Analysis of the t(3;8) of hereditary renal cell carcinoma: a palindrome-mediated translocation

Kato, Takema; Franconi, Colleen P.; Sheridan, Molly B.; Hacker, April M.; Inagakai, Hidehito; Glover, Thomas W.; Arlt, Martin F.; Drabkin, Harry A.; Gemmill, Robert M.; Kurahashi, Hiroki; Emanuel, Beverly S.

doi:10.1016/j.cancergen.2014.03.004

Cited by 21 publications

(14 citation statements)

References 54 publications

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“…Palindromic AT-rich repeats on Chromosomes 3, 8, 11, 17, and 22 also generate recurrent translocations, the most common of which is the recurrent t(11;22) that causes Emanuel syndrome (Edelmann et al 2001;Kurahashi et al 2003;Gotter et al 2007;Kato et al 2012Kato et al , 2014. Most germline translocations, however, are not recurrent, and sequencing of translocation breakpoints has revealed features of nonhomologous end-joining (NHEJ) and microhomology-mediated break-induced replication (MMBIR) at more than 60 unique translocation junctions (Chen et al 2008;Higgins et al 2008;Sobreira et al 2011;Chiang et al 2012;Robberecht et al 2013).…”

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confidence: 99%

Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis

2015

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Unbalanced translocations are a relatively common type of copy number variation and a major contributor to neurodevelopmental disorders. We analyzed the breakpoints of 57 unique unbalanced translocations to investigate the mechanisms of how they form. Fifty-one are simple unbalanced translocations between two different chromosome ends, and six rearrangements have more than three breakpoints involving two to five chromosomes. Sequencing 37 breakpoint junctions revealed that simple translocations have between 0 and 4 base pairs (bp) of microhomology (n = 26), short inserted sequences (n = 8), or paralogous repeats (n = 3) at the junctions, indicating that translocations do not arise primarily from nonallelic homologous recombination but instead form most often via nonhomologous end joining or microhomology-mediated break-induced replication. Three simple translocations fuse genes that are predicted to produce in-frame transcripts of SIRPG-WWOX, SMOC2-PROX1, and PIEZO2-MTA1, which may lead to gain of function. Three complex translocations have inversions, insertions, and multiple breakpoint junctions between only two chromosomes. Whole-genome sequencing and fluorescence in situ hybridization analysis of two de novo translocations revealed at least 18 and 33 breakpoints involving five different chromosomes. Breakpoint sequencing of one maternally inherited translocation involving four chromosomes uncovered multiple breakpoints with inversions and insertions. All of these breakpoint junctions had 0-4 bp of microhomology consistent with chromothripsis, and both de novo events occurred on paternal alleles. Together with other studies, these data suggest that germline chromothripsis arises in the paternal genome and may be transmitted maternally. Breakpoint sequencing of our large collection of chromosome rearrangements provides a comprehensive analysis of the molecular mechanisms behind translocation formation.

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confidence: 99%

Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis

2015

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“…22,29 FHIT is listed as a Tier 1 known cancer gene in the Cancer Gene Census (https://cancer.sanger.ac.uk/cosmic/census); however, the presence of a somatic VHL mutation and loss of the translocated chromosome 3 in a previous t(3;8)(p14.2;q24.1)associated RCC was unexpected. 5,22 It is possible that the recurrent involvement of FHIT in RCCassociated chromosome 3 rearrangements reflects the presence of palindromic AT-rich repeats at the t(3;8)(p14.2;q24.1) breakpoint and causes a propensity to recurrent rearrangements at this locus, 54 although we note that only a fraction of chromosome 3 translocations are associated with predisposition to RCC. 55 It is therefore conceivable that both instability of the translocated chromosome and monoallelic inactivation of FHIT contribute to RCC susceptibility.…”

Section: Discussionmentioning

confidence: 65%

“…It is possible that the recurrent involvement of FHIT in RCC‐associated chromosome 3 rearrangements reflects the presence of palindromic AT‐rich repeats at the t(3;8)(p14.2;q24.1) breakpoint and causes a propensity to recurrent rearrangements at this locus, although we note that only a fraction of chromosome 3 translocations are associated with predisposition to RCC . It is therefore conceivable that both instability of the translocated chromosome and monoallelic inactivation of FHIT contribute to RCC susceptibility.…”

Section: Discussionmentioning

confidence: 67%

Characterization of renal cell carcinoma‐associated constitutional chromosome abnormalities by genome sequencing

Smith

Whitworth

West

et al. 2020

Genes Chromosomes & Cancer

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Constitutional translocations, typically involving chromosome 3, have been recognized as a rare cause of inherited predisposition to renal cell carcinoma (RCC) for four decades. However, knowledge of the molecular basis of this association is limited. We have characterized the breakpoints by genome sequencing (GS) of constitutional chromosome abnormalities in five individuals who presented with RCC. In one individual with constitutional t(10;17)(q11.21;p11.2), the translocation breakpoint disrupted two genes: the known renal tumor suppressor gene (TSG) FLCN (and clinical features of Birt‐Hogg‐Dubé syndrome were detected) and RASGEF1A. In four cases, the rearrangement breakpoints did not disrupt known inherited RCC genes. In the second case without chromosome 3 involvement, the translocation breakpoint in an individual with a constitutional t(2;17)(q21.1;q11.2) mapped 12 Kb upstream of NLK. Interestingly, NLK has been reported to interact indirectly with FBXW7 and a previously reported RCC‐associated translocation breakpoint disrupted FBXW7. In two cases of constitutional chromosome 3 translocations, no candidate TSGs were identified in the vicinity of the breakpoints. However, in an individual with a constitutional chromosome 3 inversion, the 3p breakpoint disrupted the FHIT TSG (which has been reported previously to be disrupted in two apparently unrelated families with an RCC‐associated t(3;8)(p14.2;q24.1). These findings (a) expand the range of constitutional chromosome rearrangements that may be associated with predisposition to RCC, (b) confirm that chromosome rearrangements not involving chromosome 3 can predispose to RCC, (c) suggest that a variety of molecular mechanisms are involved the pathogenesis of translocation‐associated RCC, and (d) demonstrate the utility of GS for investigating such cases.

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“…It is proposed that all of these features foster the propensity for forming secondary structure at palindromic regions. Indeed, PATRR8 contributes to generation of not only the t(8;22), but also the constitutional t(3;8) that is associated with hereditary renal cell carcinoma predisposition, suggesting that the PATRR8 is a hotspot for palindrome-mediated translocations [ 19 ]. It is likely that for the t(8;22), as for other PATRR-related recurrent translocations such as the t(11;22) and t(17;22), DNA secondary structure might contribute to the generation of the translocation.…”

Section: Discussionmentioning

confidence: 99%

Breakpoint analysis of the recurrent constitutional t(8;22)(q24.13;q11.21) translocation

et al. 2014

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BackgroundsThe t(8;22)(q24.13;q11.2) has been identified as one of several recurrent constitutional translocations mediated by palindromic AT-rich repeats (PATRRs). Although the breakage on 22q11 utilizes the same PATRR as that of the more prevalent constitutional t(11;22)(q23;q11.2), the breakpoint region on 8q24 has not been elucidated in detail since the analysis of palindromic sequence is technically challenging.ResultsIn this study, the entire 8q24 breakpoint region has been resolved by next generation sequencing. Eight polymorphic alleles were identified and compared with the junction sequences of previous and two recently identified t(8;22) cases . All of the breakpoints were found to be within the PATRRs on chromosomes 8 and 22 (PATRR8 and PATRR22), but the locations were different among cases at the level of nucleotide resolution. The translocations were always found to arise on symmetric PATRR8 alleles with breakpoints at the center of symmetry. The translocation junction is often accompanied by symmetric deletions at the center of both PATRRs. Rejoining occurs with minimal homology between the translocation partners. Remarkably, comparison of der (8) to der(22) sequences shows identical breakpoint junctions between them, which likely represent products of two independent events on the basis of a classical model.ConclusionsOur data suggest the hypothesis that interactions between the two PATRRs prior to the translocation event might trigger illegitimate recombination resulting in the recurrent palindrome-mediated translocation.

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Analysis of the t(3;8) of hereditary renal cell carcinoma: a palindrome-mediated translocation

Cited by 21 publications

References 54 publications

Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis

Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis

Characterization of renal cell carcinoma‐associated constitutional chromosome abnormalities by genome sequencing

Breakpoint analysis of the recurrent constitutional t(8;22)(q24.13;q11.21) translocation

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