Hereditary gastrointestinal stromal tumors sharing the KIT Exon 17 germline mutation p.Asp820Tyr develop through different cytogenetic progression pathways

Abstract

Hereditary gastrointestinal stromal tumor (GIST) syndrome is a rare autosomal dominant genetic disorder originated by germline mutations in the KIT or PDGFRA genes. We report the third family with hereditary predisposition to GIST due to the KIT Exon 17 germline mutation p.Asp820Tyr and characterize the cytogenetic progression pathways followed by different GIST sharing the same primary genetic event, using a combination of chromosome banding, comparative genomic hybridization (CGH), and fluorescence in situ hybridization (FISH) analyses. The missense mutation p.Asp820Tyr was detected in the proband's rectal and gastric GIST, as well as in his aunt's GIST epiplon metastasis. The mutation p.Asp820Tyr was subsequently also found in the proband's peripheral blood DNA, as well as in that of 4 of 10 relatives thus far analyzed. CGH analysis revealed loss of 14q and 15q in the proband's gastric lesion, whereas FISH analysis of the proband's rectal GIST did not detect loss of 14q and 15q, but instead loss of 4q and 22q and gain of 20q, indicating that the two tumors were independent GIST. Chromosome banding and CGH analyses of the aunt's GIST epiplon metastasis revealed multiple cytogenetic alterations, including 1p loss, but none in common with the two proband's GIST. We conclude that, although the patients share the same KIT Exon 17 germline mutation, the multiple GIST analyzed followed different pathogenetic progression pathways, each of which did not significantly differ from what has been described in sporadic GIST.

Chromosome copy number changes carry prognostic information independent of KIT/PDGFRA point mutations in gastrointestinal stromal tumors

“…Indeed, one patient with an intestinal lesion with less than 2 cm and low mitotic rate (patient 20, categorized in the low-risk group) developed metastases and died from the disease 11 months after diagnosis. More recently, anatomic location was also considered of relevance and included in the determination of the risk of recurrence and progression [21,24]. Our findings strongly support this prediction model, as a significant proportion of small intestine or colon GIST developed metastasis, whereas most tumors located in the stomach showed no progression events.…”

“…Mutations were detected in 61 tumors (76.25%, Figure 1), namely in exon 11 (n = 52), exon 9 (n = 7) and exon 17 (n = 2). The two patients with KIT exon 17 mutation were subsequently found to be relatives and the mutation shown to be present in the germline [21]. No primary mutations were found in exon 13.…”

“…Finally, the two patients in which we identified the same KIT exon 17 mutation were recently found to be relatives. In fact, we were able to show that the p.Asp820Tyr was present also in the germline, representing the third example in the literature of hereditary GIST caused by this same mutation [21]. …”

Diagnostic criteria, specific mutations, and genetic predisposition in gastrointestinal stromal tumors

“…They occurred at earlier ages than corresponding sporadic GISTs, commonly in young adults, and median age at diagnosis is approximately 40–50 years. Some authors have suggested a possible genetic anticipation because of decreasing age at diagnosis across generations 141,144,150. However, it was not reported previously, and earlier ages at diagnosis might be only due to greater interest for GISTs and/or screening of relatives.…”

“…Today, 16 different germline mutations involving exons 8, 11, 13, or 17 of KIT or exons 12 or 14 of PDGFRA have been reported to our knowledge (Table 3). 131–150 In all publications, the pattern of inheritance is autosomal dominant with a penetrance of almost 100%. GISTs are multiple in most cases and frequently multifocal.…”