PMS2 mutations in childhood cancer.
Until recently, the PMS2 DNA mismatch repair gene has only rarely been implicated as a cancer susceptibility locus. New studies have shown, however, that earlier analyses of this gene have had technical limitations and also that the genetic behavior of mutant PMS2 alleles is unusual, in that, unlike MLH1 or MSH2 mutations, PMS2 mutations show low heterozygote penetrance. As a result, a dominantly inherited cancer predisposition has not been a feature reported in families with PMS2 mutations. Such families have instead been ascertained through childhood-onset cancers in homozygotes or through apparently sporadic colorectal cancer in heterozygotes. We present further information on the phenotype associated with homozygous PMS2 deficiency in 13 patients from six families of Pakistani origin living in the United Kingdom. This syndrome is characterized by café-au-lait skin pigmentation and a characteristic tumor spectrum, including leukemias, lymphomas, cerebral malignancies (such as supratentorial primitive neuroectodermal tumors, astrocytomas, and glioblastomas), and colorectal neoplasia with an onset in early adult life. We present evidence for a founder effect in five families, all of which carried the same R802-->X mutation (i.e., arginine-802 to stop) in PMS2. This cancer syndrome can be mistaken for neurofibromatosis type 1, with important management implications including the risk of the disorder occurring in siblings and the likelihood of tumor development in affected individuals.
De Vos
Michel
M
University of Leeds, Yorkshire Regional Genetics Service, United Kingdom.
Hayward
Bruce E
BE
Charlton
Ruth
R
Taylor
Graham R
GR
Glaser
Adam W
AW
Picton
Susan
S
Cole
Trevor R
TR
Maher
Eamonn R
ER
McKeown
Carole M E
CM
Mann
Jill R
JR
Yates
John R
JR
Baralle
Diana
D
Rankin
Julia
J
Bonthron
David T
DT
Sheridan
Eamonn
E
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D001120:Arginine; D001254:Astrocytoma / Q000235:genetics; D019080:Cafe-au-Lait Spots / Q000235:genetics; D002648:Child; D003111:Colonic Polyps / Q000235:genetics; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005910:Glioma / Q000235:genetics; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics; D016399:Lymphoma, T-Cell / Q000235:genetics; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2; D009154:Mutation; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000235:genetics; D010154:Pakistan / Q000208:ethnology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D006113:United Kingdom / Q000453:epidemiology
D004268:DNA-Binding Proteins; D001120:Arginine; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes