PMS2

Recessive cancer gene, complex genomics

A childhood cancer syndrome characterized by brain tumours, including the very rare supratentorial primitive neuroectodermal tumour (SPNET), lymphomas, or leukaemias, in combination with patchy pigmentary skin lesions (café-au-lait spots) has been recognized recently, particularly in UK Pakistani families. We used autozygosity mapping to localize the gene for this disorder to Chr. 7p22, and found that it results from homozygous mutations of the DNA mismatch repair gene, PMS2.

This disorder is unusual in a number of ways; firstly, mutations of PMS2, unlike those of the other mismatch repair genes (e.g. MLH1, MSH2) typically behave recessively. There is probably some increased risk of bowel cancer in heterozygous carriers, but for the most part parents of affected children have not had cancer themselves.

PMS2 pseudogenes on Chr.7q are indicated as grey triangles. They occur as part of larger, duplicated chromosomal segments (coloured blocks); Chr.7 is particularly rich in such low-copy number repeats. (Click for full-size image.)

Secondly, as shown in the diagram above, there is a large family of PMS2 pseudogenes, both on Chr.7q and 7p. These make mutation analysis of PMS2 very difficult. The 7p pseudogene lies close to PMS2 as part of an inverted duplication, and by a process of gene conversion or recombination, sequence exchange occurs between gene and pseudogene, making analysis even more difficult. Gene conversion can also introduce oncogenic pseudogene sequence variants into PMS2.

De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 74:954-964.

De Vos M, Hayward BE, Charlton R, Taylor GR, Glaser AW, Picton S, Cole TR, Maher ER, McKeown CM, Mann JR, Yates JR, Baralle D, Rankin J, Bonthron DT, Sheridan E (2006) PMS2 mutations in childhood cancer. J Natl Cancer Inst 98:358-61.

Hayward BE, De Vos M, Valleley EM, Charlton RS, Taylor GR, Sheridan E, Bonthron DT. Extensive gene conversion at the PMS2 DNA mismatch repair locus. Hum Mutat 28:424-30 (2007).

Last modified: 7 February 2011