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The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.
Gastroenterology. 2008 Aug; 135(2):419-28.G

Abstract

BACKGROUND & AIMS

Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers.

METHODS

We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment.

RESULTS

Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed.

CONCLUSIONS

PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.

Authors+Show Affiliations

Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18602922

Citation

Senter, Leigha, et al. "The Clinical Phenotype of Lynch Syndrome Due to Germ-line PMS2 Mutations." Gastroenterology, vol. 135, no. 2, 2008, pp. 419-28.
Senter L, Clendenning M, Sotamaa K, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135(2):419-28.
Senter, L., Clendenning, M., Sotamaa, K., Hampel, H., Green, J., Potter, J. D., Lindblom, A., Lagerstedt, K., Thibodeau, S. N., Lindor, N. M., Young, J., Winship, I., Dowty, J. G., White, D. M., Hopper, J. L., Baglietto, L., Jenkins, M. A., & de la Chapelle, A. (2008). The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology, 135(2), 419-28. https://doi.org/10.1053/j.gastro.2008.04.026
Senter L, et al. The Clinical Phenotype of Lynch Syndrome Due to Germ-line PMS2 Mutations. Gastroenterology. 2008;135(2):419-28. PubMed PMID: 18602922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. AU - Senter,Leigha, AU - Clendenning,Mark, AU - Sotamaa,Kaisa, AU - Hampel,Heather, AU - Green,Jane, AU - Potter,John D, AU - Lindblom,Annika, AU - Lagerstedt,Kristina, AU - Thibodeau,Stephen N, AU - Lindor,Noralane M, AU - Young,Joanne, AU - Winship,Ingrid, AU - Dowty,James G, AU - White,Darren M, AU - Hopper,John L, AU - Baglietto,Laura, AU - Jenkins,Mark A, AU - de la Chapelle,Albert, Y1 - 2008/05/02/ PY - 2008/02/14/received PY - 2008/03/31/revised PY - 2008/04/24/accepted PY - 2008/7/8/pubmed PY - 2008/9/3/medline PY - 2008/7/8/entrez SP - 419 EP - 28 JF - Gastroenterology JO - Gastroenterology VL - 135 IS - 2 N2 - BACKGROUND & AIMS: Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. METHODS: We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. RESULTS: Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. CONCLUSIONS: PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/18602922/The_clinical_phenotype_of_Lynch_syndrome_due_to_germ_line_PMS2_mutations_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(08)00737-3 DB - PRIME DP - Unbound Medicine ER -