RB family members as predictive and prognostic factors in human cancer

Scambia, Giovanni; Lovergine, Silvia; Masciullo, Valeria

doi:10.1038/sj.onc.1209620

Cited by 39 publications

(30 citation statements)

References 82 publications

(68 reference statements)

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“…In the absence of definite molecular markers, as in the case of STS, histological grading is adopted clinically as the sole parameter to gain information about a possible metastatic event following surgical removal of the primitive lesion. 15 Thus, although some investigations have proposed the prognostic importance of a number of clinical and histopathological markers, [16][17][18][19][20][21][22][23][24][25] and have highlighted a few sporadic molecular markers, more concrete genetic/molecular factors defining prognosis in STS patients still remain unavailable to clinicians. Similarly, as in most other tumor types, no STS molecular markers are currently accessible that, at the time of surgery, are capable of predicting with sufficient certainty the future appearance of metastases.…”

Section: Discussionmentioning

confidence: 99%

NG2 expression predicts the metastasis formation in soft‐tissue sarcoma patients

Benassi

Pazzaglia

Chiechi

et al. 2008

Journal Orthopaedic Research

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Enhanced expression levels of NG2 proteoglycan in presurgical original lesions of soft-tissue sarcoma (STS) patients defines with 55% probability the immediate (i.e., within 12 months postsurgery) risk in these individuals to develop postsurgical secondary lesions, independently of any other clinical trait. It, therefore, provides a molecular factor that alone prospects a particularly unfavorable clinical outcome in such patients. Evaluation of the timing of metastasis formation in patients with high and low levels of NG2 in their primitive lesions further stratified the patients in subsets with diverse lag phases in the occurrence of metastatic disease. In our cohort of highgrade STS cases, transcription of NG2 also showed a 81-fold amplification in metastatic lesions, when compared to primitive ones, and this gene overexpression was accompanied by an abundant but nonuniform in situ expression of its product. In a similar manner as seen in primitive lesions, patients with higher levels of metastatic NG2 encountered a significantly more dismal clinical course. Multivariate analysis asserted that in these individuals upregulation of NG2 represented an absolute independent prognostic parameter. Therefore, minimally invasive assessment of the transcription levels of the NG2 gene represents a parameter capable of predicting the arising of metastatic disease within a definite postsurgery time interval, and affords in adjunct in the definition of life expectance in STS patients. ß

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Section: Discussionmentioning

confidence: 99%

NG2 expression predicts the metastasis formation in soft‐tissue sarcoma patients

Benassi

Pazzaglia

Chiechi

et al. 2008

Journal Orthopaedic Research

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“…Abnormalities of the RB1 family (pRB, pRB2/p130, p107) have been identified in a large proportion of cancers and implicated in tumor pathogenesis and progression (10,11). Some colonic adenocarcinomas undergo allelic loss at the RB1 locus (12,13), whereas almost half of colorectal carcinomas show nonrandom chromosomal 13 gains (14,15).…”

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confidence: 99%

Loss of Rb1 in the gastrointestinal tract of Apc ^1638N mice promotes tumors of the cecum and proximal colon

Kucherlapati

Yang

Fan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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To examine the role of Rb1 in gastrointestinal (GI) tumors, we generated mice with an Apc 1638N allele, Rb tm2brn floxed alleles, and a villin-cre transgene (RBVCA). These animals had exon 19 deleted from Rb1 throughout the GI tract. We have shown previously that Rb1 deficiency is insufficient for GI tumor initiation, with inactivation of an Apc allele capable of overcoming the insufficiency. In this study we demonstrate that RBVCA mice have reduced median survival because of an increase in tumor incidence and multiplicity in the cecum and the proximal colon. Large intestinal tumors are predominantly adenomas, whereas the tumors of the small intestine are a mixture of adenomas and adenocarcinomas. We find truncation mutations to the second Apc allele in tumors of both the large and small intestine. Expression profiles of duodenal and cecal tumors relative to each other show unique gene subsets up and down regulated. Substantial expression patterns compare to human colorectal cancer, including recapitulation of embryonic genes. Our results indicate that Rb1 has significant influence over tumor location in the GI tract, and that both cecal and duodenal tumors initiate through inactivation of Apc. Expression profile analysis indicates the two tumor types differentially regulate distinct sets of genes that are over-expressed in a majority of human colorectal carcinomas.is an important cause of morbidity and mortality. Each year 150,000 new cases are reported in the United States, as well as 56,000 deaths. Studies of two predisposition syndromes have led to the identification of genes involved in the initiation of the disease. Familial adenomatous polyposis (1), a dominant autosomal hereditary syndrome, is caused by germ-line mutations in the adenomatous polyposis coli gene (APC). Many sporadic CRC cases are the result of somatic APC mutation (2). The second familial syndrome, hereditary non polyposis colorectal cancer (HNPCC), is caused by mutations in DNA mismatch repair (MMR) genes that result in an increase in mutation rate (3) responsible for the HNPCC phenotype. Mutations to both copies of APC, resulting from MMR deficiency, are required for HNPCC tumor initiation. Genetic changes in RAS, AKT, TGF-␤ signaling, and p53 have also been described at different stages of tumor progression. One of the most proximal and frequent changes is the activation of either K-RAS or N-RAS, found to occur in Ϸ50% of all CRCs. Mutations are also found in the PI3-kinase pathway. The genes or pathways involved in the rest of the tumors are not well understood. The retinoblastoma (RB1) pathway, known to be involved in many types of cancers, is not extensively documented in colon cancer.In humans, RB1 plays a tumor suppressor role in cancer of the retina (4) and several other tissues (5-9). Abnormalities of the RB1 family (pRB, pRB2/p130, p107) have been identified in a large proportion of cancers and implicated in tumor pathogenesis and progression (10, 11). Some colonic adenocarcinomas undergo allelic loss at the RB1 locus (12, 13),...

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“…In the last years, several studies have been performed in order to establish a therapeutic strategy based on the manipulation of the cyclin-RB-E2F pathway. The development of small molecules that specifically inhibit certain cyclin/CDK complexes, or that could affect E2F-dependent transcription, as well as peptides that can mimic the functional regions of RB proteins inactivated in specific tumors, is currently under investigation (Scambia, et al, 2006).…”

Section: Retinoblastoma Signaling Pathwaymentioning

confidence: 99%

“…The RB pathway consists of several proteins: the cyclin-dependent kinase inhibitor (CDKN), the cyclin D-dependent protein kinases (cdk4, cdk6), the E2F-family of transcription factors (heterodimers of E2F1-8 with DP1-2) and the RB-family (RB, p107, p130) (Knudsen, & Wang, 2010;Scambia, et al, 2006;Van Meir, et al, 2010). The Rb gene is localized on the 13q14 chromosome and was the first known human suppressor of tumors (Huang, et al, 1988).…”

Section: Retinoblastoma Signaling Pathwaymentioning

confidence: 99%

Genetics and Biology of Glioblastoma Multiforme

Carmo¹,

Crespo²,

Lopes³

2011

Molecular Targets of CNS Tumors

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RB family members as predictive and prognostic factors in human cancer

Cited by 39 publications

References 82 publications

NG2 expression predicts the metastasis formation in soft‐tissue sarcoma patients

NG2 expression predicts the metastasis formation in soft‐tissue sarcoma patients

Loss of Rb1 in the gastrointestinal tract of Apc ^1638N mice promotes tumors of the cecum and proximal colon

Genetics and Biology of Glioblastoma Multiforme

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RB family members as predictive and prognostic factors in human cancer

Cited by 39 publications

References 82 publications

NG2 expression predicts the metastasis formation in soft‐tissue sarcoma patients

NG2 expression predicts the metastasis formation in soft‐tissue sarcoma patients

Loss of Rb1 in the gastrointestinal tract of Apc 1638N mice promotes tumors of the cecum and proximal colon

Genetics and Biology of Glioblastoma Multiforme

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Loss of Rb1 in the gastrointestinal tract of Apc ^1638N mice promotes tumors of the cecum and proximal colon