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Constitutional de novo deletion of the FBXW7 gene in a patient with focal segmental glomerulosclerosis and multiple primitive tumors.

Roversi G, Picinelli C, Bestetti I, Crippa M, Perotti D, Ciceri S, Saccheri F, Collini P, Poliani PL, Catania S, Peissel B, Pagni F, Russo S, Peterlongo P, Manoukian S, Finelli P - Sci Rep (2015)

Bottom Line: Other genetic defects may be associated with patient's phenotype.In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay.Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy.

ABSTRACT
Multiple primary malignant neoplasms are rare entities in the clinical setting, but represent an important issue in the clinical management of patients since they could be expression of a genetic predisposition to malignancy. A high resolution genome wide array CGH led us to identify the first case of a de novo constitutional deletion confined to the FBXW7 gene, a well known tumor suppressor, in a patient with a syndromic phenotype characterized by focal segmental glomerulosclerosis and multiple primary early/atypical onset tumors, including Hodgkin's lymphoma, Wilms tumor and breast cancer. Other genetic defects may be associated with patient's phenotype. In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay. Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases.

No MeSH data available.


Related in: MedlinePlus

(A) Cystic lesions characterized by a cubic or flat epithelium. (B) Immunohistochemical analysis for TFE3. (C) TFE3 Break Apart probe FISH on interphase nuclei of the cystic epithelium positive for TFE3 immunostaining. Three cells each with three yellow fused signals, due to lack of traslocation of the 5′ TFE3 red probe from 3′ TFE3 green probe, show each a duplication of a TFE3 allele. (D) Dual color FISH with chromosome X (green) and 18 (red) centromeric probes on interphase nuclei of the cystic epithelium positive for TFE3 immunostaining. Most of the cells show two red chromosome 18 centromeric signals and two to four green X chromosome centromeric signals.
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f2: (A) Cystic lesions characterized by a cubic or flat epithelium. (B) Immunohistochemical analysis for TFE3. (C) TFE3 Break Apart probe FISH on interphase nuclei of the cystic epithelium positive for TFE3 immunostaining. Three cells each with three yellow fused signals, due to lack of traslocation of the 5′ TFE3 red probe from 3′ TFE3 green probe, show each a duplication of a TFE3 allele. (D) Dual color FISH with chromosome X (green) and 18 (red) centromeric probes on interphase nuclei of the cystic epithelium positive for TFE3 immunostaining. Most of the cells show two red chromosome 18 centromeric signals and two to four green X chromosome centromeric signals.

Mentions: Besides PLNRs and marked signs of glomerulosclerosis, the left kidney showed papillary adenomas, microangiomas and cystic cavities, some of which characterized by microcalcifications and lined by cubic or flat cells (Fig. 2A). Strong nuclear immunoreactivity for TFE3 occurred in the cells lining cystic cavities, while the other cells were negative (Fig. 2B). As immunoreactivity for TFE3 is a feature associated with Renal cell Carcinoma (RCC) characterized by the presence of TFE3 gene fusions13, an interphase FISH by using a break apart probe — designed to detect translocations involving the TFE3 gene at Xp11.2— was performed on formalin-fixed, paraffin-embedded tissues (FFPE) on the area of the cysts immunoreactive for TFE3 of left atrophic kidney. No evidence of a TFE3 translocation was found; however, a condition of heterogeneity characterized by normal cells mixed with cells with an increased TFE3 copy numbers (three to five fused signals) was detected (Fig. 2C). A following interphase dual color FISH by using centromeric probes for X and 18 chromosomes displayed that the increased TFE3 copy number in the immunoreactive cystic epithelium is related to X-chromosome aneuploidy (Fig. 2D). Indeed, while in the surrounding tissue a ratio near 1 between X/18 chromosome signals was scored, inside the cystic lesion the ratio raised to 1,32 (3:2), with a total 35% of nuclei showing 3 or more X chromosome signals and a ratio between X/18 chromosome signals different and major than 1.


Constitutional de novo deletion of the FBXW7 gene in a patient with focal segmental glomerulosclerosis and multiple primitive tumors.

Roversi G, Picinelli C, Bestetti I, Crippa M, Perotti D, Ciceri S, Saccheri F, Collini P, Poliani PL, Catania S, Peissel B, Pagni F, Russo S, Peterlongo P, Manoukian S, Finelli P - Sci Rep (2015)

(A) Cystic lesions characterized by a cubic or flat epithelium. (B) Immunohistochemical analysis for TFE3. (C) TFE3 Break Apart probe FISH on interphase nuclei of the cystic epithelium positive for TFE3 immunostaining. Three cells each with three yellow fused signals, due to lack of traslocation of the 5′ TFE3 red probe from 3′ TFE3 green probe, show each a duplication of a TFE3 allele. (D) Dual color FISH with chromosome X (green) and 18 (red) centromeric probes on interphase nuclei of the cystic epithelium positive for TFE3 immunostaining. Most of the cells show two red chromosome 18 centromeric signals and two to four green X chromosome centromeric signals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4612309&req=5

f2: (A) Cystic lesions characterized by a cubic or flat epithelium. (B) Immunohistochemical analysis for TFE3. (C) TFE3 Break Apart probe FISH on interphase nuclei of the cystic epithelium positive for TFE3 immunostaining. Three cells each with three yellow fused signals, due to lack of traslocation of the 5′ TFE3 red probe from 3′ TFE3 green probe, show each a duplication of a TFE3 allele. (D) Dual color FISH with chromosome X (green) and 18 (red) centromeric probes on interphase nuclei of the cystic epithelium positive for TFE3 immunostaining. Most of the cells show two red chromosome 18 centromeric signals and two to four green X chromosome centromeric signals.
Mentions: Besides PLNRs and marked signs of glomerulosclerosis, the left kidney showed papillary adenomas, microangiomas and cystic cavities, some of which characterized by microcalcifications and lined by cubic or flat cells (Fig. 2A). Strong nuclear immunoreactivity for TFE3 occurred in the cells lining cystic cavities, while the other cells were negative (Fig. 2B). As immunoreactivity for TFE3 is a feature associated with Renal cell Carcinoma (RCC) characterized by the presence of TFE3 gene fusions13, an interphase FISH by using a break apart probe — designed to detect translocations involving the TFE3 gene at Xp11.2— was performed on formalin-fixed, paraffin-embedded tissues (FFPE) on the area of the cysts immunoreactive for TFE3 of left atrophic kidney. No evidence of a TFE3 translocation was found; however, a condition of heterogeneity characterized by normal cells mixed with cells with an increased TFE3 copy numbers (three to five fused signals) was detected (Fig. 2C). A following interphase dual color FISH by using centromeric probes for X and 18 chromosomes displayed that the increased TFE3 copy number in the immunoreactive cystic epithelium is related to X-chromosome aneuploidy (Fig. 2D). Indeed, while in the surrounding tissue a ratio near 1 between X/18 chromosome signals was scored, inside the cystic lesion the ratio raised to 1,32 (3:2), with a total 35% of nuclei showing 3 or more X chromosome signals and a ratio between X/18 chromosome signals different and major than 1.

Bottom Line: Other genetic defects may be associated with patient's phenotype.In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay.Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy.

ABSTRACT
Multiple primary malignant neoplasms are rare entities in the clinical setting, but represent an important issue in the clinical management of patients since they could be expression of a genetic predisposition to malignancy. A high resolution genome wide array CGH led us to identify the first case of a de novo constitutional deletion confined to the FBXW7 gene, a well known tumor suppressor, in a patient with a syndromic phenotype characterized by focal segmental glomerulosclerosis and multiple primary early/atypical onset tumors, including Hodgkin's lymphoma, Wilms tumor and breast cancer. Other genetic defects may be associated with patient's phenotype. In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay. Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases.

No MeSH data available.


Related in: MedlinePlus