Lung: Translocations in Adenocarcinoma

2014-09-01 Jean-Loup Huret Affiliation

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note: the fusion was discovered by NGS. Many chromosome rearrangement mechanisms such as translocation, inversion,deletion or complex rearrangement may lead to the same fusion)

Classification

In the group of malignant epithelial tumours of the lungs, adenocarcinomas belong to the non-small cell carcinomas (non-small cell lung cancer (NSCLC)), as opposed to small cell carcinomas (SCLC). Other NSCLCs of the lungs are: squamous cell carcinomas, adenosquamous carcinomas, large cell carcinomas, sarcomatoid carcinomas, carcinoid tumours, and salivary gland tumours.

Clinics and Pathology

Note

KRAS (12p12) and EGFR (7p11) are mutated in 15% and 10% of NSCLCs, and PIK3CA (3q26), BRAF (7q34), and ERBB2 (17q12) are mutated in another 5% of NSCLCs. The presence of EGFR or KRAS mutations and translocations such as EML4/ALK or other tyrosine kinase fusions (see below), are mutually exclusive in lung adenocarcinoma.
Three tyrosine kinase receptors are recurrently found implicated in translocations: ALK (2p23), ROS1 (6q22), and RET (10q11). Kinase fusion positive (ALK, ROS1 and RET fusions) lung cancers are (almost) exclusively adenocarcinomas, at times squamous or adenosquamous carcinomas.
In a study of 16 patients with adenocarcinoma and one patient with large cell carcinoma, never-smokers have more often EGFR mutations or ALK-ROS1-RET translocations and smokers more often KRAS, TP53, BRAF, JAK2, JAK3 and mismatch repair gene mutations (Govindan et al., 2012).

Epidemiology

Adenocarcinomas comprise 30% to 40% of lung cancers, with geographical variations, and it is becoming more prevalent. Tobacco smoking is the major cause of lung cancer of each histological subtype, but adenocarcinoma is more frequently found in non-smokers than any other histologic types of lung cancer.

Clinics

Adenocarcinomas are more common in the peripheral lung (alveolar or bronchioalveolar cell) than in central location, and the visceral pleura is therefore frequently involved, with fibrosis. Patients with ALK, ROS1, or RET fusion transcripts are often younger nonsmoking female patients, with early lymph node metastases.

Pathology

Presence of either solid signet ring cell or cribriform patterns with abundant extracellular mucus is frequently found in ALK-ROS1-RET translocations cases (Takeuchi et al., 2012; Yoshida et al., 2013).

Genes

- As said above, three membrane associated tyrosine kinase receptors are recurrently involved in translocations in adenocarcinomas: ALK, implicated with six possible different partners; ROS1, implicated with nine possible partners; RET, implicated with three possible partners. Other tyrosine kinases can also be involved (PDGFRA (4q12), DDR1 (6p21), FGFR2 (10q26), AXL (19q13), ...).
- Eight others genes were found implicated in two distinct translocations: APAF1 (12q23, structural core of the apoptosome), CCDC6 (10q21, structural constituent of the cytoskeleton), GOPC (6q22, ion channel binding protein), H19 (11p15, non-protein coding sequence), KDELR2 (7p22, receptor), KIF5B (10p11, motor protein), SFTPA2 and SFTPB (10q22 and 2p11, surfactant-associated proteins); 138 other genes were implicated once.

Treatment

Targeted therapies: the treatments for NSCLCs have shown impressive clinical responses in patients with EGFR mutations treated with EGFR tyrosine kinase inhibitor therapy. ALK and ROS1 fusions proteins are both sensitive to treatment with the new ALK tyrosine kinase inhibitors, and clinical trials report an overall response rate of 57% in patients with ALK rearrangements. Cells expressing KIF5B/RET were found sensitive to multitargeted kinase inhibitors that inhibit RET. Therefore, more than 50% of the patients with lung adenocarcinoma may benefit from treatments with corresponding kinase inhibitors (Takeuchi et al., 2012).

Prognosis

In a study of 248 patients with NSCLC, the 2-year overall survival rates were 89% for EGFR, 73% for KRAS, 74% for ALK, and 62% for RET. There was no significant difference between patients with RET-positive and RET-negative tumors. Patients with EGFR mutations had a significantly longer overall survival than patients with KRAS mutations (Wang et al., 2012). Patients lacking EGFR mutations or translocations involving tyrosine kinases are left with a dismal 5-year survival rate of 15%.

Cytogenetics

Note

The most frequent ALK fusion in adenocarcinomas of the lung is EML4/ALK (4% to 7% of cases), and the second is KIF5B/ALK (0.5%). ROS1 fusions are found in 1% to 2.5% of patients with NSCLCs (Davies et al., 2012; Yoshida et al., 2013). RET fusions occur in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas (Takeuchi et al., 2012; Yoshida et al., 2013).
- ALK is implicated with six possible different partners: inv(2)(p21p23) or del(2)(p21p23) EML4/ALK, t(2;2)(p23;p22) STRN/ALK, t(2;3)(p23;q12) TFG/ALK, t(2;9)(p23;q31) ALK/PTPN3, t(2;10)(p23;p11) KIF5B/ALK and t(2;14)(p23;q32) KLC1/ALK;
- ROS1 is implicated with nine possible partners: t(1;6)(q21;q22) TPM3/ROS1, t(4;6)(p15;q22) SLC34A2/ROS1, t(5;6)(q33;q22) CD74/ROS1, t(6;6)(q22;q22) GOPC/ROS1, inv(6)(q22q25) EZR/ROS1, t(6;7)(q22;p22) KDELR2/ROS1, t(6;10)(q22;q21) CCDC6/ROS1, t(6;12)(q22;q14) LRIG3/ROS1, and t(6;20)(q22;q12) SDC4/ROS1;
- RET is implicated with three possible partners: inv(10)(p11q11) CCDC6/RET, inv(10)(p11q11) KIF5B/RET, and inv(10)(q11q11) NCOA4/RET.
These translocations lead to aberrant tyrosine kinase activation.

Cytogenetics morphological

The eighty six translocations reported so far in adenocarcinomas of the lung greatly differ from that ones found in squamous cell carcinoma, or that ones found in small cell carcinoma. They are the following:

t(X;X)(p22;q13) EDA/MID1 (Seo et al., 2012)
t(X;1)(q23;q24) ACSL4/DCAF6 (Govindan et al., 2012)
t(X;20)(p11;p12) SPTLC3/MAOA (Seo et al., 2012)

t(1;1)(p36;p36) UBR4/ATP13A2 (Seo et al., 2012)
t(1;1)(p36;p34) ARHGEF16/TCTEX1D4 (Seo et al., 2012)
t(1;1)(p35;p35) SRSF4/SNRNP40 (Seo et al., 2012)
t(1;1)(p34;p32) FGGY/TESK2 (Majewski et al., 2013)
t(1;1)(p13;p12) IGSF3/MAN1A2 (Seo et al., 2012)
t(1;1)(p13;p12) VANGL1/HAO2 (Govindan et al., 2012)
t(1;1)(q24;q24) CD247/GPR161 (Imielinski et al., 2012)
t(1;6)(p32;q14) ZFYVE9/CGA (Seo et al., 2012)
t(1;6)(q21;q22) TPM3/ROS1 (Takeuchi et al., 2012)
t(1;19)(q23;p13) TCF3/PBX1 (Mo et al., 2013)

t(2;2)(p23;p22) STRN/ALK (Majewski et al., 2013)
inv(2)(p21p23) del(2)(p21p23) EML4/ALK (Rikova et al., 2007; Choi et al., 2008; Koivunen et al., 2008; Majewski et al., 2013)
t(2;2)(p22;p21) MAP4K3/PRKCE (Seo et al., 2012)
t(2;2)(q21;q22) MGAT5/HNMT (Seo et al., 2012)
t(2;2)(q24;q24) STK39/B3GALT1 (Imielinski et al., 2012)
t(2;2)(q33;q33) ADAM23/SGOL2 (Imielinski et al., 2012)
t(2;3)(p23;q12) TFG/ALK (Rikova et al., 2007)
t(2;8)(p11;p21) SFTPB/DPYSL2 (Seo et al., 2012)
t(2;9)(p23;q31) ALK/PTPN3 (Jung et al., 2012)
t(2;10)(p23;p11) KIF5B/ALK (Takeuchi et al., 2009; Wong et al., 2011)
t(2;10)(p11;q22) SFTPA2/SFTPB (Seo et al., 2012)
t(2;14)(p23;q32) KLC1/ALK (Togashi et al., 2012)
t(2;19)(q11;q13) XRCC1/MAL (Seo et al., 2012)

t(3;3)(p25;p25) TTLL3/MTMR14 (Imielinski et al., 2012)
t(3;3)(p24;p24) EOMES/SLC4A7 (Imielinski et al., 2012)
t(3;3)(p21;p14) CACNA2D3/FLNB (Govindan et al., 2012)
t(3;3)(q21;q22) MGLL/SLCO2A1 (Imielinski et al., 2012)
t(3;3)(q25;q25) CP/WWTR1 (Imielinski et al., 2012)
t(3;6)(p24;q16) UBE2E1/ASCC3 (Seo et al., 2012)

t(4;6)(p15;q22) SLC34A2/ROS1 (Davies et al., 2012; Rimkunas et al 2012; Seo et al., 2012; Takeuchi et al., 2012)
t(4;12)(q12;q12) SCAF11/PDGFRA (Seo et al., 2012)

t(5;5)(q12;q12) ERBB2IP/MAST4 (Seo et al., 2012)
t(5;5)(q13;q13) ARHGEF28/UTP15 (Imielinski et al., 2012)
t(5;5)(q31;q31) UBE2D2/MATR3 (Imielinski et al., 2012)
t(5;6)(q11;p22) IL6ST/KDM1B (Seo et al., 2012)
t(5;6)(q33;q22) CD74/ROS1 (Rikova et al., 2007; Davies et al., 2012; Rimkunas et al., 2012; Seo et al., 2012)
t(5;6)(q33;q22) ROS1/CD74 (Imielinski et al., 2012)
t(5;8)(p15;q22) CMBL/NDUFAF6 (Seo et al., 2012; Takeuchi et al., 2012)
t(5;10)(q35;q11) SGMS1/STK10 (Govindan et al., 2012)
t(5;12)(q33;q14) GRIP1/TNIP1 (Govindan et al., 2012)

t(6;6)(q22;q22) GOPC/ROS1 (Rimkunas et al., 2012; Suehara et al., 2012)
t(6;6)(q22;q22) TPD52L1/TRMT11 (Seo et al., 2012)
inv(6)(q22q25) EZR/ROS1 (Takeuchi et al., 2012; Yoshida et al., 2013)
t(6;7)(q22;p22) KDELR2/GOPC (Govindan et al., 2012)
t(6;7)(q22;p22) KDELR2/ROS1 (Govindan et al., 2012)
t(6;10)(q22;q21) CCDC6/ROS1 (Seo et al., 2012)
t(6;12)(q22;q14) LRIG3/ROS1 (Takeuchi et al., 2012)
t(6;12)(q24;q13-14) UTRN/OS9 (Seo et al., 2012)
t(6;20)(q22;q12) SDC4/ROS1 (Davies et al., 2012; Takeuchi et al., 2012)

t(9;9)(q34;q34) TUBB4B/COBRA1 (Imielinski et al., 2012)
t(9;12)(p13;q23) APAF1/TLN1 (Govindan et al., 2012)
t(9;12)(p13;q23) APAF1/UNC13B (Govindan et al., 2012)

inv(10)(p11q11) CCDC6/RET (Matsubara et al., 2012; Takeuchi et al., 2012; Wang et al., 2012)
inv(10)(p11q11) KIF5B/RET (Ju et al., 2012; Kohno et al., 2012; Lipson et al., 2012; Seo et al., 2012; Suehara et al., 2012; Takeuchi et al., 2012; Wang et al., 2012)
inv(10)(q11q11) NCOA4/RET (Wang et al., 2012)
t(10;10)(q11;q11) MARCH8/PRKG1 (Govindan et al., 2012)
t(10;10)(q25;q25) SHOC2/RBM20 (Imielinski et al., 2012)
t(10;12)(q26;q24) FGFR2/CIT (Seo et al., 2012)
t(10;19)(q22;q13) FTL/SFTPA2 (Seo et al., 2012)

t(11;11)(q13;q13) RBM14/FGF3 (Seo et al., 2012)
t(11;11)(q23;q23) HYOU1/C11ORF93 (Seo et al., 2012)
t(11;13)(q24;q14) APLP2/TNFSF11 (Seo et al., 2012)
t(11;14)(p15;q11) MMP14/H19 (Seo et al., 2012)
t(11;19)(p15;p13) H19/CALR (Seo et al., 2012)

t(12;12)(q13;q14) SLC16A7/MUCL1 (Seo et al., 2012)
t(12;12)(q15;q21) RAB21/FRS2 (Seo et al., 2012)
t(12;12)(q23;q24) TXNRD1/GPR133 (Seo et al., 2012)
t(12;16)(p12;q23) KRAS/CDH13 (Seo et al., 2012)
t(12;17)(q14;q25) RASSF3/TTYH2 (Govindan et al., 2012)

t(14;19)(q13;q13) AXL/MBIP (Seo et al., 2012)

t(15;15)(q22;q24) CYP1A2/SPG21 (Imielinski et al., 2012)
t(15;22)(q21;q12) MCM5/TRPM7 (Majewski et al., 2013)

t(16;16)(p13;p13) MSLN/WDR90 (Majewski et al., 2013)

t(17;17)(p13;p13) XAF1/FAM64A (Seo et al., 2012)
t(17;17)(p12;p11) TTC19/ATPAF2 (Seo et al., 2012)
t(17;17)(q11;q12) IKZF3/NF1 (Majewski et al., 2013)
t(17;17)(q23;q23) BCAS3/MAP3K3 (Seo et al., 2012)
t(17;21)(q24;q22) BRWD1/CCDC46 (Seo et al., 2012)

t(18;18)(q11;q11) LAMA3/RIOK3 (Majewski et al., 2013)
t(18;20)(p11;q13) PHACTR3/PTPRM (Imielinski et al., 2012)

t(19;19)(p13;p13) MIER2/NMRK2 (Seo et al., 2012)
t(19;19)(p13;p13) OAZ1/SF3A2 (Imielinski et al., 2012)
t(19;19)(q13;q13) LSM14A/SIPA1L3 (Seo et al., 2012)
t(19;19)(q13;q13) RHPN2/ANKRD27 (Govindan et al., 2012)

Article Bibliography

Pubmed ID	Last Year	Title	Authors
18593892	2008	Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.	Choi YL et al
22919003	2012	Identifying and targeting ROS1 gene fusions in non-small cell lung cancer.	Davies KD et al
22980976	2012	Genomic landscape of non-small cell lung cancer in smokers and never-smokers.	Govindan R et al
22980975	2012	Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing.	Imielinski M et al
22194472	2012	A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing.	Ju YS et al
22334442	2012	Discovery of ALK-PTPN3 gene fusion from human non-small cell lung carcinoma cell line using next generation RNA sequencing.	Jung Y et al
22327624	2012	KIF5B-RET fusions in lung adenocarcinoma.	Kohno T et al
18594010	2008	EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.	Koivunen JP et al
22327622	2012	Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.	Lipson D et al
23661334	2013	Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing.	Majewski IJ et al
23154560	2012	Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad.	Matsubara D et al
23688269	2013	Detection of E2A-PBX1 fusion transcripts in human non-small-cell lung cancer.	Mo ML et al
18083107	2007	Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.	Rikova K et al
22661537	2012	Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: identification of a FIG-ROS1 fusion.	Rimkunas VM et al
22975805	2012	The transcriptional landscape and mutational profile of lung adenocarcinoma.	Seo JS et al
17625570	2007	Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.	Soda M et al
23052255	2012	Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions.	Suehara Y et al
22327623	2012	RET, ROS1 and ALK fusions in lung cancer.	Takeuchi K et al
22347464	2012	KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only.	Togashi Y et al
23150706	2012	RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer.	Wang R et al
21656749	2011	A novel KIF5B-ALK variant in nonsmall cell lung cancer.	Wong DW et al
23426121	2013	ROS1-rearranged lung cancer: a clinicopathologic and molecular study of 15 surgical cases.	Yoshida A et al

External Links

Citation

Jean-Loup Huret

Lung: Translocations in Adenocarcinoma

Atlas Genet Cytogenet Oncol Haematol. 2014-09-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/6751/chromosome-explorer/gene-explorer/submit-meetings/

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