High level amplification of N-MYC is not associated with adverse histology or outcome in primary retinoblastoma tumours

Lillington, Debra M.; Goff, Lindsey K.; Kingston, J. E.; Onadim, Zerrin; Price, Elizabeth; Domizio, Paola; Young, Bryan D.

doi:10.1038/sj.bjc.6600532

Cited by 37 publications

(44 citation statements)

References 25 publications

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“…The most prevalent karyotypic abnormality in retinoblastoma is gain of portions of the long arm of chromosome 1, seen in 21 of 27 tumors (Squire et al, 1985). At the higher resolution of comparative genomic hybridization (CGH), gain of a minimal region spanning 1q31 is the most common change seen in retinoblastoma in our study (Chen et al, 2001), and was seen cumulatively in 76/162 (47%) tumors across five published studies ( Figure 1a) (Mairal et al, 2000;Chen et al, 2001;Herzog et al, 2001;Lillington et al, 2002;van der Wal et al, 2003).…”

Section: Introductionmentioning

confidence: 65%

“…Here, our initial QM-PCR analysis of 1q gain in retinoblastoma was consistent with the CGH literature ( Figure 1a) and showed good agreement with prior CGH and cytogenetic findings on individual retinoblastoma (Figure 2b), although the superior resolution of QM-PCR identified some gains not observed by CGH. QM-PCR with STSs more closely spaced around the initially identified hotspot defined a 3.06 Mbp minimal region of gain, centered around SHGC-154194, gained in 71% of retinoblastoma (Figure 2a), considerably more than the maximum (57%) seen in any CGH study (Lillington et al, 2002), indicating the high sensitivity of QM-PCR for genomic gain. The centromeric end of this 3.06 Mbp region includes the two most commonly gained markers (7/12 each) in the breast cancer cell lines studied (Figure 2c).…”

Section: Discussionmentioning

confidence: 99%

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KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers

et al. 2005

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Gain of chromosome 1q31-1q32 is seen in >50% of retinoblastoma and is common in other tumors. To define the minimal 1q region of gain, we determined genomic copy number by quantitative multiplex PCR of 14 sequence tagged sites (STSs) spanning 1q25.3-1q41. The most frequently gained STS at 1q32.1 (71%; 39 of 55 retinoblastoma) defined a 3.06 Mbp minimal region of gain between flanking markers, containing 14 genes. Of these, only KIF14, a putative chromokinesin, was overexpressed in various cancers by real-time RT-PCR. KIF14 mRNA was expressed in 20/22 retinoblastoma samples 100-1000-fold higher than in retina (t-test P ¼ 0.00002); cell lines (n ¼ 10) had higher levels than tumors (n ¼ 12) (P ¼ 0.009). KIF14 protein was overexpressed in retinoblastoma tumors and breast cancer cell lines by immunoblot. KIF14 was expressed in 4/4 breast cancer cell lines 31-92-fold higher than in normal breast tissue, in 5/5 medulloblastoma cell lines 22-79-fold higher than in fetal brain, and in 10/22 primary lung tumors 3-34-fold higher than in normal lung. Patients with lung tumors that overexpress KIF14 showed a trend toward decreased survival. KIF14 may thus be important in oncogenesis, and has promise as a prognostic indicator and therapeutic target.

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Section: Introductionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers

et al. 2005

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“…Amplification of a genomic region strongly suggests the presence of an oncogene, and MYCN has been well characterized as such by amplification in neuroblastoma (Schwab 2004) and less commonly in RB (Lee et al, 1984;Squire et al, 1986;Sakai et al, 1988;Choi et al, 1993;Doz et al, 1996;Mairal et al, 2000;Herzog et al, 2001;Lillington et al, 2002;Zielinski et al, 2005). Based on data from 87 tumors, we provide a robust estimate that MYCN amplification occurs in only 3% of primary RB.…”

Section: Genomic Copy Number Change Suggests Proliferative Statusmentioning

confidence: 95%

“…Previously, we used quantitative multiplex polymerase chain reaction (QM-PCR) and loss of heterozygosity analyses to narrow further three of these regions to ''hot spot'' sequence tagged sites (STS) at 1q32.1 (Corson et al, 2005), 6p22 (Chen et al, 2002), and 16q22 (Marchong et al, 2004). The 2p24 region is occasionally amplified in RB, and includes the MYCN oncogene, the assumed target of the amplification (Lee et al, 1984;Squire et al, 1986;Godbout et al, 1998;Lillington et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Profiling genomic copy number changes in retinoblastoma beyond loss of RB1

Bowles

Corson

Bayani

et al. 2006

Genes Chromosomes & Cancer

114

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Loss of both RB1 alleles is rate limiting for development of retinoblastoma (RB), but genomic copy number gain or loss may impact oncogene(s) and tumor suppressor genes, facilitating tumor progression. We used quantitative multiplex polymerase chain reaction to profile "hot spot" genomic copy number changes for gain at 1q32.1, 6p22, and MYCN, and loss at 16q22 in 87 primary RB and 7 cell lines. Loss at 16q22 (48%) negatively associated with MYCN gain (18%) (Fisher's exact P = 0.031), gain at 1q32.1 (62%) positively associated with 6p "hot spot" gain (43%) (P = 0.033), and there was a trend for positive association between 1q and MYCN gain (P = 0.095). Cell lines had a higher frequency of MYCN amplification than primary tumors (29% versus 3%; P = 0.043). Novel high-level amplification of 1q32.1 in one primary tumor, confirmed by fluorescence in situ hybridization, strongly supports the presence of oncogene(s) in this region, possibly the mitotic kinesin, KIF14. Gene-specific quantitative multiplex polymerase chain reaction of candidate oncogenes at 1q32.1 (KIF14), 6p22 (E2F3 and DEK), and tumor suppressor genes at 16q22 (CDH11) and 17q21 (NGFR) showed the most common gene gains in RB to be KIF14 in cell lines (80%) and E2F3 in primary tumors (70%). The patterns of gain/loss were qualitatively different in 25 RB compared with 12 primary hepatocellular carcinoma and 12 breast cancer cell lines. Gene specific analysis of one bone marrow metastasis of RB, prechemotherapy and postchemotherapy, showed the typical genomic changes of RB pretreatment, which normalized after chemotherapy.

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“…Based on this genetic mutation, one possible target gene that may be an essential prognostic factor is N-myc , whose amplification is associated with poor prognosis in retinoblastoma [2] . However, N-myc amplification could not be detected in retinoblastoma tissues with PCR or Southern blot methods [3,4] . Recently, we also reported that N-myc amplification is rarely detected in retinoblastoma tissues by fluorescence in situ hybridiza-tion [5] , which was confirmed in a newly established retinoblastoma cell by comparative genomic hybridization [6] .…”

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confidence: 99%

Neurotrophin Receptors TrkA and TrkB in Retinoblastoma Are Differentially Expressed Depending on Cellular Differentiation

Kim¹,

Kim²,

Kim³

et al. 2009

Tumor Biol

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Retinoblastoma is the most common primary intraocular malignancy in children. With the progression of retinoblastoma, retinoblastoma cells lose their ability to differentiate. Regardless of many attempts to identify prognostic factors in retinoblastoma, further investigation for prognostic factors of retinoblastoma progression is still required because of the lack of sensitivity and specificity of these prognostic factors in predicting disease progression. We demonstrated that the differential expression of the neurotrophin receptors TrkA and TrkB is closely related to the differentiation of retinoblastoma cells. While retinoblastoma cells expressed TrkA as well as TrkB, their growth rates were not influenced by the addition of nerve growth factor to the culture medium. In experimental animal models of retinoblastoma, TrkA expression was primarily detected in more differentiated areas with high nm23 immunoreactivity whereas TrkB expression was apparent in more proliferative areas with high Ki67 immunoreactivity. With retinoic-acid-induced differentiation of retinoblastoma cells, TrkA expression significantly increased whereas TrkB significantly decreased. The differential expression of TrkA and TrkB with differentiation of retinoblastoma cells was mediated by extracellular-signal-regulated kinase 1/2 activation, which was confirmed by immunocytochemistry of TrkA. Therefore, our results suggest that the differential expression of TrkA and TrkB could be valuable as a therapeutic target, for instance using specific inhibitors.

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High level amplification of N-MYC is not associated with adverse histology or outcome in primary retinoblastoma tumours

Cited by 37 publications

References 25 publications

KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers

KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers

Profiling genomic copy number changes in retinoblastoma beyond loss of RB1

Neurotrophin Receptors TrkA and TrkB in Retinoblastoma Are Differentially Expressed Depending on Cellular Differentiation

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