| Disease | Lung adenocarcinoma |
| Epidemiology | ROS1 translocations are found in 0.9 to 1.7% of non small cell lung carcinomas and the majority of the cases are adenocarcinoma (Bergethon et al., 2012; Davies et al., 2012; Takeuchi et al., 2012). Multiple fusion partners have been identified and LRIG3 is one of them. As for LRIG3-ROS1, only one case, a 57-year-old Japanese male patient, has been reported to date (Takeuchi et al., 2012). |
| Clinics | The patient had a 5 pack year of smoking history and was diagnosed as having stage 1A lung adenocarcinoma. |
| Pathology | This case showed moderately differentiated micropapillary pattern. A mucinous cribriform pattern which is frequently seen in cancers with kinase fusions was not found. This case was negative for EGFR and KRAS mutations as with the most cases harboring ROS1 gene fusions. |
| Treatment | The primary tumor was surgically removed and the patient received post-operative chemotherapy with UFT. Although not administered in this case, Crizotinib and other ALK inhibitors have been reported to be effective in lung cancers with ROS1 translocations (Bergethon et al., 2012; Shaw et al., 2012). |
| Prognosis | With 5 years of follow-up, the patient was alive without relapse. |
| Hybrid Gene |
| Transcript | LRIG3-ROS1 fusion transcript was detected. |
| Detection | A 218 bp cDNA fragment harboring the fusion point can be detected with LRIG3 forward primer (5'-ACACAGATGAGACCAACTTGC-3') and ROS1 reverse primer (5'-CACTGTCACCCCTTCCTTG-3'). |
| Fusion Protein |
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| Description | A. The schematic structure of LRIG3, ROS1, and LRIG3-ROS1 proteins and the cDNA sequence around the fusion point: Exon 16 of LRIG3 fused to exon 35 of ROS1. The break point of ROS1 allows the resulting fusion protein to retain the kinase domain (red). LRIG3 contains a transmembrane domain (orange). B: RT-PCR confirmation of LRIG3-ROS1 fusion: Lane M and N represent the size standard (20-bp ladder) and the non-template control, respectively. C. Fusion FISH analysis: A fusion signal (yellow) was observed in consequence of the fusion of LRIG3 (red) and ROS1 (green). |
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| Description | The fusion protein encompasses the constitutive activation of ROS1 tyrosine kinase. However, the mechanism of it is largely unknown. The role of LRIG3 here has not been clarified. LRIG3 protein does not contain a coiled-coil domain as in the case with most of the other ROS1 fusion partners (Takeuchi et al., 2012).
In respect of the downstream signaling, several growth and survival signaling pathways which are common to other receptor tyrosine kinases have been shown to be involved. These include PI3K/AKT, JAK/STAT3, RAS/MAPK/ERK, VAV3, and SHP-1 and SHP-2 pathways (Chin et al., 2012; Davies and Doebele, 2013). |
| Oncogenesis | The oncogenicity of LRIG3-ROS1 fusion was proven in a focus formation assay and a nude mouse tumorigenicity assay (Takeuchi et al., 2012). |
| | |
| ROS1 rearrangements define a unique molecular class of lung cancers. |
| Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, Iafrate AJ. |
| J Clin Oncol. 2012 Mar 10;30(8):863-70. doi: 10.1200/JCO.2011.35.6345. Epub 2012 Jan 3. |
| PMID 22215748 |
| |
| Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer. |
| Chin LP, Soo RA, Soong R, Ou SH. |
| J Thorac Oncol. 2012 Nov;7(11):1625-30. doi: 10.1097/JTO.0b013e31826baf83. (REVIEW) |
| PMID 23070242 |
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| Molecular pathways: ROS1 fusion proteins in cancer. |
| Davies KD, Doebele RC. |
| Clin Cancer Res. 2013 Aug 1;19(15):4040-5. doi: 10.1158/1078-0432.CCR-12-2851. Epub 2013 May 29. (REVIEW) |
| PMID 23719267 |
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| Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. |
| Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL, Berge EM, Terracciano LM, Cappuzzo F, Incarbone M, Roncalli M, Alloisio M, Santoro A, Camidge DR, Varella-Garcia M, Doebele RC. |
| Clin Cancer Res. 2012 Sep 1;18(17):4570-9. doi: 10.1158/1078-0432.CCR-12-0550. Epub 2012 Aug 23. |
| PMID 22919003 |
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| Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. |
| Shaw AT, Camidge DR, Engelman JA, Solomon BJ, Kwak EL, Clark JW, Salgia R, Shapiro G, Bang YJ, Tan W, Tye L, Wilner KD, Stephenson P, Varella-Garcia M, Bergethon K, Iafrate AJ, Ou SHI. |
| J Clin Oncol 2012;30:(suppl; abstr 7508). |
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| RET, ROS1 and ALK fusions in lung cancer. |
| Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y. |
| Nat Med. 2012 Feb 12;18(3):378-81. doi: 10.1038/nm.2658. |
| PMID 22327623 |
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