Rama Modali

Merkel cell carcinoma subgroups by merkel cell polyomavirus DNA relative abundance and oncogene expression

Merkel cell polyomavirus (MCPyV) was recently discovered in Merkel cell carcinoma (MCC), a clinically and pathologically heterogeneous malignancy of dermal neuroendocrine cells. To investigate this heterogeneity, we developed a tissue microarray (TMA) to characterize immunohistochemical staining of candidate tumor cell proteins and a quantitative PCR assay to detect MCPyV and measure viral loads. MCPyV was detected in 19 of 23 (74%) primary MCC tumors, but 8 of these had less than 1 viral copy per 300 cells. Viral abundance of 0.06–1.2 viral copies/cell was directly related to presence of retinoblastoma gene product (pRb) and terminal deoxyribonucleotidyl transferase (TdT) by immunohistochemical staining (p ≤ 0.003). Higher viral abundance tumors tended to be associated with less p53 expression, younger age at diagnosis and longer survival (p ≤ 0.08). These data suggest that MCC may arise through different oncogenic pathways, including ones independent of pRb and MCPyV.

Merkel cell polyomavirus is not detected in mesotheliomas.

BACKGROUND Merkel cell polyomavirus (MCPyV) is the first polyoma virus consistently linked to the etiology of a human cancer. Serological studies indicate that the virus is commonly acquired in childhood, with seroprevalence reaching 50% or higher among young adults. The modes of MCPyV transmission are still unclear, but it has been identified in respiratory tract samples. Given its respiratory tropism, we examined whether MCPyV could be detected in mesothelioma tissue, a malignancy induced in animal models by another polyomavirus, SV40. OBJECTIVE To determine if MCPyV DNA can be detected in mesothelioma. STUDY DESIGN DNA was extracted from 45 fresh-frozen mesothelioma samples. PCR was used to detect and quantify the abundance of MCPyV DNA, and a human control gene, in duplicates of the tissues. DNA from a sequence verified MCC tumor was used as a positive control. RESULTS The human control gene was detected at high levels in all but three mesothelioma tissues. MCPyV DNA was detected in only one mesothelioma, and the level of viral DNA was very low. CONCLUSIONS These results are inconsistent with the hypothesis that MCPyV is etiologically linked to mesothelioma.

Dopamine D2 receptor polymorphisms and adenoma recurrence in the Polyp Prevention Trial

Epidemiological evidence suggests that obesity may be causally associated with colorectal cancer. Dopamine and the dopaminergic reward pathway have been implicated in drug and alcohol addiction as well as obesity. Polymorphisms within the D2 dopamine receptor gene (DRD2) have been shown to be associated with colorectal cancer risk. We investigated the association between DRD2 genotype at these loci and the risk of colorectal adenoma recurrence in the Polyp Prevention Trial. Odds ratios (OR) and 95% confidence intervals (CI) for risk of adenoma recurrence were calculated using unconditional logistic regression. Individuals with any, multiple (≥2) or advanced adenoma recurrence after 4 years were compared to those without adenoma recurrence. Variation in intake of certain dietary components according to DRD2 genotype at 3 loci (rs1799732; rs6277; rs1800497) was also investigated. The DRD2 rs1799732 CT genotype was significantly associated with all adenoma recurrence (OR: 1.30; 95% CI: 1.01, 1.69). The rs1800497 TT genotype was also associated with a significantly increased risk of advanced adenoma recurrence (OR: 2.40; 95% CI: 1.11, 5.20). The rs1799732 CT and rs1800497 TT genotypes were significantly associated with adenoma recurrence in the Polyp Prevention Trial. Increased risk of adenoma recurrence as conferred by DRD2 genotypes may be related to difference in alcohol and fat intake across genotypes. Published 2008 Wiley‐Liss, Inc.

Oncogenes and Tumor Suppressor Genes Involved in Human Lung Carcinogenesis

Carcinogenesis is a multistage process involving both genetic and epigenetic aberrations. Activation of proto-oncogenes and/or inactivation of tumor suppressor genes may occur in an early stage of carcinogenesis, i.e., tumor initiation, as well as in the later stages e.g., tumor conversion and progression (Fig. 1). For example, activation of Ki-ras by base substitution mutations is an early event in human colon carcinogenesis (Vogelstein et al., 1988), whereas amplification of N-myc is associated with the tumor progression stage of human neuroblastoma (Brodeur et al., 1987). In the inherited form of retinoblastoma, a defective tumor suppressor gene, Rb-1, is found in the germline DNA and the second Rb-1 allele is inactivated most frequently by deletion or recombinational mechanisms during the initia1 stages of carcinogenesis (Knudson, 1985; Hansen et al., 1985; Cavenee et al., 1986; Friend et al., 1986; Fung et al., 1987). In contrast, the inactivation by somatic mutation of both alleles of the p53 gene appears to occur during tumor progression of human carcinomas of the colon (Baker et al., 1989), breast and lung (Nigro et al., 1989).

Polynucleotide kinase 3' phosphatase variant, dietary variables and risk of adenoma recurrence in the Polyp Prevention Trial.

Polymorphisms in a number of genes encoding for DNA repair enzymes have been associated with altering the function of these enzymes and increasing risk of a number of cancers, including colon cancer. We have investigated the association between a common variant in polynucleotide kinase 3′ phosphatase (PNKP), a putative DNA repair enzyme, and risk of adenoma recurrence in the Polyp Prevention Trial participants. We also investigated possible interaction or effect modification between carriage of the variant allele, dietary components and risk of adenoma recurrence. Unconditional logistic regression models were used to calculate the odds ratios and 95% confidence intervals for an association between the G/T polymorphism, PNKP T5644G and risk of adenoma recurrence. We observed no association between carriage of the variant allele and risk of adenoma recurrence. Furthermore, we found no effect modification between genotype, dietary components and risk of adenoma recurrence. The PNKP T5644G variant does not seem to be involved in adenoma recurrence in the Polyp Prevention Trial.