The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

Leigha Senter, Mark Clendenning, Kaisa Sotamaa, Heather Hampel, Jane Green, John D. Potter, Annika Lindblom, Kristina Lagerstedt, Stephen N Thibodeau, Noralane Morey Lindor, Joanne Young, Ingrid Winship, James G. Dowty, Darren M. White, John L. Hopper, Laura Baglietto, Mark A. Jenkins, Albert de la Chapelle

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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.

Original languageEnglish (US)
JournalGastroenterology
Volume135
Issue number2
DOIs
StatePublished - Aug 2008

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Hereditary Nonpolyposis Colorectal Neoplasms
Germ-Line Mutation
Phenotype
Mutation
Penetrance
Neoplasms
Endometrial Neoplasms
Counseling
Colorectal Neoplasms
Guidelines
Pseudogenes
DNA Mismatch Repair
Multiplex Polymerase Chain Reaction
Incidence
North America

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Senter, L., Clendenning, M., Sotamaa, K., Hampel, H., Green, J., Potter, J. D., ... de la Chapelle, A. (2008). The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations. Gastroenterology, 135(2). https://doi.org/10.1053/j.gastro.2008.04.026

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations. / Senter, Leigha; Clendenning, Mark; Sotamaa, Kaisa; Hampel, Heather; Green, Jane; Potter, John D.; Lindblom, Annika; Lagerstedt, Kristina; Thibodeau, Stephen N; Lindor, Noralane Morey; Young, Joanne; Winship, Ingrid; Dowty, James G.; White, Darren M.; Hopper, John L.; Baglietto, Laura; Jenkins, Mark A.; de la Chapelle, Albert.

In: Gastroenterology, Vol. 135, No. 2, 08.2008.

Research output: Contribution to journalArticle

Senter, L, Clendenning, M, Sotamaa, K, Hampel, H, Green, J, Potter, JD, Lindblom, A, Lagerstedt, K, Thibodeau, SN, Lindor, NM, Young, J, Winship, I, Dowty, JG, White, DM, Hopper, JL, Baglietto, L, Jenkins, MA & de la Chapelle, A 2008, 'The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations', Gastroenterology, vol. 135, no. 2. https://doi.org/10.1053/j.gastro.2008.04.026
Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD et al. The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations. Gastroenterology. 2008 Aug;135(2). https://doi.org/10.1053/j.gastro.2008.04.026
Senter, Leigha ; Clendenning, Mark ; Sotamaa, Kaisa ; Hampel, Heather ; Green, Jane ; Potter, John D. ; Lindblom, Annika ; Lagerstedt, Kristina ; Thibodeau, Stephen N ; Lindor, Noralane Morey ; Young, Joanne ; Winship, Ingrid ; Dowty, James G. ; White, Darren M. ; Hopper, John L. ; Baglietto, Laura ; Jenkins, Mark A. ; de la Chapelle, Albert. / The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations. In: Gastroenterology. 2008 ; Vol. 135, No. 2.
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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.",
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AU - Clendenning, Mark

AU - Sotamaa, Kaisa

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AU - Green, Jane

AU - Potter, John D.

AU - Lindblom, Annika

AU - Lagerstedt, Kristina

AU - Thibodeau, Stephen N

AU - Lindor, Noralane Morey

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

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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.

AB - 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.

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