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RB1 gene mutations in Argentine retinoblastoma patients. Implications for genetic counseling.

Abstract Retinoblastoma (RB) is an inherited childhood ocular cancer caused by mutations in the tumor suppressor RB1 gene. Identification of RB1 mutations is essential to assess the risk of developing retinoblastoma in the patients´ relatives. Retinoblastoma is a potentially curable cancer and an early diagnosis is critical for survival and eye preservation. Unilateral retinoblastoma is mostly non-heritable and results from two somatic mutations whereas bilateral retinoblastoma is heritable and results from one germline and one somatic mutation, both have high penetrance, 90%. The purpose of this study was to identify causative RB1 mutations in RB patients with different clinical presentations. A comprehensive approach was used to study a cohort of 34 patients with unilateral, bilateral and trilateral retinoblastoma. Blood and tumor DNA was analyzed by sequencing and multiplex ligation-dependent probe amplification (MLPA) assay. Validation of an insertion mutation was performed by cloning the PCR product. Most of the patients in our cohort had unilateral RB, eight patients had bilateral RB and one patient had a trilateral tumor with ocular and suprasellar/sellar locations. Other tumors in addition to retinoblastoma were also found in the affected families. One patient had two syndromes, retinoblastoma and schwannomatosis, and another RB patient had a father with a retinoma. Five out of the 25 unilateral RB patients carried germinal mutations (20%), which were mostly missense mutations. The bilateral and trilateral patients carried splice-site, nonsense and frameshift mutations as well as a whole RB1 gene deletion. Missense mutations were associated with mild phenotype: unilateral retinoblastoma, retinoma or no tumor. In this study we identified causative RB1 mutations in most bilateral RB patients and in some unilateral RB patients, including five novel mutations. These data are crucial for genetic counseling and confirm the need to perform complete genetic screening for RB1 mutations in both constitutional and tumor tissues.
PMID
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Authors

Mayor MeshTerms

Genetic Counseling

Keywords
Journal Title plos one
Publication Year Start



 

PMID- 29261756
OWN - NLM
STAT- MEDLINE
DCOM- 20180108
LR  - 20180108
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 12
DP  - 2017
TI  - RB1 gene mutations in Argentine retinoblastoma patients. Implications for genetic
      counseling.
PG  - e0189736
LID - 10.1371/journal.pone.0189736 [doi]
AB  - Retinoblastoma (RB) is an inherited childhood ocular cancer caused by mutations
      in the tumor suppressor RB1 gene. Identification of RB1 mutations is essential to
      assess the risk of developing retinoblastoma in the patients relatives.
      Retinoblastoma is a potentially curable cancer and an early diagnosis is critical
      for survival and eye preservation. Unilateral retinoblastoma is mostly
      non-heritable and results from two somatic mutations whereas bilateral
      retinoblastoma is heritable and results from one germline and one somatic
      mutation, both have high penetrance, 90%. The purpose of this study was to
      identify causative RB1 mutations in RB patients with different clinical
      presentations. A comprehensive approach was used to study a cohort of 34 patients
      with unilateral, bilateral and trilateral retinoblastoma. Blood and tumor DNA was
      analyzed by sequencing and multiplex ligation-dependent probe amplification
      (MLPA) assay. Validation of an insertion mutation was performed by cloning the
      PCR product. Most of the patients in our cohort had unilateral RB, eight patients
      had bilateral RB and one patient had a trilateral tumor with ocular and
      suprasellar/sellar locations. Other tumors in addition to retinoblastoma were
      also found in the affected families. One patient had two syndromes,
      retinoblastoma and schwannomatosis, and another RB patient had a father with a
      retinoma. Five out of the 25 unilateral RB patients carried germinal mutations
      (20%), which were mostly missense mutations. The bilateral and trilateral
      patients carried splice-site, nonsense and frameshift mutations as well as a
      whole RB1 gene deletion. Missense mutations were associated with mild phenotype: 
      unilateral retinoblastoma, retinoma or no tumor. In this study we identified
      causative RB1 mutations in most bilateral RB patients and in some unilateral RB
      patients, including five novel mutations. These data are crucial for genetic
      counseling and confirm the need to perform complete genetic screening for RB1
      mutations in both constitutional and tumor tissues.
FAU - Parma, Diana
AU  - Parma D
AD  - Catedra de Genetica, Facultad de Farmacia y Bioquimica, Universidad de Buenos
      Aires. Buenos Aires. Argentina.
FAU - Ferrer, Marcela
AU  - Ferrer M
AD  - Division de Neurocirugia, Hospital de Clinicas "Jose de San Martin", Universidad 
      de Buenos Aires. Buenos Aires. Argentina.
FAU - Luce, Leonela
AU  - Luce L
AD  - Catedra de Genetica, Facultad de Farmacia y Bioquimica, Universidad de Buenos
      Aires. Buenos Aires. Argentina.
FAU - Giliberto, Florencia
AU  - Giliberto F
AD  - Catedra de Genetica, Facultad de Farmacia y Bioquimica, Universidad de Buenos
      Aires. Buenos Aires. Argentina.
FAU - Szijan, Irene
AU  - Szijan I
AUID- ORCID: http://orcid.org/0000-0002-6511-9120
AD  - Catedra de Genetica, Facultad de Farmacia y Bioquimica, Universidad de Buenos
      Aires. Buenos Aires. Argentina.
LA  - eng
PT  - Journal Article
DEP - 20171220
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Retinoblastoma Protein)
SB  - IM
MH  - Argentina
MH  - Base Pairing
MH  - Base Sequence
MH  - Child, Preschool
MH  - Exons/genetics
MH  - Female
MH  - *Genetic Counseling
MH  - Heterozygote
MH  - Humans
MH  - Infant
MH  - Infant, Newborn
MH  - Male
MH  - Mutation/*genetics
MH  - Pedigree
MH  - Penetrance
MH  - Retinoblastoma/*genetics
MH  - Retinoblastoma Protein/*genetics
MH  - Treatment Outcome
PMC - PMC5738096
EDAT- 2017/12/21 06:00
MHDA- 2018/01/09 06:00
CRDT- 2017/12/21 06:00
PHST- 2017/06/28 00:00 [received]
PHST- 2017/11/30 00:00 [accepted]
PHST- 2017/12/21 06:00 [entrez]
PHST- 2017/12/21 06:00 [pubmed]
PHST- 2018/01/09 06:00 [medline]
AID - 10.1371/journal.pone.0189736 [doi]
AID - PONE-D-17-24494 [pii]
PST - epublish
SO  - PLoS One. 2017 Dec 20;12(12):e0189736. doi: 10.1371/journal.pone.0189736.
      eCollection 2017.