Lung: Adenocarcinoma with t(6;12)(q22;q14.1) LRIG3/ROS1

2014-02-01   Kana Sakamoto , Yuki Togashi , Kengo Takeuchi 

1.Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

Clinics and Pathology

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.

Genes Involved and Proteins

Gene name

LRIG3 (Leucine-Rich Repeats And Immunoglobulin-Like Domains 3)

Location

12q14.1

Dna rna description

Leucine-Rich Repeats And Immunoglobulin-Like Domains Protein 3.

Gene name

ROS1 (ROS proto-oncogene 1 , receptor tyrosine kinase)

Location

6q22.1

Dna rna description

C-Ros Oncogene 1, Receptor Tyrosine Kinase.

Result of the chromosomal anomaly

Transcript

LRIG3-ROS1 fusion transcript was detected.

Detection protocole

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).
Atlas Image
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).

Description

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).

Bibliography

Pubmed IDLast YearTitleAuthors
222157482012ROS1 rearrangements define a unique molecular class of lung cancers.Bergethon K et al
230702422012Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer.Chin LP et al
237192672013Molecular pathways: ROS1 fusion proteins in cancer.Davies KD et al
229190032012Identifying and targeting ROS1 gene fusions in non-small cell lung cancer.Davies KD et al
223276232012RET, ROS1 and ALK fusions in lung cancer.Takeuchi K et al

Citation

Kana Sakamoto ; Yuki Togashi ; Kengo Takeuchi

Lung: Adenocarcinoma with t(6;12)(q22;q14.1) LRIG3/ROS1

Atlas Genet Cytogenet Oncol Haematol. 2014-02-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/6496/lung-adenocarcinoma-with-t(6;12)(q22;q14-1)-lrig3-ros1