Familial gastrointestinal stromal tumors with KIT germline mutation in a Chinese family:A case report

BACKGROUND Familial gastrointestinal stromal tumors(GISTs)is a rare autosomal dominant disorder characterized by an array of clinical manifestations.Only 35 kindreds with germline KIT mutations and six with germline PDGFRA mutations have been reported so far.It is often characterized by a series of manifestations,such as multiple lesions and hyperpigmentation.However,the effect of imatinib treatment in these patients is still uncertain.CASE SUMMARY Here,we report two patients(father and daughter)in a Chinese family(for the first time)with germline KIT mutation,and described their pathology,genetics and clinical manifestations.A 25-year-old Chinese woman went to hospital because of abdominal pain,and computed tomography showed multiple tumors in the small intestine.Small pigmented spots appeared on the skin within a few months after birth.Her father also had multiple pigmented spots and a history of multifocal GISTs.Multiple GISTs associated with diffuse interstitial Cajal cells(ICCs)hyperplasia were positive for CD117 and DOG-1.Gene sequencing revealed a germline mutation at codon 560 of exon 11(p.V560G)of KIT gene in these two patients.Imatinib therapy showed the long-lasting disease stability after resection.Remarkably,the hypopigmentation of the skin could also be observed.Luckily germline KIT mutation has not been identified yet in the 3-year-old daughter of the female patient.CONCLUSION Diagnosis of familial GISTs depends on combination of diffuse ICCs hyperplasia,germline KIT/PDGFRA mutation,hyperpigmentation and family history.

Mutation of the KIT Gene, excluding Exon 11, in Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors(GISTs)are derived from the interstitial cells of Cajal,and are the most common mesenchymal tumors of the gastrointestinal tract[1].KIT proto-oncogene,receptor tyrosine kinase(KIT),and platelet-derived growth factor receptor alpha(PDGFRA)gene mutations are found in approximately 85%–90% cases of GIST.

Analysis of CD117-negative gastrointestinal stromal tumors

AIM: To identify the gastrointestinal stromal tumors(GISTs) that are negative for CD117 expression by immunohistochemistry and to characterize their malignant potential.METHODS: A total of 108 primary mesenchymal tumors of the gastrointestinal tract were screened to select CD117-negative tumors, from which KIT(exons 9, 11, 13, and 17)and PDGFRA (exons 10, 12, 14, and 18) were sequenced to identify GISTs. Tumor recurrence and distant metastasis were used as the criteria of malignancy.RESULTS: The result showed that approximately 25%(29/108) of the gastrointestinal mesenchymal tumors were negative for CD117 and approximately 6% (7/108)of the tumors were CD117-negative GISTs. All these CD117-negative tumors had a mutated KITand a wildtype PDGFRA. All CD117-negative GISTs with mutations at codons 557/558 of KIThad mitotic counts ＞10/50 high power field, and 75% (3/4) of them showed multiple recurrence or distant metastasis.CONCLUSION: CD1 17-negative KITmutated GISTs account for approximately 6% of the gastrointestinal mesenchymal tumors. Tumor recurrence or distant metastasis correlates to both theKITmutations at codons 557/558 and the mitotic counts, but not to the tumor size.

Treatment of patients with advanced gastrointestinal stromal tumor of small bowel: Implications of imatinib mesylate

AIM： To examine the impact of imatinib mesylate （Glivec） on patient survival and response and its safety, and the correlation of the response rate with the kit gene mutation status. METHODS： Thirty-three of 74 （44.6%） small bowel gastrointestinal stromal tumor （GIST） patients who developed recurrence after curative resection and not treated with Glivec were classified as group A patients. Twenty-two advanced small bowel GIST patients treated with Glivec were classified as group B patients. Clinicopathological features, post-recurrence and overall survival rates were compared. Each tumor in group B patients was investigated for mutations of kit or plateletderived growth factor alpha （PDGFRA）. The mutation type was correlated with clinical outcomes. The antitumor effect and safety of Glivec in group B patients were also assessed. RESULTS： Advanced small bowel GIST patients treated with Glivec had substatntially longer post-recurrence survival and higher overall survival rates than those not treated with Glivec. A total of 15 patients had a partial response （PR） （67.8%）. Activated mutations of c-kit were found in 16 of 19 tested patients and no PDGFRA mutant was identified. In 13 patients with GISTs harboring exon 11 kit mutations, the partial response rate （PR） was 69.3%, whereas two of three patients with tumors containing an exon 9 kit mutation had an overall response rate （ORR） of 66.7% （not significant）. CONCLUSION： Glivec significantly prolongs the postrecurrence and overall survival of Asian patients with advanced GISTs. Glivec induces a sustained objective response in more than half of Asian patients withadvanced small bowel GISTs. Activated mutations of kit exon 11 are detectable in the vast majority of GISTs. There is no difference in the PR rate for patients whose GISTs have kit exon 9 and exon 11 mutations.