Fractional allelic loss in non–end-stage cirrhosis: Correlations with hepatocellular carcinoma development during follow-up

Roncalli, Massimo; Bianchi, Paolo; Grimaldi, Giorgia Ceva; Ricci, Daniele; Laghi, Luigi; Maggioni, Marco; Opocher, Enrico; Borzio, Mauro; Coggi, Guido

doi:10.1053/he.2000.5790

Cited by 39 publications

(19 citation statements)

References 30 publications

(53 reference statements)

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“…Indeed we found that most cirrhoses and the vast majority of malignant tumors had promoter methylation affecting at least a single gene. Thus, in addition to well-recognized molecular abnormalities such as loss of heterozygosity, deletion, and point mutation, [16][17][18][19][20] inactivation of cell cycle inhibitors by epigenetic mechanisms seems to play an important role in human hepatocarcinogenesis. We have also found that methylated cirrhosis usually associates to methylated HCC, suggesting a common mechanism of gene inactivation from cirrhosis to HCC.…”

Section: Discussionmentioning

confidence: 99%

Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma

et al. 2002

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One of the main regulatory pathways reported to be altered in hepatocellular carcinoma (HCC) is that of cell cycle control involving RB1 gene-related cell inhibitors. We investigated p14 ARF , p15 INK4B M ethylation of normally unmethylated CpG islands is an alternative mechanism for loss of function of tumor suppressor genes in human cancer. p16 INK4A is one of the most important tumor suppressor genes belonging to the family of cell cycle inhibitors, encoding a protein that binds competitively to cyclin-dependent-kinase-4 proteins. In hepatocellular carcinoma (HCC), methylation of p16 INK4A promoter has already been documented with variable frequency. [1][2][3][4] Wong et al. 5 recently reported p16 INK4A promoter methylation in 81% of sera samples of patients with methylated HCC. This result is particularly interesting for early diagnosis and possible therapeutic implications because promoter methylation is potentially reversible. It is known that cirrhosis is a favorable background for HCC development so that, not unexpectedly, p16 INK4A methylation was also recently reported by Kaneto et al. 6 in 30% of cirrhoses, suggesting its potential clinical use for selecting patients at high risk for HCC.The functional significance of promoter methylation was also established in a number of studies showing that this epigenetic abnormality usually corresponds the abrogation of messenger RNA (mRNA) synthesis and protein expression in both tumoral and nontumoral liver tissue. 3,4,6 Interestingly, concurrent inactivation of tumor suppressor genes of RB1 gene-related pathways such as p16 INK4A , p14 ARF , and p15 INK4B by promoter methylation has been shown not only in many types of human tumors, such as meningiomas, central nervous system lymphomas, and glial tumors, 7-9 but also in early preneoplastic Abbreviations: HCC, hepatocellular carcinoma; PCR, polymerase chain reaction. From the

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Section: Discussionmentioning

confidence: 99%

Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma

et al. 2002

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“…This position appears partially conservative, and others have questioned whether it was appropriate to continue using dinucleotide markers for the purpose of MSI identification (Laghi et al, 2004). Furthermore, the appropriate use of mononucleotide markers was instrumental in ruling out MSI as a frequent cancer phenotype in organs other than the colon, in which it was improperly assessed merely by taking advantage of dinucleotide microsatellites used for LOH assessment (Roncalli et al, 2000). Taking for granted that using BAT26 alone might lead to some (unknown) underestimation of the true MSI, owing to the non-recognition of the cases with biallelic hMSH2 deletion, we screened by this marker probably the largest mono-institutional series of consecutive surgically resected CRCs and found a 10% MSI prevalence (Malesci et al, 2007).…”

Section: Improving the Standards For Msi Identification By Evaluatingmentioning

confidence: 99%

Differences and evolution of the methods for the assessment of microsatellite instability

2008

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Microsatellite instability (MSI) originates from the systematic accumulation of uncorrected deletion/insertion in repetitive DNA tracts in cancer cells with a deficient mismatch repair system. Among colorectal cancers, the MSI signature identifies hereditary cases arising in patients with germline mutations in hMLH1, hMSH2, PMS2 and a fraction of those with hMSH6 mutations, as well as sporadic cancers with epigenetic hMLH1 promoter hypermethylation. Considering the specific pathogenesis, pathological features, natural history and response to 5-fluoro-uracil-based chemotherapy of the MSI cancers, confusion about the genetic markers for MSI recognition seems surprising. In this clinically relevant field, an agreement has not been reached concerning the use of di-or mononucleotide markers for MSI assessment. The Revised Bethesda Guidelines still recommend a panel of markers consisting of mono-and dinucleotides, despite being questioned whether it is congruous to continue to use dinucleotide markers for MSI identification. In any event, no single marker is accurate enough for MSI testing, and an awareness of their pros and cons is required for proper interpretation of results. In recent years, several papers have reported different prevalence of MSI in unrelated series, largely depending on the detection and classification method, suggesting that MSI test interpretation also requires the understanding of the phenomenon rather than simply the crude satisfaction of panel recommendations. Inaccuracies can otherwise lead to under-or overdiagnosis and inaccurate disease classification, which always have a negative impact on the clinical practice of medicine.

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“…Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and the fourth most common cause of cancer-related death in the world [1] . Male predominance is, however, more obvious in populations at high risk of developing this tumor (mean ratio 3.7:1.0) than in those at low or intermediate risk (2.4:1.0) [2] .…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical analysis of p53, cyclinD1, RB1, c-fos and N-ras gene expression in hepatocellular carcinoma in Iran

Moghaddam¹,

Haghighi

Samiee

et al. 2007

WJG

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AIM:To study the effect of some genes especially those involved in cell cycle regulation on hepatocellular carcinoma. METHODS:Paraffin-embedded tissue samples of 25 patients (18 males and 7 females) with hepatocellular carcinoma were collected from 22 pathology centers i n Te h ra n d u r i n g 2 0 0 0 -2 0 0 1 , a n d s t a i n e d u s i n g immunohistochemistry method (avidin-biotin-peroxidase) for detection of p53, cyclinD1, RB1, c-fos and N-ras proteins. RESULTS:Six (24%), 5 (20%), 12 (48%) and 2 samples (8%) were positive for p53, cyclinD1, C-fos and N-ras expression, respectively. Twenty-two (88%) samples had alterations in the G1 cell-cycle checkpoint protein expression (RB1 or cyclinD1). P53 positive samples showed a higher (9 times) risk of being positive for RB1 protein than p53 negative samples. Loss of expression of RB1 in association with p53 over-expression was observed in 4 (66.7%) of 6 samples. Loss of expression of RB1 was seen in all cyclinD1 positive, 20 (90.9%) N-ras negative, and 11 (50%) C-fos positive samples, respectively. CyclinD1 positive samples showed a higher (2.85 and 4.75 times) risk of being positive for c-fos and N-ras expression than cyclinD1 negative samples. CONCLUSION:The expression of p53, RB1 and c-fos genes appears to have a key role in the pathogenesis of hepatocellular carcinoma in Iran. Simultaneous overexpression of these genes is significantly associated with their loss of expression during development of hepatocellular carcinoma.

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Fractional allelic loss in non–end-stage cirrhosis: Correlations with hepatocellular carcinoma development during follow-up

Cited by 39 publications

References 30 publications

Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma

Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma

Differences and evolution of the methods for the assessment of microsatellite instability

Immunohistochemical analysis of p53, cyclinD1, RB1, c-fos and N-ras gene expression in hepatocellular carcinoma in Iran

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