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Re: PMS2 mutations in childhood cancer

Dear Editor,

We refer to the recent paper by Durno et al. "Family history and molecular features of children, adolescents and young adults with colorectal carcinoma" (doi:10.1136/gut.2005.066092).

Among other patients with early-onset colorectal cancer (CRC), the authors discuss a girl with CRC onset at age 12, and a subsequent second primary tumour (glioblastoma). This patient appears to be the sister of a male Turcot syndrome patient described in 1995.[1] However, although referred to in that original report, she was not explicitly stated to carry the same PMS2 mutation (R134X) as her brother, and so whether her mutation was assumed, or verified by Durno et al. is unclear.

More importantly, the authors have overlooked the fact that both these siblings have since been shown to be compound heterozygotes for the PMS2 mutations R134X and 2184delTC.[2] The fact that these patients have germline mutations on both alleles offers an explanation for the earlier observation of a high degree of microsatellite instability (MSI) in their constitutional DNA, not just in tumour DNA.[3]

We have previously pointed out that in the childhood cancer families so far described, PMS2 mutations behave recessively, the parents of the homozygous or compound heterozygous patients being, by and large, tumour-free.[2]

While other recent publications do suggest that heterozygous PMS2 mutations can predispose to colorectal cancer [4-7], these mutations appear, for unknown reasons, to be less penetrant than "classical" HNPCC alleles of, for example, MLH1 or MSH2. Certainly, on present evidence, a heterozygous PMS2 mutation is unlikely to account for a childhood cancer presentation.

Indeed, given that one of the other cases described by Durno et al. was also homozygous, for an MLH1 mutation, we would like to emphasize again that a childhood (as opposed to early adult) presentation of CRC or other MSI-positive tumour should signal the possibility of a biallelic mismatch repair defect. Demonstration of microsatellite instability in constitutional DNA would in such circumstances point directly to the likelihood of biallelic mutation of one of the MMR genes, with important implications for genetic management.

References

1. Hamilton SR, Liu B, Parsons RE et al. The molecular basis of Turcot's syndrome. N Engl J Med 1995;332:839-847.

2. De Vos M, Hayward BE, Picton S, et al. Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 2004;74:954-964.

3. Parsons R, Li GM, Longley M et al. Mismatch repair deficiency in phenotypically normal human cells. Science 1995;268:738-740.

4. Nakagawa H, Lockman JC, Frankel WL, et al. Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 2004;64:4721-4727.

5. Truninger K, Menigatti M, Luz J, et al. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 2005;128:1160-1171.

6. Worthley DL, Walsh MD, Barker M, et al. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 2005;128:1431-1436.

7. van der Klift H, Wijnen J, Wagner A, et al. Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Genes Chromosomes Cancer 2005 Jun 7; [Epub ahead of print]