Abstract
Background and aims
Mutations in DNA mismatch repair genes are associated with high risk of digestive malignancies [hereditary non-polyposis colorectal cancer (HNPCC); Lynch syndrome]; mutations of APC and MYH are associated with classic and attenuated familial adenomatous polyposis (FAP). Although the early onset of tumors in both syndromes is characteristic of their genetic origin, pediatric malignancies remain rare. Certain reports have found familial colorectal cancer (CRC) occurring in very young patients associated with mutations in more than one gene.
Materials and method
A family corresponding to the Amsterdam criteria for HNPCC, including two cases of colorectal cancer before the age of 25 years, was analyzed for mutations in the MSH2 genes by sequencing. Because polyposis was observed in a patient who developed CRC at age 16, the APC gene was also sequenced.
Results
A truncating mutation in the MSH2 gene, c.258_259delTG, was carried by patients developing cancer of the colon (two patients), uterus, kidney, bladder, and/or small intestine at ages 16, 24, 43, 44, 45, and 57, respectively. A patient with CRC at age 16 was found to carry the APC c.3183_3187del5 mutation as well as the MSH2 mutation, and it is inferred that her father, deceased of CRC at age 24, was also a double heterozygote.
Interpretation
These results confirm that vigilance is required when interpreting molecular results for families with very young patients, as more than one gene may contribute to the genetic risk. Cancer screening measures must also be adapted to the earlier and more penetrant risk to double heterozygotes.
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References
Knudsen A, Bisgaard M, Bülow S (2003) Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Can 2(1):43–55
Olschwang S, Blanché H, Moncuit Cd, Thomas G (2007) Similar colorectal cancer risk in patients with monoallelic and biallelic mutations in the MYH gene identified in a population with adenomatous polyposis. Genet Test 11(3):315–320
Abdel-Rahman WM, Mecklin JP, Peltomäki P (2006) The genetics of HNPCC: application to diagnosis and screening. Crit Rev Oncol Hematol 58(3):208–220
Scott RJ, McPhillips M, Meldrum CJ, Fitzgerald PE, Adams K, Spigelman AD, Sart D, Tucker K, Kirk J (2001) Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet 68:118–127<!–-[AU3] Reference list | The data "HFC Service" was deleted in reference item [4]. Kindly check if appropriate.-->
Raevaara T, Gerdes A, Lönnqvist K, Tybjaerg-Hansen A, Abdel-Rahman W, Kariola R, Peltomäki P, Nyström-Lahti M (2004) HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1. Genes Chromosomes Cancer 40(3):261–265
Rey J, Noruzinia M, Brouillet J, Sarda P, Maudelonde T, Pujol P (2004) Six novel heterozygous MLH1, MSH2, and MSH6 and one homozygous MLH1 germline mutations in hereditary nonpolyposis colorectal cancer. Cancer Genet Cytogenet 155(2):140–151
Müller A, Schackert H, Lange B, Rüschoff J, Füzesi L, Willert J, Burfeind P, Shah P, Becker H, Epplen J, Stemmler S (2006) A novel MSH2 germline mutation in homozygous state in two brothers with colorectal cancers diagnosed at the age of 11 and 12 years. Am J Med Genet A 140(3):195–199
Felton KEA, Gilchrist DM, Andrew SE (2007) Constitutive deficiency in DNA mismatch repair. Clin Genet 71:483–498
Okkels H, Sunde L, Lindorff-Larsen K, Thorlacius-Ussing O, Gandrup P, Lindebjerg J, Stubbeteglbjaerg P, Oestergaard J, Nielsen F, Krarup H (2006) Polyposis and early cancer in a patient with low penetrant mutations in MSH6 and APC: hereditary colorectal cancer as a polygenic trait. Int J Colorectal Dis 21:847–850
van Puijenbroek M, Nielsen M, Reinards T, Weiss M, Wagner A, Hendriks Y, Vasen H, Tops C, Wijnen J, van Wezel T, Hes F, Morreau H (2007) The natural history of a combined defect in MSH6 and MUTYH in a HNPCC family. Fam Cancer 6(1):43–51
Auclair J, Leroux D, Desseigne F, Lasset C, Saurin J, Joly M, Pinson S, Xu X, Montmain G, Ruano E, Navarro C, Puisieux A, Wang Q (2007) Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat 28(11):1084–1090
Soravia C, DeLozier C, Dobbie Z, Berthod C, Arrigoni E, Bründler M, Blouin J, Foulkes W, Hutter P (2006) Double frameshift mutations in APC and MSH2 in the same individual. Int J Colorectal Dis 21(1):79–83
Bisgaard ML, Fenger K, Bulow S, Niebuhr E, Mohr J (1994) Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat 3:121–125
Acknowledgments
We thank Sylviane Olschwang at the Institut Paoli Calmettes for APC gene sequencing, Qing Wang at the Centre Leon Berard for MSH2 sequencing, Thierry Frebourg at the Centre Hospitalier Universitaire Rouen for MSH2 qualitative analysis, and Lydia Raziq at the Centre Jean Perrin for additional genotyping assistance. This work was supported by the French Institut National de Cancer (INCa).
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Uhrhammer, N., Bignon, YJ. Report of a family segregating mutations in both the APC and MSH2 genes: juvenile onset of colorectal cancer in a double heterozygote. Int J Colorectal Dis 23, 1131–1135 (2008). https://doi.org/10.1007/s00384-008-0526-9
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DOI: https://doi.org/10.1007/s00384-008-0526-9