¾ê¤è¤ê¤â, ÁýÉýÎΰè¤Ë´Þ¤Þ¤ì¤ë°äÅÁ»Ò¤ÎÁȤ߹ç¤ï¤»¤Ë¤è¤ë¤È¤³¤í¤¬Â礭¤¤¤Î¤«¤â¤·¤ì¤Ê¤¤.

¿ôÉ´¤«¤é¿ôÀé¤ÎmRNA¤òƱ»þ¤Ëɾ²Á¤¹¤ëµ»½Ñ¤Î³«È¯¤Ë¤è¤ê, °Û¾ï¤ÊDNA¤«¤éž¼Ì¤µ¤ì¤¿ mRNAs¤Îȯ¸½¥Ñ¥¿¡¼¥ó¤«¤é³èÀ­²½¤µ¤ì¤¿¥×¥í¥°¥é¥à¤ä¼ðáç¤ÎÀ­¼Á¤òͽ¬¤¹¤ë¤³¤È¤¬²Äǽ¤È¤Ê¤Ã¤¿(ʬ»Ò¥·¥°¥Í¥Á¥ã¡¼)---> Æý´â¤Îʬ»ÒʬÎà


*1  Bell DW. Our changing view of the genomic landscape of cancer.J Pathol. 2010 Jan;220(2):231-43.PMID:19918804
*2  Wood LD, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007 Nov 16;318(5853):1108-13. PMID:17932254
*3  Olopade O,et al. Advances in breast cancer: pathways to personalized medicine. Clin Cancer Res. 2008 Dec 15;14(24):7988-99.PMID:19088015
*4  Turnbull C, Rahman N. Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet. 2008;9:321-45.PMID:18544032
*5  Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med. 2008 Nov 13;359(20):2143-53.PMID:19005198
*6  Turnbull C, Rahman N. Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet. 2008;9:321-45.PMID:18544032
*7  Win AK, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012 Mar 20;30(9):958-64.PMID:22331944
*8  Win AK, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012 Mar 20;30(9):958-64.PMID:22331944
*9  13¤Î¸¦µæ¤Ç¤Ï¥ê¥¹¥¯Áý²Ã¤Ï¤ß¤é¤ì¤Ê¤«¤Ã¤¿, °ìÊý, 8¤Ä¤Î¸¦µæ¤Ç¤Ï°ìÈ̽¸ÃĤÎ2¡Á18ÇܤΥꥹ¥¯¤ÎÁý²Ã¤¬¤ß¤é¤ì¤¿¤È¤µ¤ì¤Æ¤¤¤ë&note{Win01:Win AK, et al. Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Res. 2013 Mar 19;15(2):R27. . PMID:23510156
*10  Xu Q, et al. Pre-miR-27a rs895819A/G polymorphisms in cancer: a meta-analysis. PLoS One. 2013 Jun 7;8(6):e65208. PMID:23762318
*11  Hoffman AE, et al. microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis. Cancer Res. 2009 Jul 15;69(14):5970-7.PMID:19567675
*12  Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med. 2008 Nov 13;359(20):2143-53.PMID:19005198
*13  Hirshfield KM, et al. Germline mutations and polymorphisms in the origins of cancers in women. J Oncol. 2010;2010:297671.PMID:20111735
*14  Narod SA. Modifiers of risk of hereditary breast cancer.Oncogene. 2006 Sep 25;25(43):5832-6.PMID:16998497
*15  Turner NC, Reis-Filho JS.¡¡Basal-like breast cancer and the BRCA1 phenotype. Oncogene. 2006 Sep 25;25(43):5846-53.PMID:16998499
*16  Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002 Jan 25;108(2):171-82. PMID:11832208
*17  Copson ER, et al.Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.Lancet Oncol. 2018 Feb;19(2):169-180.PMID 29337092
*18  Venkitaraman AR.Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002 Jan 25;108(2):171-82.
*19  Xia B, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006 Jun 23;22(6):719-29.
*20  Zhang F, et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 2009 Mar 24;19(6):524-9.
*21  »°ÌÚµÁÃË BRCA°äÅÁ»Ò¤Î´ðÁäȹçÀ®Ã×»àÎÅË¡¤Î³«È¯¤Ë¤à¤±¤Æ¡¡°å³Ø¤Î¤¢¤æ¤ß 2017;261(5):423-428
*22  Ciccia A, et al, The DNA damage response: making it safe to play with knives. Mol Cell. 2010 Oct 22;40(2):179-204.
*23  Ceccaldi R, et al. Repair Pathway Choices and Consequences at the Double-Strand Break.Trends Cell Biol. 2016 Jan;26(1):52-64.
*24  ½ÂëÀµ»Ë¤Û¤«ÊÔ½¸¡¡¤¬¤óÀ¸Êª³Ø¥¤¥é¥¹¥È¥ì¥¤¥Æ¥Ã¥É2011;155-157, ÍÓÅÚ¼Ò Åìµþ
*25  Konecny GE, Kristeleit RS, PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br J Cancer. 2016 Nov 8;115(10):1157-1173.
*26  Mirza MR, et al., Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016 Dec 1;375(22):2154-2164.
*27  Timms KM, et al., Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes.Breast Cancer Res. 2014 Dec 5;16(6):475.
*28  Pitroda SP, et al., DNA repair pathway gene expression score correlates with repair proficiency and tumor sensitivity to chemotherapy. Sci Transl Med. 2014 Mar 26;6(229):229ra42.
*29  Bell DW. Our changing view of the genomic landscape of cancer.J Pathol. 2010 Jan;220(2):231-43.PMID:19918804
*30  Wood LD, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007 Nov 16;318(5853):1108-13. PMID:17932254
*31  Stratton MR, et al. The cancer genome. Nature. 2009 Apr 9;458(7239):719-24. PMID:19360079
*32  Copeland NG, Jenkins NA. Deciphering the genetic landscape of cancer--from genes to pathways.Trends Genet. 2009 Oct;25(10):455-62.
*33  Kao J, Pollack JR. RNA interference-based functional dissection of the 17q12 amplicon in breast cancer reveals contribution of coamplified genes.Genes Chromosomes Cancer. 2006 Aug;45(8):761-9.PMID:16708353
*34  Chin K, et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell. 2006 Dec;10(6):529-41.PMID:17157792
*35  Bentires-Alj M, et al. A role for the scaffolding adapter GAB2 in breast cancer.Nat Med. 2006 Jan;12(1):114-21. PMID:16369543
*36  Yu Q, et al. Requirement for CDK4 kinase function in breast cancer.Cancer Cell. 2006 Jan;9(1):23-32. PMID:16413469 Comment in Is Cyclin D1-CDK4 kinase a bona fide cancer target? [Cancer Cell. 2006]

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