G. Keller

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patients perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond

IMPORTANCE E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. OBJECTIVES To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. DESIGN, SETTING, AND PARTICIPANTS Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. MAIN OUTCOMES AND MEASURES Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. RESULTS Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. CONCLUSIONS AND RELEVANCE This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.

Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients

Germline mutations of the cell adhesion molecule E-cadherin have been shown for the first time to underlie a hereditary diffuse type gastric cancer syndrome (HDGC) in Maori families,1 and subsequently have been reported in HDGC patients of various ethnic origins.2–9 Gastric cancer may also be associated with other hereditary tumour syndromes, which are mainly characterised by carcinomas of other organs. One of these syndromes is the HNPCC syndrome (hereditary nonpolyposis colorectal cancer syndrome), which is caused by germline mutations in DNA mismatch repair genes.10 Furthermore, gastric cancer has been observed in the context of the Li Fraumeni syndrome, a rare cancer syndrome due to germline mutations of the TP53 tumour suppressor gene,11–14 as well as in association with the FAP and Peutz–Jeghers syndrome.15 Despite known molecular genetic causes, contributing to a genetic predisposition to gastric cancer, a considerable number of familial cases have been reported that were not attributable to one of this hereditary syndromes, suggesting that unknown susceptibility genes for gastric cancer might exist. Putative tumour suppressor genes that are commonly inactivated in sporadic gastric cancers, such as the RUNX3 or HPP1 genes, are potential candidate susceptibility genes.16,17 In a previous study, we identified one E-cadherin germline mutation among seven diffuse type familial gastric cancer patients, indicating that in addition to E-cadherin , other genes might be involved in genetic predisposition to the disease in this patient group.4 There were three goals of the present study. First, we aimed to extend our analysis of E-cadherin germline mutations to a higher number of patients, to evaluate the contribution of germline mutations in this gene to German familial and early onset gastric cancer patients and to characterise identified missense mutations for their functional relevance. Secondly, we wished to analyse the role …

CDH1 c-160a promotor polymorphism is not associated with risk of stomach cancer

We have combined data from case control studies designed to test the hypothesis that the c‐160a promotor polymorphism in the gene coding for the cell adhesion molecule E‐cadherin (CDH1) is associated with stomach cancer. A total of 899 individuals (433 patients and 466 controls) were analyzed. The genotype frequencies did not differ significantly between cases and controls, and the genotype‐specific risks were not significantly different from unity, with an odds ratio for heterozygotes compared with the common homozygote of 1.3 (95% CI 0.98–1.8) and 1.2 (0.68–2.0) for rare homozygotes compared with common homozygotes. We found no evidence for differences in risk for the intestinal‐ and diffuse‐type histopathologic subgroups.

The prognostic impact of O6-Methylguanine-DNA Methyltransferase (MGMT) promotor hypermethylation in esophageal adenocarcinoma

Promotor hypermethylation is a common event in human cancer. O6‐Methylguanine‐DNA Methyltransferase (MGMT) is a gene involved in DNA repair, which is methylated in a variety of cancer types. In colorectal cancer and lung cancer, hypermethylation of MGMT has been correlated with p53 mutation. In the present study, 132 samples of esophageal adenocarcinoma and 58 samples of normal esophageal tissue were investigated for MGMT hypermethylation status by methylation‐specific real‐time PCR and results were correlated to clinicopathological parameters, patients survival, p53 mutation and expression of p53 protein and MGMT protein. In the carcinomas, hypermethylation of MGMT was found in 63.6% of cases and loss of MGMT protein expression in 48.5% of cases. Furthermore, MGMT hypermethylation was found in 5.7% of normal esophageal smooth muscle tissue, in 20.0% of esophageal squamous epithelium and in 61.5% of nonneoplastic Barretts mucosa. In the carcinomas, hypermethylation of the MGMT gene was correlated with loss MGMT protein expression (p < 0.0001) and with high tumor differentiation (p = 0.0079). In contrast, no correlation between MGMT hypermethylation, Laurens classification, WHO classification, tumor size, gender, age, pT category and pN category, and p53 status was found. Neither MGMT hypermethylation nor loss of MGMT protein expression was correlated with patients survival. In conclusion, MGMT hypermethylation in esophageal adenocarcinoma is a frequent event that is associated with loss of MGMT protein expression but not with patients outcome.

Activation of the PI3K/AKT pathway correlates with prognosis in stage II colon cancer

Background:Patients with UICC/AJCC stage II colon cancer have a high 5-year overall survival rate after surgery. Nevertheless, a significant subgroup of patients develops tumour recurrence. Currently, there are no clinically established biomarkers available to identify this patient group. We applied reverse-phase protein arrays (RPPA) for phosphatidylinositide-3-kinase pathway activation mapping to stratify patients according to their risk of tumour recurrence after surgery.Methods:Full-length proteins were extracted from formalin-fixed, paraffin-embedded tissue samples of 118 patients who underwent curative resection. RPPA technology was used to analyse expression and/or phosphorylation levels of six major factors of the phosphatidylinositide-3-kinase pathway. Oncogenic mutations of KRAS and BRAF, and DNA microsatellite status, currently discussed as prognostic markers, were analysed in parallel.Results:Expression of phospho-AKT (HR=3.52; P=0.032), S6RP (HR=6.3; P=0.044), and phospho-4E-BP1 (HR=4.12; P=0.011) were prognostic factors for disease-free survival. None of the molecular genetic alterations were significantly associated with prognosis.Conclusions:Our data indicate that activation of the PI3K/AKT pathway evidenced on the protein level might be a valuable prognostic marker to stratify patients for their risk of tumour recurrence. Beside adjuvant chemotherapy targeting of upregulated PI3K/AKT signalling may be an attractive strategy for treatment of high-risk patients.

Familiäre Häufung von GERD und assoziierter Tumorerkrankungen — Indizien einer auch genetischen Erkrankungsdisposition

Eine familiare Haufung von Refluxerkrankungen, Barrettosophagus und Adenokarzinomen des gastroosophagealen uberganges bis hin zu scheinbar autosomal-dominant imponierenden Erbgangen wurde im eigenen Patientengut beobachtet und in der Literatur beschrieben. Neben exogenen Faktoren sind fur diese familiare Haufung auch genetische Faktoren zu vermuten. Zur Vorbereitung molekularbiologischer Untersuchungen bei GERD wurden daher Patienten mit der uberweisungsdiagnose „V.a. Refluxerkrankung“ im Rahmen einer Funktionsdiagnostik Familienanamnesefragebogen vorgelegt. Familienanamnestische Ad hoc-Angaben von 119 konsekutiven Patienten, die im gastroenterologischen Funktionslabor der Chirurgischen Klinik eine Refluxdiagnostik erhielten, wurden hinsichtlich der Haufigkeit des Symptoms, Sodbrennen„ und Tumorerkrankungen in der Familie ausgewertet (Gruppe A und B). 40 Patienten ohne Refluxsymptomatik wurden in einer Allgemeinarztpraxis auserhalb des Klinikums befragt (Gruppe C). 21 der 119 Patienten zeigten keine objektivierbare Refluxerkrankung (Gruppe B). Bei 98 Patienten konnte eine Refluxerkrankung gesichert werden (Gruppe A). Lediglich 18% der Patienten in Gruppe A gaben keine weiteren Refluxerkrankungen in der Familie an (B: 29%; C: 55%). 50% der Indexpatienten der Gruppe A konnten mindestens 2 weitere Familienmitglieder mit Refluxsymptomen benennen (B: 27%; C: 5%). Mindestens 3 weitere refluxpositive Familienmitglieder wurden von 25% der Indexpatienten in Gruppe A angegeben (B: 4%; C: 0%). 5 und 6 zusatzliche Familienmitglieder mit dem Symptom, Sodbrennen“ wurden von 4 (Gruppe A), 1 (Gruppe B) bzw. keinem (Gruppe C) Patienten benannt. 21 der 98 Indexpatienten in Gruppe A (21%) gaben mindestens eine weitere Tumorerkrankung der Speiserohre oder des Magens an (5% Gruppe B und C). Bei 18 Indexpatienten der Gruppe A mit negativer Refluxfamilienanamnese ist nur eine Familie mit einer Tumorerkrankung des Magens oder der Speiserohre anzutreffen (6%). In der Gruppe der 80 weiteren Indexpatienten der Gruppe A mit mindestens 1 weiteren Refluxerkrankung treten in ca. 25% der Familien Tumorerkrankungen auf unabhangig von der Anzahl der Familienmitglieder mit Refluxsymptomatik. Drei Familien mit jeweils 2 Tumorerkrankungen der Speiserohre oder des Magens weisen 4, 5 und 6 Familienmitglieder mit Refluxsymptomatik inklusive Indexpatienten auf (Gruppe A). Eine Frequenz von 25% refluxerkrankter Indexpatienten mit einer familiaren Haufung von Refluxsymptomen bei mindestens 4 Familienmitgliedern ist bemerkenswert hoch und wurde bisher wenig beachtet. Sie kann gleichermasen auf eine korperlich-konstitutionelle, exogene oder hereditare Komponente der Genese hinweisen. Eine exakte Objektivierung familienanamnestischer Daten ist in einem weiteren Schritt erforderlich, um potentielle Familien mit niedrigem und hohem Risiko fur die Refluxerkrankung und assoziierte Tumorerkrankungen zu identifizieren. Dieses Patientenkollektiv bietet die Moglichkeit zu einer molekularbiologischen Analyse konstitutioneller Polymorphismen sowie potentieller Zielgene im Sinne von Erbgangen mit niedriger und hoher Penetranz fur die Refluxerkrankung.

New Molecular Aspects in Gastric Cancer: Possible Clinical Implications

The investigation of molecular and genetic changes in tumor cells has brought new insights into the evolution of human malignancies. We have focused on the identification and characterization of genet