Sporadic early onset colorectal carcinoma (EOCRC) which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve identification of distinct sub-types of colorectal cancers (CRC) with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45–60 years were excluded to help define “young” and “old” groups. Thirty-nine cases of sporadic EOCRC (patients≤45 years with microsatellite stable tumors) were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years) and to groups of patients with microsatellite instability. Each group was tested for TP53, KRAS, BRAF, PIK3CA mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013). Genetic studies also showed the absence of BRAF mutations (p = 0.022) and the methylator phenotype (p = 0.005) in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF) and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01). This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways including the TNFR1 pathway have been identified as potential biomarkers for both the diagnosis and treatment of this disease.

Occasional EBV infection of human NK cells may lead to malignant diseases such as naso-pharyngeal NK lymphoma although NK cells do not express CD21, the primary receptor for EBV. Here we show that during early EBV infection in patients, NK cells attacked EBV-infected autologous B cells. In vitro, NK cells activated by conjugation to CD21+ B-EBV cell targets transiently acquired a weak CD21+ phenotype by synaptic transfer of few receptor molecules onto their own membrane. In the presence of viral particles, these ectopic receptors allowed EBV binding to the novel NK cell host. Hence, trans-synaptic acquisition of viral receptor from target cells might constitute an unsuspected mode of infection for otherwise unreachable lymphoid hosts.

Although deregulated expression of specific microRNAs (miRNAs) has been described in solid cancers and leukemias, little evidence of miRNA deregulation has been reported in ALK-positive (ALK ؉ ) anaplastic large cell lymphomas (ALCL). These tumors overexpress the major antiapoptotic protein myeloid cell leukemia 1 (MCL-1), a situation that could compensate for the lack of BCL-2. We report that ALK ؉ ALCL cell lines and biopsy specimens (n ‫؍‬ 20) express a low level of miR-29a and that this down- IntroductionAnaplastic lymphoma kinase-positive (ALK ϩ ) anaplastic large cell lymphoma (ALCL) is now recognized as a distinct entity in the World Health Organization (WHO) classification of hematopoietic tumors 1,2 and is characterized by the expression of an oncogenic fusion protein involving the ALK tyrosine kinase receptor. 3,4 Most of the activated pathways downstream to this fusion protein with a constitutive tyrosine kinase activity have been characterized and play major roles in lymphomagenesis in ALK ϩ ALCL, controlling key cellular processes such as proliferation, survival, and cell migration (for review see Chiarle et al 5 ). Another characteristic of ALK ϩ ALCLs is the lack or low expression of the antiapoptotic proteins BCL-2 and BCL-XL, suggesting a possible explanation for their relatively good prognosis. However, these tumors overexpressed MCL-1 (myeloid cell leukemia-1), an oncogene of particular interest, belonging to BCL-2 family of apoptosisregulating proteins, 6 and also involved in programming differentiation 7 and promoting cell viability. 8 MCL-1 expression could compensate for the lack of immunohistochemically detectable BCL-2 and BCL-XL expression in ALK ϩ ALCL. [9][10][11] Some studies have suggested that the Jak-STAT and PI3K pathways activated in ALK ϩ tumors could be involved in up-regulating MCL-1 but other pathways at the posttranscriptional level, such as microRNAs, might also contribute to its high expression in ALK ϩ ALCL cases (see reviews by Akgul 12 and Michels et al 13 ).Micro-RNAs (miRNAs) are small noncoding RNAs that regulate target gene expression posttranscriptionally through base pairing within the 3Ј-UTR regions of the target messenger RNAs and inducing their degradation, translational inhibition, or both of the encoded proteins. 14,15 MiRNAs play key regulator roles in fundamental biologic processes including cell differentiation, apoptosis, cell proliferation, organ development, and hematopoiesis (see review by Kluiver et al 16 ). family members have been shown to be down-regulated in several hematopoietic neoplasms, including chronic lymphocytic leukemia with poor prognosis, 17 acute myeloid leukemia, 18 and mantle cell lymphoma, 19 as well as solid cancers such as lung cancer, 20 hepatocellular carcinoma, 21 and invasive breast cancer. 22 More particularly, miR-29a, miR-29b, or both directly target the antiapoptotic protein MCL-1 in cholangiocarcinoma, 23 hepatocellular carcinoma, 21 and acute myeloid leukemia (AML). 18 However, to date, only one study has addressed th...