Anaplastic lymphoma kinase (ALK) gene alteration in signet ring cell carcinoma of the gastrointestinal tract

Abstract

Objectives: ALK-EML4 translocation is an established driver aberration in non-small cell lung cancer (NSCLC), with reported predilection for cases with signet ring histology. We assessed the presence of anaplastic lymphoma kinase (ALK) gene rearrangements in signet ring cancers arising in the stomach and colon. Methods: Histologically confirmed cases of signet ring adenocarcinoma of the stomach or the colon were identified. The presence of the classic ALK and EML4 fusion gene was initially determined by fluorescence in-situ hybridization (FISH) technique. Immunohistochemistry (IHC) was performed using two previously validated antibodies, ALK1 clone (1:100; DAKO) and 5A4 (Novocastra, Leica Biosystems) along with positive controls of ALK-translocated lung cancer. Results: We employed 42 cases of signet ring carcinoma diagnosed between 2001 and 2011; 25 gastric and 17 colon cancer. Median age 63.3 years; male/female 17/25; race, black 47.5%, white 47.5%, others, 5%; stage I, 21.4%; stage II, 31%; stage III, 26.2%; stage IV, 21.4%. One of 42 cases (2.3%) was positive for ALK translocation by FISH using the standard criteria of at least 15% positive cells for the break-apart signal (50-70 cells enumerated per case). Using a less restrictive cut-off of 10% positive cells, 7 cases (16%) were considered possibly positive. None of the 'possibly positive' cases was found to harbor ALK translocation by another molecular testing approach (IHC). IHC with two previously validated monoclonal antibodies showed 0 of 42 (0%) cases positive. Conclusions: ALK gene rearrangement is very rare in gastrointestinal cancers and enrichment strategy focusing on signet ring cell histology did not significantly improve the detection rate.

Expression of CDX-2 and ALK in primary gastric carcinoma

“…Moreover, Ferreri et al (2012) reported in their study on ALCL that ALK + ALCL cases were characterized by five distinctive patterns: young age, male predominance, advanced stage, systemic symptoms, and extranodal involvement. Moreover, increased proportion of signet ring cell gastric carcinoma cases with ALK + immunostaining in this study was in agreement with other studies, in which Alese et al (2015) found increased ALK gene rearrangement in signet ring cell carcinoma of gastrointestinal tract. Moreover, Popat et al (2012) observed that ALK rearranged lung adenocarcinomas had the signet ring morphology, suggesting the biologic function of ALK rearrangement in signet ring cell carcinoma.…”

“…In our study, ALK expression was found in only 11.8% of gastric carcinoma cases. Similarly, a low incidence of ALK gene rearrangement in gastrointestinal tumors was reported by Alese et al (2015), who found that ALK gene rearrangement detected with immunohistochemistry is rare in gastrointestinal cancers.…”

The Landscape of Actionable Gene Fusions in Colorectal Cancer

“…ALK and ROS1 rearrangements (enlisted in Table 1a) rarely have been also identified in mCRC using technologies based on fluorescence in situ hybridization (FISH) [61], exon array profiling [62], and next generation sequencing (NGS) [14,33] performed on archival tumor specimens.…”

Case Report: RAB10-ALK: A Novel ALK Fusion in a Patient With Gastric Cancer

“…Previous studies on the gene fusion mutations in gastric or signet ring adenocarcinoma are few, which may be related to the usual use of methods other than NGS in the past. For example, in 42 cases of signet ring cell carcinoma of the gastrointestinal tract, two different ALK antibody based IHC did not detect the “possibly positive” cases with ALK translocation detected by FISH ( 6 ). With the application of NGS technology and other genomic technologies, GC is currently being studied and typed in more detail at the molecular level.…”