Purpose-Microsatellite instability (MSI) is the hallmark of cancer with DNA mismatch repair (MMR) deficiency and underlies 20-30% of endometrial cancer. Some in vitro studies suggest that radiation effects are modulated by the MMR system, however, little is known about the relationship between MSI and radiation response. The aim of this study was to elucidate whether MSI predicts clinical outcome in radiation treated endometrioid endometrial cancer (EEC).Methods-We have studied a consecutive series of 93 patients with EEC treated with extrafacial hysterectomy and postoperative radiotherapy. The median clinical follow up of patients was of 138 months, with a maximum of 232 months. Five quasimonomorphic mononucleotide markers (BAT-25, BAT-26, NR21, NR24 and NR27) were used for MSI classification.Results-Twenty five patients (22%) were classified as MSI. Either in the whole series and in early stages (I and II), univariate analysis showed a significant association between MSI and a poorer 10-years local disease free (LDFS), disease free (DFS), and cancer-specific survival (CSS). In multivariate analysis, MSI was excluded from de final regression model in the whole series, but in early stages, MSI provided additional significant predictive information independent of traditional prognostic and predictive factors (age, stage, grade and vascular invasion) for DFS (HR, 3.25, 95%

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Microsatellite instability (MSI) and mutations in the PTEN gene are among the molecular alterations involved in endometrial carcinogenesis. There is conflicting information regarding to their role in this type of tumor. For this reason, we have studied both molecular lesions in a large population-based series of 205 patients with sporadic endometrial cancer. MSI was found in 41 (20.0%) of the tumors and PTEN mutations were found in 74 (36.1%). There were differences in genotype between tumors with and without MSI. Tumors with MSI showed both a higher frequency of PTEN mutations (58.5% vs. 30.4%) (p 5 0.002, Fisher's exact test) and a higher number of insertions or deletions (I/D) of one nucleotide within the mononucleotide tracts of the PTEN gene (45.8% vs. 11.4% out of all I/D, p 5 0.005). Conversely, G:C to A:T transitions in CpG dinucleotides were found mostly in microsatellite stable tumors (57.7% vs. 18.2% out of all single-base substitutions, p 5 0.037). Overall, 67.6% of tumors with mutated PTEN exhibited multiple mutations or allelic imbalance (AI). Multiple PTEN mutations in the same tumor were more frequent in tumors with MSI (60% vs. 25.7%); by contrast the presence of AI accompanying PTEN mutation was higher in microsatellite stable tumors (74.3% vs. 40%) (p 5 0.028). In addition, patients with both genetic alterations were diagnosed at more advanced stage of progression (54.2% for MSI vs. 20.0% for MSS, p 5 0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1-13.1], p 5 0.034, log-rank test) than patients with only the PTEN gene mutated. Our data suggest that the DNA mismatch repair system status influences: (i) both the frequency and the mutational spectrum of PTEN; (ii) the nature of one of the hits that inactivate this tumor-suppressor gene; and (iii) the clinical condition and behavior of the patients. ' 2006 Wiley-Liss, Inc.Key words: microsatellite instability; PTEN mutation; endometrial cancer Microsatellite instability (MSI) is caused by defects in the DNA mismatch repair (MMR) system, either by mutations or by epigenetic events leading to gene silencing. 1,2 Tumors with MSI are characterized by a massive instability in simple repeated sequences and mutations in many cancer-related genes, particularly those with simple repeated sequences in their coding regions. [3][4][5][6][7] Tumors with MSI display a strong microsatellite mutator phenotype (MMP), which underlies a mutational pathway for gastrointestinal cancer that differs in genotype and phenotype from cancers with microsatellite stability (MSS).The MMP pathway for colon cancer possesses several peculiar characteristics in genotype. These tumors show a paradoxically low incidence of mutations affecting the prototypical cancer genes for colon cancer, namely the APC and p53 tumor suppressor genes and the K-ras oncogene. 3,[8][9][10][11] This low mutational incidence is also accompanied by a decreased incidence of loss of heterozygosity (LOH), 1,3,12 which is reflected at the cytogenetic level in freque...

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The EPH/EFN family of receptor tyrosine kinases regulates cell adhesion and migration and has an important role in controlling cell positioning in the normal intestinal epithelium. Inactivation of EPHB2 has recently been shown to accelerate tumorigenesis in the colon and rectum, and we have previously demonstrated frequent frameshift mutations (41%) in an A9 coding microsatellite repeat in exon 17 of EPHB2 in colorectal tumors with microsatellite instability (MSI). In this study, we extended these analyses to extracolonic MSI cancers, and found frameshift EPHB2 mutations in 39% (25/64) of gastric tumors and 14% (8/56) of endometrial tumors. Regression analysis of these EPHB2 mutation data on the basis of our previously proposed statistical model identified EPHB2 as a selective target of frameshift mutations in MSI gastric cancers but not in MSI endometrial carcinomas. These results suggest a functional role for EPHB2 in gastric tumor progression, and emphasize the differences between the tumorigenic processes in MSI gastrointestinal and endometrial cancer.

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The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.

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