Patient Characteristics.

<p>Abbreviations: *Age at diagnosis; ⁺Response to induction therapy, CCR, complete clinical responder; NR, non-responder; <b>^†</b> Alive (A) or Deceased (D) in 2009 ; MA, microarray; TLDA, Taqman low density array card; PF, Cisplatin/5FU; T1PF, Cisplatin/5FU/Paclitaxel; T2PF, Cisplatin/5FU /Docetaxel.</p

Gene Signature That Predicts Response to PF.

<p>Gene Signature That Predicts Response to PF.</p

Statistical Summary for 10 Gene Predictor.

*<p>The samples in this group contained all but one of the samples analyzed by MA. **Samples in this group contained the 5 additional samples analyzed by TLDA that were not analyzed by MA.</p

Characteristics of Patients (TLDA Study).

<p>Characteristics of Patients (TLDA Study).</p

Characteristics of Patients (Microarray Study).

*<p>The probability was calculated with the Fisher Exact Test.</p>**<p>Alcohol was consumed predominantly in the form of red wine.</p><p>Note that the HPV status could not be ascertained for one individual of the Responder group.</p

Representative HES, p16 and HPV staining of biopsies from NR and CCR individuals.

<p>HES-NR and HES CCR correspond to hematoxylin-eosin-safran staining of representative non-responder and complete clinical responder individuals, respectively, and IHC-p16 and HIS-oncogenic HPV correspond to representative positive immunohistochemistry for the p16 antigen (brown staining) and hybridization <i>in situ</i> for oncogenic HPV DNA (blue punctate nuclear staining), respectively. The bar represents 40 microns in the upper panels and 20 microns in the lower panels.</p

Multidimensional scaling in three dimensions (using Euclidean distances) of the microarray (MA) and TLDA (TLDA) gene expression data.

<p>The 10-gene classifier clearly separates the members of the NR (blue spheres) and CCR (red spheres) groups. 82–83 per cent of the variability is contained in these first three dimensions.</p

Sporadic Early-Onset Colorectal Cancer Is a Specific Sub-Type of Cancer: A Morphological, Molecular and Genetics Study

<div><p>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 <i>TP53</i>, <i>KRAS</i>, <i>BRAF</i>, <i>PIK3CA</i> 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 <i>BRAF</i> 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.</p></div

Beta catenin immunostaining in MSS tumors.

<p><b>A.</b> Cross-section of a tumor from an MSS-Old patient shows only membrane staining. <b>B</b>. Cross-section of a tumor from a sporadic EOCRC (MSS–Young) patient shows strong cytoplasmic and nuclear staining with a loss of membrane staining, reflecting Wnt/beta catenin activation.</p

Clinico-pathological features of each group showing significant differences among the 79 variables studied.

<p>Data are expressed as absolute number and relative percentage. SD: standard deviation, M/F: male/female, UICC: Union for International Cancer Control (2002 classification), CRC: colorectal cancer. *: One case with liver and ovary metastases, 6 cases with liver and lung metastases, one case with liver and brain metastasis and one case with ovary and peritoneum metastasis. **: Two cases presented with liver and peritoneum metastases.</p