Anaplastic lymphoma kinase (ALK) gene rearrangements in radiation‐related human papillary thyroid carcinoma after the Chernobyl accident

Abstract

Childhood radiation exposure has been associated with increased papillary thyroid carcinoma (PTC) risk. The role of anaplastic lymphoma kinase (ALK) gene rearrangements in radiation‐related PTC remains unclear, but STRN‐ALK fusions have recently been detected in PTCs from radiation exposed persons after Chernobyl using targeted next‐generation sequencing and RNA‐seq. We investigated ALK and RET gene rearrangements as well as known driver point mutations in PTC tumours from 77 radiation‐exposed patients (mean age at surgery 22.4 years) and PTC tumours from 19 non‐exposed individuals after the Chernobyl accident. ALK rearrangements were detected by fluorescence in situ hybridisation (FISH) and confirmed with immunohistochemistry (IHC); point mutations in the BRAF and RAS genes were detected by DNA pyrosequencing. Among the 77 tumours from exposed persons, we identified 7 ALK rearrangements and none in the unexposed group. When combining ALK and RET rearrangements, we found 24 in the exposed (31.2%) compared to two (10.5%) in the unexposed group. Odds ratios increased significantly in a dose‐dependent manner up to 6.2 (95%CI: 1.1, 34.7; p = 0.039) at Iodine‐131 thyroid doses >500 mGy. In total, 27 cases carried point mutations of BRAF or RAS genes, yet logistic regression analysis failed to identify significant dose association. To our knowledge we are the first to describe ALK rearrangements in post‐Chernobyl PTC samples using routine methods such as FISH and IHC. Our findings further support the hypothesis that gene rearrangements, but not oncogenic driver mutations, are associated with ionising radiation‐related tumour risk. IHC may represent an effective method for ALK‐screening in PTCs with known radiation aetiology, which is of clinical value since oncogenic ALK activation might represent a valuable target for small molecule inhibitors.

Characterization of thyroid cancer driven by known and novel ALK fusions

“…The average age of patients in our series was comparable to that of patients with PTCs unselected for genetic alterations: 43.4 (8-76) versus 46.8 (15-89) years, respectively (Cancer Genome Atlas Research Network 2014). The current study describes two pediatric patients, confirming previous observations of this fusion occurring in pediatric patients (Chou et al 2015, Vanden Borre et al 2017, Arndt et al 2018. The overall predilection for female patients appears to be more prominent in ALK-translocated group: 4.5:1 versus 2.7:1 among PTC patients unselected for ALK fusions (Cancer Genome Atlas Research Network 2014).…”

“…ALK-translocated thyroid carcinomas can occur both in patients with and without a history of radiation exposure. However, the prevalence of ALK fusions appears to be higher, up to 7.6-9% (Hamatani et al 2012, Arndt et al 2018, Efanov et al 2018, in PTCs from radiationexposed patients. An additional approach to increasing the chance of identifying ALK fusions is to exclude thyroid carcinomas with other, more common driver mutations such as BRAF, RAS, and RET/PTC.…”

The Immune Landscape of Thyroid Cancer in the Context of Immune Checkpoint Inhibition

“…Mutations of genes encoding the phosphoinositide-3-kinase–protein kinase B/ Akt -mammalian target of rapamycin (PI3K-PKB/ Akt-mTOR ) pathway were more frequent in ATC than PDTC (39% versus 11%). Anaplastic lymphoma kinase ( ALK ) gene rearrangements have been found in ATC [37] and in PTC [38]. GLIS3 rearrangements are prevalent in hyalinizing trabecular tumor (HTT), which is a rare TC with a characteristic trabecular growth pattern and hyalinization [39].…”

Radiation-Induced Thyroid Cancers: Overview of Molecular Signatures

“…A significant positive correlation between the 131 I thyroid dose and the incidence of chromosomal rearrangements was found, and the study reasonably claimed these could be induced by the radiation exposure. The dose-dependent incidence of the gene rearrangement was also reported for the ETV6-NTRK3 and STRN-ALK rearrangements [39,40]. By contrast, other reports concluded that the prevalence of the RET/PTC rearrangements were not associated with the exposure [72] or individual radiation doses [73].…”

“…As a result, the RET/PTC fusion proteins are constitutively active, and stimulate the mitogen-activated protein kinase (MAPK) pathway and other signaling cascades in a ligand-independent way [34,35,36,37]. Other types of rearrangements, such as ETV6-NTRK3 [38,39] and STRN-ALK [40,41], were also identified in the Chernobyl childhood thyroid cancer (Table 1).…”