Robert Stoehr

To detect novel Wnt-pathway genes involved in tumourigenesis, this study analysed the RNA expression levels of 40 genes of the Wnt pathway by chip hybridization of microdissected matched pairs of 54 primary prostate carcinomas. Eleven genes showed greater than two-fold differential expression in at least 10% of prostate cancers. Three of these genes encode extracellular components of the Wnt pathway (WNT2, WIF1, SFRP4); two are receptors (FZD4, FZD6); two belong to the intracellular signal cascade (DVL1, PPP2CB); one regulates transcription (TCF4); and three represent genes regulated by this pathway (CCND2, CD44, MYC). While SFRP4, FZD4, FZD6, DVL1, TCF4, and MYC are up-regulated, WIF1, WNT2, PPP2CB, CCND2, and CD44 are down-regulated in certain prostate cancer patients. Wnt inhibitory factor 1 (WIF1) and secreted frizzled related protein (SFRP4) showed the most significant aberrant expression at the RNA level. WIF1 was down-regulated in 64% of primary prostate cancers, while SFRP4 was up-regulated in 81% of the patients. Immunohistochemical analysis using a polyclonal antibody revealed strong cytoplasmic perinuclear WIF1 expression in normal epithelial cells of the prostate, breast, lung, and urinary bladder. Strong reduction of WIF1 protein expression was found in 23% of prostate carcinomas, but also in 60% of breast, 75% of non-small cell lung (NSCLC), and 26% of bladder cancers analysed. No significant association between WIF1 down-regulation and tumour stage or grade was observed for prostate, breast or non-small cell lung carcinomas, indicating that loss of WIF1 expression may be an early event in tumourigenesis in these tissues. However, down-regulation of WIF1 correlated with higher tumour stage in urinary bladder tumours (pTa versus pT1-pT4; p = 0.038).

Urothelial carcinoma of the renal pelvis and ureter may develop sporadically or as a manifestation of hereditary nonpolyposis colorectal cancer. The majority of hereditary nonpolyposis colorectal cancer is caused by mutation of the human DNA mismatch repair (MMR) genes and is detected by associated microsatellite instability (MSI). Seventy-three unselected urothelial carcinomas of the ureter and/or renal pelvis were screened for MSI using the National Cancer Institute-designated reference panel (plus BAT40). Instability of at least two microsatellite markers (MSI-high) was detected in 15 samples (21%). Immunohistochemical staining of the MMR proteins (hMSH2, hMLH1, or hMSH6) was absent in 13 of 15 (87%) MSI tumors, and alteration of coding sequence microsatellites (TGFbetaRII, Bax, hMSH3, and hMSH6) was found at frequencies of 7-33% in these samples. Tumors with MSI had significantly different clinical and histopathological features including higher prevalence in female patients, low tumor stage and grade, and a papillary and frequently inverted growth pattern. Our results suggest a molecular pathway of tumorigenesis that is similar to MMR-deficient colorectal cancers and consistent with the notion that the site distributions of hereditary or sporadic MSI-high tumors may reflect tissue-specific susceptibility to lesions processed by the MMR machinery.

Gastrointestinal (GI) neoplasms with rhabdoid features have been reported since 1989 under diverse names (giant cell carcinoma, pleomorphic carcinoma, malignant rhabdoid tumor, adenocarcinoma with rhabdoid features/phenotype, anaplastic carcinoma, etc.), but their clinicopathologic spectrum, SMARCB1 (INI1) status and relationship to common GI carcinomas have not been clarified yet. We describe 2 carcinomas from the stomach and the cecum with exclusive rhabdoid morphology. The patients died of disease at 6 and 10 months, respectively. The tumors coexpressed vimentin, pancytokeratin, and EMA. Both showed complete loss of nuclear SMARCB1/INI1. Molecular analysis (KRAS, EGFR, BRAF, PIK3CA, and microsatellite studies) revealed a CpG-island methylator phenotype in the cecal tumor (CIMP(+)/MLH1(-)/BRAF(V600E)/MSI-H), confirming epithelial origin. The gastric tumor showed poorly differentiated adenocarcinoma in regional nodes, again confirming epithelial derivation. Other genes tested were wild type in both cases. Review of reported cases (total: 39) revealed a glandular component in 33%. Affected sites are: stomach (13), colon (11), small bowel (10), and distal esophagus (5). Of the 34 patients with follow-up ≥12 months, 29 (85%) died within 1 year (mean: 4 mo). Molecular tests were performed in 8/39 cases. A CIMP(+)/BRAF(V600E)/MLH1(-) phenotype was found in 3/4 right colon tumors. Loss of nuclear SMARCB1 protein was noted in 3/6 cases tested. This study highlights the heterogeneity of rhabdoid GI neoplasms and supports their epithelial derivation. Rhabdoid phenotype likely represents a common pathway of dedifferentiation with frequent loss of SMARCB1 and highly aggressive course. The CIMP phenotype represents a novel subset of rhabdoid GI carcinomas. This rare variant should be distinguished from proximal-type epithelioid sarcoma and other SMARCB1-deficient mimics.