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Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome.

Ammerlaan AC, Ararou A, Houben MP, Baas F, Tijssen CC, Teepen JL, Wesseling P, Hulsebos TJ - Br. J. Cancer (2007)

Bottom Line: Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers.This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay.In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurogenetics, Academic Medical Center, Amsterdam, The Netherlands.

ABSTRACT
Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.

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Haplotyping of family members and LOH analysis of tumours using microsatellite markers from chromosome 22. Patients with the germline INI-mutation are represented by black symbols and proven nonexpressing carriers of this mutation by dotted symbols. Haplotypes were constructed assuming minimal numbers of recombinations. Haplotypes for the grandfather (between brackets) were inferred. N: noninferred marker allele. MBT-1, MBT-3, and MBT-4(R) are the marker alleles retained in the MBT of patients III-1, III-3, and III-4 (R, recurrent tumour), respectively. M-1 and My-1 represent marker alleles retained in meningioma and myoepithelioma of patient III-1, respectively.
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fig1: Haplotyping of family members and LOH analysis of tumours using microsatellite markers from chromosome 22. Patients with the germline INI-mutation are represented by black symbols and proven nonexpressing carriers of this mutation by dotted symbols. Haplotypes were constructed assuming minimal numbers of recombinations. Haplotypes for the grandfather (between brackets) were inferred. N: noninferred marker allele. MBT-1, MBT-3, and MBT-4(R) are the marker alleles retained in the MBT of patients III-1, III-3, and III-4 (R, recurrent tumour), respectively. M-1 and My-1 represent marker alleles retained in meningioma and myoepithelioma of patient III-1, respectively.

Mentions: Written informed consent was obtained from patient III-1 (for pedigree see Figure 1). Each of the four cousins developed an MBT at a young age (<5 years). After removal of the tumour, patient III-1 received adjuvant chemotherapy (methotrexate, vincristine, and prednisolone) followed by craniospinal radiotherapy (3300 cGy in 22 doses) with a boost of 2100 cGy on the location of the tumour. He developed an intracranial meningioma and a myoepithelioma of the lip at, respectively, 25 and 26 years of age. Patient III-4 developed a recurrent brain tumour almost 2 years after removal of the primary brain tumour and treatment with chemotherapy (vincristine, procarbazine, and methotrexate). The sister of the paternal grandfather (I-1) of the four cousins died of an uncharacterised brain tumour at the age of 2 years. The clinical findings for the patients are summarised in Table 1.


Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome.

Ammerlaan AC, Ararou A, Houben MP, Baas F, Tijssen CC, Teepen JL, Wesseling P, Hulsebos TJ - Br. J. Cancer (2007)

Haplotyping of family members and LOH analysis of tumours using microsatellite markers from chromosome 22. Patients with the germline INI-mutation are represented by black symbols and proven nonexpressing carriers of this mutation by dotted symbols. Haplotypes were constructed assuming minimal numbers of recombinations. Haplotypes for the grandfather (between brackets) were inferred. N: noninferred marker allele. MBT-1, MBT-3, and MBT-4(R) are the marker alleles retained in the MBT of patients III-1, III-3, and III-4 (R, recurrent tumour), respectively. M-1 and My-1 represent marker alleles retained in meningioma and myoepithelioma of patient III-1, respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361463&req=5

fig1: Haplotyping of family members and LOH analysis of tumours using microsatellite markers from chromosome 22. Patients with the germline INI-mutation are represented by black symbols and proven nonexpressing carriers of this mutation by dotted symbols. Haplotypes were constructed assuming minimal numbers of recombinations. Haplotypes for the grandfather (between brackets) were inferred. N: noninferred marker allele. MBT-1, MBT-3, and MBT-4(R) are the marker alleles retained in the MBT of patients III-1, III-3, and III-4 (R, recurrent tumour), respectively. M-1 and My-1 represent marker alleles retained in meningioma and myoepithelioma of patient III-1, respectively.
Mentions: Written informed consent was obtained from patient III-1 (for pedigree see Figure 1). Each of the four cousins developed an MBT at a young age (<5 years). After removal of the tumour, patient III-1 received adjuvant chemotherapy (methotrexate, vincristine, and prednisolone) followed by craniospinal radiotherapy (3300 cGy in 22 doses) with a boost of 2100 cGy on the location of the tumour. He developed an intracranial meningioma and a myoepithelioma of the lip at, respectively, 25 and 26 years of age. Patient III-4 developed a recurrent brain tumour almost 2 years after removal of the primary brain tumour and treatment with chemotherapy (vincristine, procarbazine, and methotrexate). The sister of the paternal grandfather (I-1) of the four cousins died of an uncharacterised brain tumour at the age of 2 years. The clinical findings for the patients are summarised in Table 1.

Bottom Line: Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers.This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay.In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurogenetics, Academic Medical Center, Amsterdam, The Netherlands.

ABSTRACT
Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.

Show MeSH
Related in: MedlinePlus