Valeria Pascale

E-cadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer

AIM CDH1 germline alterations occur in about 40% of hereditary diffuse gastric cancer (HDGC) families. CDH1 germline mutations are also documented in few early onset diffuse gastric cancer patients (EODGC) without family history, but the real frequency in this setting in unknown. In these patients, the advanced stage at the time of diagnosis remains a clinical burden due to the poor long term survival. METHODS The entire coding region and exon flanking sequences of the CDH1 gene was analysed by direct sequencing in 21 EODGC patients aged ≤50 years. The potential deleterious nature for a new CDH1 missense variant was assessed by cell-cell aggregation and invasion assays. Somatic CDH1 mutation, loss of heterozygosity (LOH) and promoter hypermethylation was explored in the tumour from one CDH1 germline mutation carrier. RESULTS Two novel CDH1 germline variants were identified in 21 EODGC cases, c.670C>T and -63C>A. Functional analysis of the c.670C>T missense variant classified this mutation as non-pathogenic. The analysis of CDH1 somatic second hits failed to demonstrate E-cadherin structural and epigenetic alterations in the tumour sample. CONCLUSION Data from the present work and a systematic review of the literature revealed that CDH1 germline mutations occurred in 7.2% of EOGC patients invariably with diffuse of mixed histology. From these, proved CDH1 mutation pathogenicity has been assigned only to 2.3% of the cases who were recurrently diagnosed before 35 years old. Germline CDH1 mutation remain the only germline genetic defect described in this type of patients and CDH1 mutation screening should be recommended for patients with these characteristics.

Molecular key to understand the gastric cancer biology in elderly patients—The role of microsatellite instability

Microsatellite instability (MSI) in gastric cancer (GC) is associated with older age. We present the clinicopathological results of younger and older patients with MSI GC.

The Role of Microsatellite Instability in Positive Margin Gastric Cancer Patients

Purpose. A positive resection margin (RM+) is acknowledged as a poor prognostic factor after gastrectomy. Microsatellite instability (MSI-H) gastric cancer has been identified as a subgroup of gastric cancer that may be associated with an improved prognosis. The aim of the study was an analysis of MSI status on patients with margin involvement after gastrectomy and examination of the association between MSI, margin status, and survival outcomes. Methods. From a large prospectively annotated surgical database we collected clinicopathological and survival data on patients who had undergone a potentially curative resection for gastric cancer. MSI status was assessed using a standard 5-marker quasi-monomorphic mononucleotide repeat panel. Patients who were R+ and either microsatellite stable (MSS) or MSI-H were identified and clinicopathological characteristics and disease specific survival was compared. Results. Three hundred and eighty-six patients were identified; 102 (26.4%) cancers were MSI-H. The proportion of R+ resections was not significantly different in MSS and MSI-H groups. For MSS patients 3-, 5-, and 10-year disease-specific survival rates were 9.1%, 0%, and 0%, respectively; for patients with MSI-H R+ tumors these were 38.5%, 30.8%, and 15.4%, respectively. In Cox analysis MSI-H, female gender, and T ≥3 were significantly associated with survival. Conclusions. Patients with MSI-H gastric cancer may have long-term survival despite R+ margin status. The molecular division of gastric cancer may be an important step in identifying possible tailored surgical treatments corresponding to clinical and pathological factors.

PIK3CA mutation in gastric cancer and the role of microsatellite instability status in mutations of exons 9 and 20 of the PIK3CA gene

BACKGROUND A better understanding of molecular gastric cancer (GC) entities may help in tailored treatments of that neoplasm. The PIK3CA mutation is one of the most important in many cancers. OBJECTIVES We performed a comparison of clinical and pathological data of the PIK3CA mutation in GC patients. MATERIAL AND METHODS The analysis was done on 472 patients operated on in 1 center. Polymerase chain reaction (PCR) was used for the screening of PIK3CA (exon 9 and 20). For microsatellite instability (MSI) we used 5 quasi-monomorphic mononucleotide repeats - BAT-26, BAT-25, NR-24, NR-21, and NR-27. The clinical and pathological data was analyzed. RESULTS PIK3CA mutation was observed in 10 out of 472 GC patients (2.1%). Nine out of 10 were MSI (9 of 111 MSI patients - 8.1%). Half of the 10 patients had mutations in exon 9 and the other half in exon 20. A majority of patients with the PIK3CA mutation had MSI (p < 0.001). The 5-year survival of MSI patients with the PIK3CA mutation was 40% and without the mutation, 70.4% (p = 0.309). For patients with the mutation in exon 9, the 5-year survival was 0%, and for those with the mutation in exon 20, 80% (p = 0.031). The Cox proportional hazards regression analysis did not show that PIK3CA is statistically correlated with a worse overall survival. CONCLUSIONS PIK3CA mutation in GC is a rare finding. It is strongly associated with the MSI molecular subgroup, presenting a worse outcome than other MSI patients. A completely different outcome is associated with the mutation in exon 9 compared to the mutation in exon 20, with the latter being more favorable.