Re vi ew ᢸᙜ ୰ᓥ೺䠈୰ᒣెᏊ

Cancer Scr eening R ec o mmenda tions and Clinic al Manag emen t of Inherit ed G ast ro in te st in al Cancer Syndr omes in Childhood Acha tz MI, Po rt er CC , Brugi!er es L, Druk er H, Fr ebour g T, Fo u lk es W D , Kr at z C P, Ku ip er RP , Hans for d JR, Hernand ez HS, Na thanson KL , Ko h lm an n W K , Dor os L, Onel K, Schneider KW , Sc ollon SR, Ta b o ri U , To mlinson GE,E va ns DGR, Plon SE

CCR PEDIATRIC ONCOLOGY SERIES

Re vi ew ᢸᙜ ୰ᓥ೺䠈୰ᒣెᏊ

2017ᖺ10᭶29᪥⇃ᮏ⌜➨2ᅇ⌜఍㆟

㈨ᩱ㻝㻟㻚㻌㻯㼍㼚㼏㼑㼞㻌㻿㼏㼞㼑㼑㼚㼕㼚㼓㻌㻾㼑㼏㼛㼙㼙㼑㼚㼐㼍㼠㼕㼛㼚㼟㻌㼍㼚㼐㻌㻯㼘㼕㼚㼕㼏㼍㼘㻌㻹㼍㼚㼍㼓㼑㼙㼑㼚㼠㻌㼛㼒㻌㻵㼚㼔㼑㼞㼕㼠㼑㼐㻌 㻳㼍㼟㼠㼞㼛㼕㼚㼠㼑㼟㼠㼕㼚㼍㼘㻌㻯㼍㼚㼏㼑㼞㻌㻿㼥㼚㼐㼞㼛㼙㼑㼟㻌㼕㼚㻌㻯㼔㼕㼘㼐㼔㼛㼛㼐䛾䝺䝡䝳䞊䝽䞊䜽

䛿䛨䜑䛻 The hereditary gastrointestinal cancer syndromes ha ve tr aditionally been divided into two categories 1. substantial number of gastrointestinal polyps [e.g. , familial adenomatous polyposis (F AP)] 2. those that predominantly present with a cancer phenotype and a smaller number of polyps (e.g. , constitutional mismatch repair deficiency syndrome)

䝸䞁䝏⑕ೃ⩌䛿᝿ᐃ䛧䛶䛔䛺䛔䠛

ศ㢮䛿䜋䜌ྠ䛨 9 2016 ᖺ⛅ ᨵゞ䛥䜜䛯 9 ௒ᅇ䛾⇃ᮏ⌜䛷䛿䚸 FA P 䛸 LS 䛻㛵䛧䛶䛿䚸䛣䛱䜙䛸䛾ᩚ ྜᛶ䜒☜ㄆ䛜ᚲせ ኱⭠⒴◊✲఍ ᐙ᪘ᛶ኱⭠⒴ጤဨ఍⦅ 㑇ఏᛶ኱⭠⒴デ⒪䜺䜲䝗䝷䜲䞁䠄㻳㻸䠅

FA P Familial adenoma tous polyposis ᐙ᪘ᛶ⭢⭘ᛶ䝫䝸䝫䞊䝅䝇 ᐙ᪘ᛶ኱⭠⭢⭘⑕ ᑠඣ៏ᛶ≉ᐃ⑌⑓䛻ㄆᐃ῭䜏 ➨ 4 ḟᣦᐃ㞴⑓䛻⏦ㄳ୰ 䠘䠘䠘䛜䜣䛸䛾㛵㐃䛷䛣䜜䜎䛷ㄆᐃ䛥䜜䛪

FA P „ ⑌ᝈᴫせ 䞉 APC 㑇ఏᏊ䛾⏕Ṫ⣽⬊⣔ิኚ␗䛻㉳ᅉ䛩䜛ᖖᰁⰍయඃᛶ㑇ఏ ᛶ⑌ᝈ 䞉 UK 䛻䛚䛡䜛᭷⑓⋡䛿 1/9,000 ࠥ 18,000 䠈䠄ᅜෆᝈ⪅ᩘ䛿⣙ 7,000 ே ?) 䞉ⱝᖺ䠄㏻ᖖ 10 ṓ௦䠈᭱ᖺᑡ 8 䛛᭶䠅䛛䜙ከᩘ䛾኱⭠⭢⭘䜢ㄆ䜑䚸 ኱⭠䛜䜣䛾䝸䝇䜽䛜㧗䛔 䞉኱⭠඲᦬⾡䜢⾜䛺䜟䛺䛔䛸ᖹᆒ 39 ṓ䛷኱⭠䛜䜣䜢ྜే䛩䜛䚸⛥ 䛻ᑠඣ䜔ᛮ᫓ᮇ䛾኱⭠䛜䜣ྜే౛䜒䛒䜛 䞉ᑠඣᮇ䛻༑஧ᣦ⭠䠈✵⭠䠈⫶䛾䝫䝸䞊䝥䜢క䛖 䞉༑஧ᣦ⭠䛜䜣 䠄ங㢌㒊⭘⒆䜢ྵ䜐䠅 䛿኱⭠䛜䜣䛻ḟ䛔䛷㢖ᗘ䛾 ከ䛔ᾘ໬⟶⭘⒆ 䛚䜘䛭 10 ಶ ௨ୖ䛾䝫䝸䞊䝥 䜒䛱䜝䜣㏞䛖⑕౛䜒䛒䜚䜎䛩

FA P „ ⑌ᝈᴫせ 䞉Ⰻᛶ⭘⒆䛷䛒䜛⭡⭍ 䝕䝇䝰䜲䝗 ⭘⒆䛿⾡ᚋ෌Ⓨ⋡䛜㧗䛟኱⭠䛜䜣 䛻ḟ䛠Ṛᅉ䛸䛺䛳䛶䛔䜛 䞉ᏙⓎ䛾䝕䝇䝰䜲䝗⭘⒆䛷䛿య⣽⬊䛾 CTNNB1 ኚ␗䜢ㄆ䜑䜛䛣䛸䛜 ከ䛟䠈 FA P 䛻క䛖䝕䝇䝰䜲䝗⭘⒆䛸䛾㚷ู䛾ཧ⪃䛻䛺䜛 䞉ᑠඣᮇ䛻 nuchal type fibroma 䠄䛖䛺䛨䠷ୖ⫼㒊䜢ྵ䜐䠹䛾⥺⥔⭘䠅 䠄 Gardner -associated fibroma: GAF 䠅䜢ྜే䛩䜛䛣䛸䛜䛒䜛 > GAF 䜢ᣢ䛴ᑠඣ䛿䜎䛪䚸 APC 㑇ఏᏊ᳨ᰝ䛜່䜑䜙䜜䜛 . FA P

„⑌ᝈᴫせ 䞉ඛኳᛶ⥙⥙⭷Ⰽ⣲ୖ⓶⭘኱䠄congenital hypertrophy of the retinal pigment epithelium: CHRPE䠅䠈㐣๫ṑ䞉ᇙἐ ṑ䠈㦵⭘䠈⓶⭵ᄞ⬊䠈㌾㒊⭘⒆䛾ྜే䛜䛒䜛

‡ ඛኳᛶ⥙⭷Ⰽ⣲ୖ⓶⫧኱䛿⥙⭷ୖ䛾୙㐃⥆ᖹᆠ䛺Ⰽ⣲ᛶ⑓ኚ䛷䠈 ⮫ᗋ⑕≧䛿䛺䛟 ἞⒪䛾ᚲせ䛿䛺䛔 䚹 ‡ どຊ䛻ᙳ㡪䛿䛺䛟䠈ᝏᛶ໬䜒䛧䛺䛔䚹 ‡ FA P ᝈ⪅䛾⣙ 80% 䛻ྜే䛧 , ⏕ୗ᫬䜘䜚ㄆ䜑䜛䛣䛸䛛䜙䠈ᑠඣ䛺䛹 䛾 FA P ⿵ຓデ᩿䛻᭷⏝ 䛷䛒䜛䚹 䕔ඛኳᛶ⥙⭷Ⰽ⣲ୖ⓶⫧኱ Congenital h ypertroph y of

the retinal pigment epithelium:

CHRPE

FA P „ ⑌ᝈᴫせ 䞉 FA P 䛿 3 ṓ䜎䛷䛻 ⫢ⱆ⭘ 䛾ྜే䛜 0.3 ࠥ 1.6% 䛒䜛 9 Aretz S , et al, P ediatr Blood Cancer 2006; 47:811–8. 9 Giardiello FM, et al. J P ediatr 1991;119:766–8. ‡ ⫢ⱆ⭘䛾 10% 䛻 APC ኚ␗䜢ㄆ䜑䠈䜎䛯 FA P 䛾ᐙ᪘Ṕ䛿䛺䛔䛣䛸䜒 . ⭘⒆䛾 CTNNB1 䛾≉䛻䜶䜽䝋䞁 3 䛾య⣽⬊ኚ␗䜎䛯䛿 in- fr ame deletions 䛜 APC ኚ␗䛻䜘䜛⫢ⱆ⭘䛸䛾༊ู䛻ᙺ❧䛴 ‡ FA P 䛾ᑠඣ䛾 0.42 ࠥ 0.75 䠂䛻⫢ⱆ⭘䛜Ⓨ⏕䛩䜛䛸᥎ᐃ䛥䜜䛶䛔䜛 ‡ デ᩿䛿⭡㒊㉸㡢Ἴ䛺䛹⏬ീ᳨ᰝ䛷⾜䜟䜜 , 90% 䛾ᝈ⪅䛷 Į - 䝣䜵䝖 䝥䝻䝔䜲䞁 (AFP) 㧗್ 䛜䜏䜙䜜䜛 159 䠅 Hughes L J, Michels VV : Risk of hepatoblastoma in familial adenomatous polyposis. Am J Med Genet 1992; 43: 1023—1025 FA P

„⑌ᝈᴫせ 䞉ᑠඣᮇ䛾୰ᯡ⚄⤒⣔⭘⒆䠄≉䛻WNT㧊ⱆ⭘䠅䛾ྜే䛜䛒䜛 䠄1%ᮍ‶䠅 䞉⏥≧⭢ங㢌䛜䜣䠄cribriform-morulavariantᆺ䠖⠠ᆺளᆺ䠅䛾⏕ᾭⓎ⑕䝸䝇䜽䛿2 ࠥ7䠂䠈20ࠥ30ṓ௦ዪᛶ䛻ከ䛔 䞉Gardenr⑕ೃ⩌䛿FAP䛻㦵⭘䠈㌾㒊⭘⒆䠄㢮ୖ⓶ᄞ⬊䠈⥺⥔ ⭘䠈䝕䝇䝰䜲䝗୺せ䠅䜢ྜే䛧䛯⑓ᆺ 䞉Turcot⑕ೃ⩌䛿FAP䛻୰ᯡ⚄⤒⣔⭘⒆䜢ྜే䛧䛯⑓ᆺ

FA P Ͳ ge n et ic s „ Classical F A P 䛾 90% 䛻ᶵ⬟Ḟኻᆺኚ␗䠄䝘䞁䝉䞁䝇䜎䛯 䛿䝣䝺䞊䝮䝅䝣䝖䠅䛜ྠᐃ䛥䜜䜛 „ FA P ᝈ⪅䛾 75 ࠥ 80% 䛿ぶ䛛䜙䛾㑇ఏ䛷䛒䜛 „ de novo 䛾 FA P ᝈ⪅䛾 20% 䛿య⣽⬊䝰䝄䜲䜽ኚ␗䛻䜘䜛 „ 1B promoter 㡿ᇦ䛾ኚ␗䛜⛥䛻䛒䜛 „ ᮏ⑌ᝈ䛜⮫ᗋⓗ䛻␲䜟䜜䜛⑕౛䛾䛚䜘䛭 10% 䛷㑇ఏᏊデ ᩿䛷ኚ␗䜢ྠᐃ䛷䛺䛔䛸᥎ᐃ䛥䜜䜛 „ ᮏ⑌ᝈ䛜␲䜟䜜䜛⑕౛䠄⥙⭷ᡤぢ䜎䛯䛿 cribriform- morula v ariant ᆺ⏥≧⭢ங㢌䛜䜣䛜䛒䜚ᶵ⬟䛻ᙳ㡪䛩䜛 APC ኚ␗䛾䛺䛔⑕౛䜢ྵ䜐䠅䠈䛷䛿 10 ṓ௦䛷኱⭠ෆど㙾᳨ ᰝ䛾᪋⾜䜢᳨ウ䛩䜛

FA P : ge notype/phenotype co rr el at io n s „ Classical F A P 䛻ẚ㍑䛧䛶㐜Ⓨᛶ䛻Ⓨ⑕䛧䝫䝸䝫䞊䝅䝇䛜㍍⑕ 䛺 attenuated F A P(AF AP) 䛷䛿 APC 㑇ఏᏊ䛾䜶䜽䝋䞁 9 䠈 5’ 䜎 䛯䛿 3’ ᮎ➃䛾䝞䝸䜰䞁䝖䛜ሗ࿌䛥䜜䛶䛔䜛 „ 䝕䝇䝰䜲䝗⭘⒆䛿⏕Ṫ⣽⬊⣔ิ䛾 Codon543-713 䠈 Codon1310-2011 䛾ኚ␗䛷Ⓨ⑕䝸䝇䜽䛜㧗䛔 „ ⫢ⱆ⭘䛾Ⓨ⑕䛸㛵㐃䛩䜛㑇ఏᆺ䛾ሗ࿌䛿䛺䛔 (No region in the APC gene specifically correlates with the dev elopment of hepatoblastoma in F A P families,as mutations throughout the gene ha ve been described in these children) „ Genotype 䛻䜘䜛⟶⌮ᣦ㔪䛿 contro ve rsial 䛷䛒䜛

FIG. 1. Genot ype–phenot ype correlations of extr a-intestinal familial adenomatous polyposis (F AP) manifestations according to the av ailable liter ature. No genot ype–phenot ype correlations ha ve been established for pancreatic carcinoma, br ain tumors or adrenal gland adenomas. CHRPE congenital h ypertroph y of the retinal pigment epithelium. E. J . Groen

et al

. Annals of Surgical Oncology 15(9):2439–2450 FA P : Cancer scr eening /sur veillance pr ot oc ol

SyndromeTumorPediatricsurveillanceFrequency 䠄Startingage;Frequency) FAPColorectalcancer UpperGIcancer Papillarythyroid cancer Hepatoblastoma Desmoidtumor Medulloblastoma

Flexiblesigmoidoscopy orCS EGD Paltipation(&US) US&serumAFP Physicalexamination (abdominopelvicMRI*) Physicalexamination

10–15y;annually 20Ͳ25y; 15–19y;annually EarlyinfantͲ;every4Ͳ6 monthsuntil7y Followingcolectomyor othersurgery;1Ͳ3years Childhood;annually Attenuated FAPColorectumCS15–19y;every2Ͳ3years untiladenomasare detected,atwhichtime frequencyincreasedto annually *ACG䛾GL䛷䛿ᐃᮇⓗ䛺⏬ീ᳨ᰝ䜢᥎ዡ䛧䛶䛔䛺䛔䛜䠈ᙜWS䛷䛿䝕䝇䝰䜲䝗⭘⒆䛾 ᐙ᪘Ṕ䛾䛒䜛⑕౛䛻䠈኱⭠඲᦬ᚋ䛿1~3ᖺẖ䠈䛭䛾ᚋ5~10ᖺẖ䛾MRI䜢ᥦ᱌䛩䜛

኱⭠⒴ண㜵䛾እ⛉἞⒪䜸䝥䝅䝵䞁 „ To tal abdominal colectom y with endo ileorectal anastomosis (T AC/IRA) „ To tal proctocolectom y with end ileostom y 䠄 TPC/EI) „ To tal proctocolectom y with ileal puch- anal anastomosis(TPC/IP AA) ⾡ᘧ䛾㑅ᢥ䛿⑓ែ䛸ᝈ⪅䛾ዲ䜏䜢⪃៖䛧䛶Ỵᐃ䛩䜛 䝕䝇䝰䜲䝗⭘⒆䛾䝝䜲䝸䝇䜽ኚ␗䜢᭷䛩䜛⑕౛䛿䠈ᡭ⾡䛾᫬ᮇ䛿㐜䛟䠈 ୍ᮇⓗ䛻⾜䛺䛖䛣䛸䛜⌮᝿䛷䛒䜛

CQ5䠖FAP䛾኱⭠⒴䛻ᑐ䛩䜛ண㜵ⓗ኱⭠ษ㝖䛜᥎ዡ䛥䜜䜛ᖺ㱋䛿䠛 ኱⭠⒴䛾᭷⑓⋡䛾Ⅼ䛛䜙䠈඾ᆺⓗFAP䛷䛿᪩䛡䜜䜀10ṓ௦ᚋᮇ䛛䜙䠈 ከ䛟䛿20ṓ௦䛻ᡭ⾡䜢ཷ䛡䜛䛣䛸䛜᥎ዡ䛥䜜䛶䛔䜛

FA P : chemopr ev en tion „ ᢠ⅖⑕⸆䜔㞴ᾘ໬ᛶ䝕䞁䝥䞁䛾◊✲䛜䛒䜛䛜䠈Ⓨ⒴䝸䝇䜽䜢ᅇ 㑊䛷䛝䜛䜶䝡䝕䞁䝇䛿༑ศ䛷䛿䛺䛔

FA P : ge netic co unseling consider at ions

„FAP䛾䝸䝇䜽䛾䛒䜛ᑠඣ䛻䛚䛡䜛㑇ఏᏊ᳨ᰝ䛾䝍䜲䝭䞁䜾䛿㆟ㄽ䛜䛒䜛䠊 „10ṓ䛻䛺䜛๓䛾㑇ఏᏊ᳨ᰝ䛷䛿௨ୗ䜢⪃៖䛩䜛 䞉デ⒪䛻┤᥋ᙳ㡪䛜䛒䜛䛛䠄౛䠖⫢ⱆ⭘䛾䝇䜽䝸䞊䝙䞁䜾䠅 䞉ᐙ᪘䛾ᕼᮃ 䞉clinician practice

FA P 䛸ඹ䛻⏕䛝䜛䛣䛸䛿ᚰ⌮♫఍ⓗᙳ㡪䛜኱䛝䛔 ໟᣓⓗ䛺㑇ఏ䜹䜴䞁䝉䝸䞁䜾䛜㔜せ 㑇ఏ䜹䜴䞁䝉䝷䞊䛸䝯䞁䝍䝹䝦䝹䝇䜹䜴䞁䝉䝷䞊䛾㛗ᮇ䝣䜷䝻䞊䛜ᚲせ

9 FA P 䛾⾑⦕⪅䛻ᑐ䛩䜛㑇ఏᏛⓗ᳨ᰝ䜔デ᩿ⓗ᳨ᰝ䠄ୗ㒊ᾘ໬⟶ෆ ど㙾᳨ᰝ䠅䛷䛿䠈ᮍᡂᖺ⪅䛜ᑐ㇟䛸䛺䜛䛣䛸䛜ẚ㍑ⓗከ䛔䚹 9 ᮍᡂᖺ⪅䛻ᑐ䛩䜛䛣䜜䜙䛾᳨ᰝ䜢ᐇ᪋䛩䜛ୖ䛷䛿䠈௦ㅙ⪅䛛䜙䛾 ྠព䛰䛡䛷䛺䛟䠈⿕㦂⪅䛾⌮ゎᗘ䛻ᛂ䛨䛯ㄝ᫂䜢⾜䛔䠈ᮏே䛾஢ゎ 䠄 䜲䞁䝣䜷䞊䝮䝗䞉䜰䝉䞁䝖 䠅䜢ᚓ䜛䛣䛸䛜ᮃ䜎䛧䛔䚹 9 ⾑⦕⪅䛻ᑐ䛩䜛㑇ఏᏛⓗ᳨ᰝ䛷䛿䠈ྠ⬊ෆ䛷␗䛺䜛⤖ᯝ䠄ኚ␗ಖ ᣢ⪅䛸ኚ␗䜢ಖᣢ䛧䛶䛔䛺䛔⪅䠅䛸䛺䜛ሙྜ䛜䛒䜛䚹 9 ኚ␗䜢ཷ䛡⥅䛜䛺䛛䛳䛯䜒䛾䛜ཷ䛡⥅䛔䛰䜒䛾䛻ᑐ䛧䛶䛂⮬ศ䛰䛡 䛜ຓ䛛䛳䛶䛧䜎䛳䛶⏦䛧ヂ䛺䛔䛃䛺䛹⮬㈐䛾ᛕ䠄 surviv or guilt 䠅䜢 ᢪ䛟䛣䛸䛜䛒䜚䠈㑇ఏ䜹䜴䞁䝉䝸䞁䜾䛷䛿䠈ኚ␗䜢ཷ䛡⥅䛜䛺䛛䛳䛯 ᐙ᪘䛻ᑐ䛧䛶䜒ᚰ䛾䜿䜰䛜ᚲせ䛺䛣䛸䛜䛒䜛䚹 CQ 1 6 䠖 FA P 䛾㑇ఏ䜹䜴䞁䝉䝸䞁䜾䛾ὀពⅬ䛿䠛 ᥎ዡ䜹䝔䝂䝸䞊䠖 B FA P ᝈ⪅䜔ᮍⓎ⑕⪅䜢ྵ䜐ᐙ᪘䠄⾑⦕⪅䠅䛻ᑐ䛩䜛 㑇ఏ䜹䜴䞁䝉䝸䞁䜾䛾㝿䛻䛿䠈 FA P 䛻㛵䛩䜛᝟ሗᥦ ౪䠈ᚰ⌮♫఍ⓗᨭ᥼䜢⾜䛖ᚲせ䛜䛒䜛䚹

MAP MUTYH Ͳ associa ted polyposis ᖖᰁⰍయຎᛶ㑇ఏ ⑓ែ䛿 attenuated F AP FA P ␲䛔䛷 APC 㑇ఏᏊኚ␗䛜䛺䛔ሙྜ䛻⪃៖ ᾘ໬⟶䛾䝃䞊䝧䜲䝷䞁䝇䛿 18 ṓ䛛䜙 䝁䝯䞁䝖 ௒ᅇ䛿᫬㛫䛾㛵ಀ䛷ヲ⣽䛺䝇䝷䜲䝗↓䛧䛷䛔䛛䛜䛷䛧䜗䛖䛛 ணഛ䝇䝷䜲䝗䛒䜚 PJ S Pue tz Ͳ Jegher s sy ndr ome 䝫䜲䝒䞉䝆䜵䜺䞊䝇⑕ೃ⩌ ➨ᅄḟᑠඣ៏ᛶ≉ᐃ⑌⑓䠈ᣦᐃ㞴⑓䛻⏦ㄳ୰

PJ S

„⑌ᝈᴫせ 䞉STK11㑇ఏᏊ䛾ኚ␗䛻䜘䜛ᖖᰁⰍయඃᛶ㑇ఏᛶ⑌ᝈ 䞉ᅜෆ᥎ᐃᝈ⪅ᩘ600ࠥ2,400ே 䞉ᾘ໬⟶䛾㐣ㄗ⭘ᛶ䝫䝸䝫䞊䝅䝇䛸ཱྀ၁䞉ཱྀ⭍⢓⭷䛺䛹䛾Ⰽ⣲ ᩬ䜢≉ᚩ䛸䛩䜛 䞉Ⰽ⣲ỿ╔䛿ฟ⏕ඣ䛛䜙ㄆ䜑䠈ᖺ㱋䛸䛸䜒䛻ⷧ䛟䛺䜛 䞉ᾘ໬⟶䝫䝸䞊䝥䛿ᑠ⭠䛸኱⭠䛻ዲⓎ䛧䠈ฟ⾑䠈㈋⾑䠈⭡③䠈⭠ 㔜✚䛾ཎᅉ䛸䛺䜛 䞉⭠㔜✚䜢10ṓ䜎䛷䛻15%䠈20ṓ䜎䛷䛻50%䛻ేⓎ 䞉ᾘ໬⟶䠈⮅⮚䠈ஙᡣ䠈⢭ᕢ䠈༸ᕢ䛾ᝏᛶ⭘⒆䜢20ṓ䜎䛷䛻1ࠥ 2%䠈50ṓ䜎䛷䛻30%䠈70ṓ䜎䛷䛻80%䛾㢖ᗘ䛷ྜే䛩䜛

PJ S „ ⑌ᝈᴫせ 䞉ẚ㍑ⓗ⛥䛺ᝏᛶ⭘⒆䛸䛧䛶䠈ዪᛶ䛻䛚䛡䜛 ov arian sex cord tumors with annular tubules(SCT A T) 䠈 mucinous tumors of the o vary , well-differentiated adenocarcinoma of the cervix 䛜䛒䜛 䞉 SCT A T 䛿᭱ᖺᑡ䛷 4 ṓ䛾ዪඣ䛾ሗ࿌䛜䛒䜛 䞉⏨ᛶ䛷䛿⢭ᕢ䛾 large-cell calcifying Sertoli cell tumors(L CCSCT) 䜢୧ഃ䛻ㄆ䜑䜛䛣䛸䛜䛒䜛 䞉ᑠඣᮇ䛾ᛶ⭢⭘⒆䛿䠈ᛶ䝩䝹䝰䞁䜢ศἪ䛩䜛䛸ᛮ᫓ᮇ᪩Ⓨ⑕ 䜔ዪᛶ໬ஙᡣ䜢క䛖䛣䛸䛜䛒䜛

PJ S

„デ᩿ᇶ‽ ୗグ䛾䛔䛪䜜䛛䜢‶䛯䛩 䞉2ಶ௨ୖ䛾PJS-type䛾䝫䝸䞊䝥 䞉PJS-type䛾䝫䝸䞊䝥䛜䛒䜚䠄ಶᩘ㛵ಀ䛺䛟䠅䠈㏆ぶ⪅䛻PJS䛾ᐙ᪘ Ṕ䜢᭷䛩䜛 䞉㏆ぶ⪅䛻PJS䛾ᐙ᪘Ṕ䜢᭷䛧䠈⢓⭷䛻≉ᚩⓗ䛺Ⰽ⣲ᩬ䜢ㄆ䜑䜛 䞉PJS-type䛾䝫䝸䞊䝥䛜䛒䜚䠄ಶᩘ㛵ಀ䛺䛟䠅䠈≉ᚩⓗ䛺Ⰽ⣲ᩬ䜢ㄆ 䜑䜛 ௨ୗ䛾⑌ᝈ䜢㚷ู䛩䜛 ⱝᖺᛶ䝫䝸䝫䞊䝅䝇⑕ೃ⩌䚸hereditary mixed polyposis syndrome, PTEN hamartomatumor syndrome, Carney complex

PJ S Ͳ ge n et ic s „ ཝᐦ䛻⮫ᗋデ᩿䛷☜ᐃ౛䛸䛥䜜䛯⑕౛䛾 90% 䛻 STK11 䠄 LKB1 䠅㑇ఏᏊ䛾ᶵ⬟Ḟኻᆺኚ␗䛜ྠᐃ䛥䜜䜛 „ JPS ᝈ⪅䛾 25% 䛿 de novo ⑕౛䛷䛒䜛

PJ S: ge notype/phenotype co rr el at io n s „ ẚ㍑ⓗ⑕౛ᩘ䛾ከ䛔◊✲䛷䛿 genotype/phenotype corr ela tions 䜢ㄆ䜑䛺䛔䛸⤖ㄽ䛥䜜䛶䛔䜛

PJ S: ca n ce r scr eening pr ot oc ol „ ᾘ໬⟶䛾䝃䞊䝧䜲䝷䞁䝇䛿ᑠඣᮇ䛻䛿ᝏᛶ⭘⒆䛾ྜే䛿 ⛥䛷䛒䜛䛣䛸䛛䜙䠈ᾘ໬⟶䛾㛢ሰ䜢䛝䛯䛧䛖䜛䝫䝸䞊䝥䛾デ ᩿䛸἞⒪䛜୺䛺┠ⓗ䛷䛒䜛 „ ᑗ᮶䛾Ⓨ⒴䛾䝸䝇䜽䜢⪃៖䛧䛶䠈⿕᭚䜢㑊䛡䛯䝥䝻䝖䝁䞊䝹 䜢᥎ዡ䛩䜛

PJ S: ca n ce r scr eening pr ot oc ol

TumorriskPediatric surveillanceFrequency 䠄Age,;Frequency)

St omach/duodenum Small bow el Color ectum Ov ar y/ cer vix

#

Te st e s

EG D Small bow el ca ps u le endosc op y (SBCE) CS Ph ys ic al ex amina tion Ph ys ic al ex amina tion

8y*; ev er y 3 ye ar s if polyp s ar e fo und 8y* ; ev er y 2

Ͳ

3 ye ar s 8y* ; ev er y 2

Ͳ

3 ye ar s Childhood; annually Childhood; annually

䠆

8

ṓ䛷䝃䞊䝧䜲䝷䞁䝇㛤ጞ䠈⑕≧䛜䛒䜛ሙྜ䛻䛿䛭䛾᫬Ⅼ䛷㏿䜔䛛䛻㛤ጞ䛩䜛䠈

4

ࠥ

5

ṓ䛷⭠㔜✚䛾ண㜵䛸䛧䛶䝃䞊䝧䜲䝷䞁䝇䜢᥎ዡ䛩䜛ពぢ䜒䛒䜛

#

ᡂே䛷䛿

25

ṓ䛛䜙ங䛜䜣䛸༸ᕢ䞉Ꮚᐑ㢕䛜䜣䠈

30

ṓ䛛䜙⮅䛜䜣᳨デ䜢⾜䛺䛖

䝃䞊䝧䜲䝷䞁䝇䛾⪃៖஦㡯 Pe u tz Ͳ Jegher s Ͳ Sy ndr ome & Cancer RR all cancer = 15.2 (n = 210 pa tien ts) ‡ Esophagus = 57 ‡ St omach =213 ‡ Small in te st ine = 520 ‡ Colon = 84 ‡ Pancr eas = 132

‡ Lung = 17 ‡ Br es t = 15.2 ‡ Ut erus = 16 ‡ Ov ar y =27 ‡ No signific an t incr ease in te st ic u la r or cer vic al cancer Giardiello at al, Gastroenterology 119:1447- 53 ,2000

᪥ᮏ䛷䛒䜜䜀⌧ᅾ䛺䜙ᑠ⭠䜹䝥䝉䝹䛷䝇䜽䝸䞊䝙䞁䜾䚸἞⒪䛿䝎䝤䝹䝞䝹䞊䞁ෆど㙾

ṓ !? ⣙䠔 о 䠍䠌 ṓ !? ᑠ⭠ ྛ✀䛜䜣䛾⨯ᝈ⋡䛾䝕䞊䝍ሗ࿌ Figure 2. The cumulativ e ca ncer risks for PJS patients..

ColorectalcancerExtraͲgastrointestinalcancer

AnycancerGastrointestinalcancers

ᐇ㝿䛻䛿ᑠ⭠䝫䝸䞊䝥䠄Ⰻᛶ䠅䛻䜘 䜛㛢ሰ⑕≧䝁䞁䝖䝻䞊䝹䛜ㄢ㢟

PJ S: ge netic co unseling co nsider ations „ Ⰽ⣲ᩬ䛿ᖺ㱋䛸䛸䜒䛻┠❧䛯䛺䛟䛺䜛䛣䛸䜢ㄝ᫂䛩䜛 „ Ⓨ⒴䛻㛵㐃䛩䜛㑇ఏᏊኚ␗䛜᫂䜙䛛䛻䛺䜛䜎䛷䛿䠈䛩䜉䛶䛾 PJS ᝈ⪅䜢䝝䜲䝸䝇䜽⑕౛䛸⪃䛘䠈䝃䞊䝧䜲䝷䞁䝇䜢⾜䛺䛖䛣䛸䜢 ᥎ዡ䛩䜛

JPS Juv enile polyposis sy ndr ome ⱝᖺᛶ䝫䝸䝫䞊䝅䝇 ➨ᅄḟᑠඣ៏ᛶ≉ᐃ⑌⑓䠈ᣦᐃ㞴⑓䛻⏦ㄳ୰

JPS „ ⑌ᝈᴫせ 䞉 BMPR1A 䜒䛧䛟䛿 SMAD4 㑇ఏᏊ䛺䛹䛾ኚ␗䛻䜘䜛ᖖᰁⰍయඃ ᛶ㑇ఏᛶ⑌ᝈ 䞉㐣ㄗ⭘ᛶ䝫䝸䞊䝥䛷䛒䜛ⱝᖺᛶ䝫䝸䞊䝥䛜ከⓎ䛩䜛ᖖᰁⰍయ ඃᛶ㑇ఏᛶ⑌ᝈ 䞉 ᅜෆ᥎ᐃᝈ⪅ᩘ 80 ࠥ 1,200 ே๓ᚋ䛸᥎ᐃ 䞉ᑠඣᮇ䛻⾑౽䠈㈋⾑䠈⭡③䠈⭠㔜✚䛷Ⓨ⑕ 䞉 30% 䛾⑕౛䛻ᚰ⮚䜒䛧䛟䛿୰ᯡ⚄⤒䛾⾑⟶ᛶ⑓ኚ䜢ྜే䛩䜛 䞉༢Ⓨ䛾ⱝᖺᛶ䝫䝸䞊䝥䛿⒴໬䛸䛿㛵ಀ䛧䛺䛔䠊୍᪉䠈 JPS 䛷䛿 ኱⭠䛜䜣䛾⏕ᾭⓎ⑕䝸䝇䜽䛿┦ᑐ༴㝤ᗘ 34 ಸ䠈 39% 䛸㧗⋡䛷 䛒䜛䠊 䞉⫶䛾䝫䝸䞊䝥䛜䛒䜛⑕౛䛷䛿䠈⫶䛜䜣䛾Ⓨ⑕䜢 21% 䛻ㄆ䜑䜛 JPS

„デ᩿ᇶ‽ ୗグ䛾䛔䛪䜜䛛䜢‶䛯䛩 䞉኱⭠䛻5ಶ௨ୖ䛾ⱝᖺᛶ䝫䝸䞊䝥䠄ᖺ㱋䛷䛿䛺䛟⤌⧊ᆺ䠅 䞉኱⭠௨እ䛾ᾘ໬⟶䛻ⱝᖺᛶ䝫䝸䞊䝥䛜ከⓎ䛩䜛 䞉኱⭠䛻ⱝᖺᛶ䝫䝸䞊䝥䛜䛒䜚䠄ಶᩘ㛵ಀ䛺䛟䠅䠈JPS䛾ᐙ᪘Ṕ䛜 䛒䜛

JPS: ge n et ic s „ ᮏ⑕䛷䛿 BMPR1A 䛾ኚ␗䜢 20% 䠈 SMAD4 䛾ኚ␗䜢 40% 䛻 ㄆ䜑䜛 „ JPS ᝈ⪅䛾 25% 䛿 de novo ⑕౛䛷䛒䜛 „ ᐙ᪘Ṕ䛾䛺䛔⑕౛䛷䛿ୖグ㑇ఏᏊ䛾ኚ␗䜢䛧䜀䛧䜀ㄆ䜑䛺䛔

JPS: ge notype/phenotype corr ela tions „ SMAD4 ኚ␗䛷䛿 hereditary hemorrhagic telangiectasia (HHT) 䠈⾑⟶⣔䛾␗ᖖ䠈⢓⭷䛾ẟ⣽⾑⟶ ᣑᙇ䠈⬻䞉ᾘ໬⟶䞉⫵䞉⫢⮚䛾ື㟼⬦ወᙧ䜢ྜే䛩䜛

JPS: ca n ce r scr eening pr ot oc ol „ 5mm ௨ୖ䛾䝫䝸䞊䝥䛿ෆど㙾ⓗ䛻ษ㝖䛧䠈Ⓨ⒴䛾ண㜵䛺䜙䜃 䛻⭠㔜✚䜢ண㜵䛩䜛 „ ᖺ䛻 1 ᅇ䛿デᐹ䠈⾑ᾮ᳨ᰝ䜢⾜䛺䛖 Tu m o r risk P e dia tric sur veillance Fr equency

䠄

Ag e,;Fr e quency) Color ectum St omach Small bow el

CS EG D SBCE

12 Ͳ 15 y; ever y 1 Ͳ 3 ye ar s 15 y; ever y 1 Ͳ 2 ye ar s 15 y; ever y 1 Ͳ 2 ye ar s * ⑕≧䠄⾑౽䠈㈋⾑䠈⭠㔜✚䛺䛹䠅䛜䛒䜜䜀䛥䜙䛻పᖺ㱋䛷䜒 䝃䞊䝧䜲䝷䞁䝇䜢㛤ጞ䛩䜛 Hepa to blas to ma/ o ther liv er malignancies „ Hepa toblas toma 䛾 80% 䛿ᇶ♏⑌ᝈ䛾䛺䛔ᏙⓎ౛䛷䠈ṧ䜚䛾 20% 䛿ୗグ䛻௦⾲䛥䜜䜛ᇶ♏⑌ᝈ䜢᭷䛩䜛 䞉 Beckwith- Wiedemann syndrome(BWS) 䞉 Simpson-Golabi-Behmel syndrome 䞉 Sotos syndrome 䞉 FA P 䞉 18 trisom y „ ௦ㅰᛶ⑌ᝈ䛾䛖䛱⫢㞀ᐖ䜢䛝䛯䛩䝏䝻䝅䞁⾑⑕ 1 ᆺ䠈䝣䝬䝸 䝹䜰䝉䝖㓑㓟Ỉ㓟໬㓝⣲Ḟᦆ⑕䠈⢾ཎ⑓䛷䛿 hepatocellular carcinoma 䠈⛥䛻 hepatoblastoma 䜢ྜ ే䛩䜛

䜎䛸䜑 „ FA P 䛿኱⭠⒴◊✲఍ 㑇ఏᛶ኱⭠⒴デ⒪䜺䜲䝗䝷䜲䞁䛸䛾 ᩚྜᛶ䜢☜ㄆ䛩䜛 . „ PJS ,JP 䛿 CCR 䜢ᇶ‽䛻䛧䚸᪂䛧䛔䜶䝡䝕䞁䝇䜢ධ䜜䜛ᚲせ 䛜䛒䜛䛛 . 䠚䠚ෆど㙾᳨ᰝ䜈䛾䝝䞊䝗䝹䛜ప䛔ᮏ㑥䛷䚸⊂ ⮬䛾䜶䝡䝕䞁䝇䛜䛒䜛䛛 . 䠚䜹䝥䝉䝹䛿᪋⾜䛧᫆䛔

ணഛ䝇䝷䜲䝗 Ta b le 1. Cancer sur veillance rec ommenda tions in the pedia tric ag e ra n ge

SyndromeGeneInherit ance pattern

TumorriskPediatric surveillanceFrequency 䠄Age,;Frequency) FAPAPCADColorectum Thyroid Liver hepatoblastoma Desmoid Medulloblastom a

CS* Paltipation US&serum AFP PS&MRI PS

10–15y;annually 15–19y;annually EarlyinfantͲ;4Ͳ6 monthsuntil7y Followingcolectomy orothersurgery;1Ͳ3 years Childhood;annually Attenuated FAPColorectumCS15–19y;every3years toannually MUTYHͲ associated polyposis

MUT YHARColorectum Gastric/duodenu m

CS EGD18y;every2years 20Ͳ25y;every1Ͳ5 years

MAP

„⑌ᝈᴫせ 䞉MUTYH㑇ఏᏊ䛾⏕Ṫ⣽⬊⣔ิኚ␗䛻㉳ᅉ䛩䜛ᖖᰁⰍయຎᛶ 㑇ఏᛶ⑌ᝈ 䞉ሷᇶ㝖ཤಟ᚟㑇ఏᏊ䛷䛒䜛MUTYH䛾୧䜰䝺䝹ኚ␗ 䞉኱⭠䛻10ࠥ100ಶ䛾⭢⭘䜢ㄆ䜑䜛attenuated FAP䛾⑓ᆺ䜢 ♧䛧䠈⏕ᾭ䛾኱⭠䛜䜣䛾䝸䝇䜽60% 䞉༑஧ᣦ⭠䛾⭢⭘䜔䛜䜣䛾ྜే䛜5%ᮍ‶ 䞉60ṓ䜎䛷䛻10ಶ௨ୖ䛾኱⭠⭢⭘䜢ㄆ䜑䜛⑕౛䠈⮫ᗋⓗ䛻FAP 䛜␲䜟䜜䜛䛜APC㑇ఏᏊኚ␗䛜᫂䜙䛛䛷䛺䛔⑕౛䛜㑇ఏᏊ ᳨ᰝ䛾ᑐ㇟ 䞉ᩘ౛䛾⑕౛ሗ࿌䜢㝖䛝ᑠඣᮇ䛾኱⭠䛜䜣䛾Ⓨ⑕䛿⛥ 䞉ᾘ໬⟶䛾ᝏᛶ⭘⒆䛾䝃䞊䝧䜲䝷䞁䝇䛿18ṓ㐣䛞䛶䛛䜙

MAP: Cancer scr eening /sur veillance pr ot oc ol

SyndromeGeneInherit ance pattern TumorriskPediatric surveillanceFrequency 䠄Age,;Frequency) MUTYHͲ associated polyposis

MUT YHARColorectum Gastric/duodenu m CS EGD18y;every2years 25Ͳ30y;every1Ͳ5 years