ALK遺伝子検査の手引き ver2.11 201509.18

1 2 1 ALK 2011 8 1 2011 10 12 2011 11 2 2015 6 6 2015 7 28 2015 7 29 ALK 2 3 1. ALK 3 2. ALK 3 3. ALK 5 4. ALK 6 5. 8 6. ALK 8 FISH 8 RT-PCR reverse transcriptase-PCR 9 IHC 10 11 11 11 12 12 12 7.

2 14 8. ALK 15 9. ALK 16 17 ALK 3 EML4-ALK 2007 (1) BCR-ABL ABL ALK 3~5 ALK ALK (2) 2011 2012 2 ALK 2014 4 2014 7 ALK ALK ALK ALK 1 2011 update 2 2007 cDNA 3T3 1 EML4 ALK rearrangement( ) translocation( ) (fusion gene)

3 ALK 2 IMT 1980 RAS EMK4-ALK 1(1) EML4 echinoderm microtubule-associated protein-like 4 ALK anaplastic lymphoma kinase (1) ( ) ALK ALK coiled-coil (3) Cell Signaling Technology ALK (4) EML4-ALK ALK (5) ALK anaplastic lymphoma inflammatory myofibroblastic tumor IMT 2 (Coffin C M, Watterson J, Priest J R ,et al: Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor).)

4 A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol 19: 859 872, 1995) EML4-ALK variant 1 EML4 ALK EML4-ALK ALK-EML4 EML coiled-coil domain, ALK EML4-ALK 15 14 13 32 1 2 3 19 20 21 15 14 13 32 1 2 3 19 20 21 1 2 3 1319 3 2 1 EML4 ALKALK EML41 2 3 1320 TKALKEML4 EML4 ALK variant 1 Coiled coil 2 ALK 4 EML4 NPM,TPM3, TFG, ATIC, CLTC1, MSN, TPM4, ALO17, MYH9 IMT TPM4, RANBP2, CARS, SEC31L1 (6)

5 ALK ALK 20 19 p NPM, TPM3, EML4 coiled-coil ALK ALK ALK EGFR ALK EML4-ALK 10 variant ( ) EML4 N coiled-coil ALK 20 variant 10-70 EML4 13 ALK 20 variant 1 EML4 6 ALK 20 variant 3a/b 30% ( ) ALK KIF5B 24 ALK 20 (7) KIF5B 15 (8) KIF5B EML4-ALK ALK Cell Signaling Technology 41 150 (4) 1 H2228 3 ALK 3 EML4-ALK E6;A20 E13;A20 TFG TRK fused gene ALK (Horn L, Pao W.)

6 EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 2009; 27: 4232-5. E13;A20E20;A20E6a/b;A20E14;ins11del49A20 E2;A20 ins117A20E13; ins69A20E14; del12A20E15del19; del20A20E18;A20V1V2V3a/3bV4V5a/bV6V7V4 V5 E17ins61; ins34A20V8E24; A20E15; A20 EML4 ALKTFG ALKKIF5B ALKE3;A20 Modified from Sasaki T et al., Eur J Cancer, 2010 Tyrosine kinaseTyrosine kinaseTyrosine kinaseTyrosine kinaseTyrosine kinaseTyrosine kinaseTyrosine kinaseTyrosine kinaseTyrosine kinaseTyrosine kinaseTyrosine kinaseTyrosine kinaseTyrosine kinase EML4-ALK Sasaki T, Rodig SJ, Chirieac LR, Janne PA.

7 The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010; 46: 1773-80. ALK 5 TFG coiled-coil ALK 1 2-5% 4-5 (9) EGFR ( ) ALK 50 ALK 10 ALK ALK CAP/IASLC/AMP (10) ALK EGFR KRAS HER2 ALK ALK ALK EGFR KRAS (11)

8 Inamura EML4-ALK 11 6 acinar type 5 papillary WHO 4 acinar 2 papillary 5 mixed (12) 11 Thyroid transcription factor-1 TTF-1 cell ALK ALK ALK ALK 6 lineage EGFR Rodig - BAC acinar papillary solid ALK 1/22 4/124 0/46 11/134 solid type (11) signet ring cell ALK 2% 10% 10% ALK 3/295 2/21 12/26 (13) ALK 4.

9 ALK ALK c-MET ROS-1 MET First-in-human I 2006 Part1 ALK MET prescreening Part2 250mg ALK MET molecularly defined expansion cohort ALK ALK ALK Inflammatory myofibroblastic tumor EML4-ALK ALK expanded cohort 2008 ALK 19 preliminary 2009 (14) 2010 New England Journal of Medicine ALK II PROFILE 1001 (2) Update 2012 The Lancet Oncology (15) PROFILE 1001 ALK Expanded cohort FISH 149 ALK 71% 97% 84% 143 CR 87 8 16 , PFS (95% (CI); ) 6 12 (95%CI; ) (95%CI.)

10 144 97 Grade1/2 20 96 , 64% 84 , 56% 74 , 50% 58 , 39% 44 , 30% 41 , 28% 31 , 21% Grade 3/4 36 9 ALT 6 6 6 AST 5 3 < Grade4 1 > RECIST (PD) PD 69 39 PD 12 PD (15) 2011 2012 3 30 ALK ALK III PROFILE 1007 (16) PROFILE 1014 (17) PROFILE 1007 2013 PROFILE 1014 2014 New England Journal of Medicine PROFILE 1007 FISH ALK 347 500 mg/m2,day1 75mg/m2,day1 ( 250mg ) 1.