Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer

Karen H. Lu, John O. Schorge, Kerry J. Rodabaugh, Molly S. Daniels, Charlotte C. Sun, Pamela T. Soliman, Kristin G. White, Rajyalakshmi Luthra, David M. Gershenson, Russell R. Broaddus

Research output: Contribution to journalArticle

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Abstract

Purpose: Age younger than 50 years at the time of colon cancer diagnosis is often used as a screening criterion for Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). The purpose of this study was to determine the prevalence of MLH1, MSH2, and MSH6 mutations in an unselected cohort of women diagnosed with endometrial cancer at age younger than 50 years. Methods: A prospective, multicenter study was performed at three institutions. After written consent was obtained, germline mutation testing by full sequencing and large deletion analysis of the MLH1, MSH2, and MSH6 genes was performed. Tumor studies included immunohistochemistry of MLH1, MSH2, and MSH6; microsatellite instability analysis; and hypermethylation of the MLH1 promoter. Results: Of the 100 women, nine (9%; 95% CI, 4.2 to 16.4) carried a deleterious germline mutation: seven women with mutations in MSH2, one woman with a mutation in MLH1, and one woman with a mutation in MSH6. Two additional women had molecular studies consistent with the diagnosis of Lynch syndrome. The mean body mass index (BMI) for the entire cohort was 34.4, which is significantly higher than 29.2, the mean BMI for the mutation carriers. Predictors of finding a germline mutation included having a first-degree relative with a Lynch syndrome-associated cancer, endometrial tumor with loss of MSH2 expression, tumors with high microsatellite instability, and lower BMI. Conclusion: In this prospective study of endometrial cancer patients younger than age 50 years, 9% were found to carry germline Lynch syndrome-associated mutations. In addition to young age of onset, family history, BMI, and molecular tumor studies can improve the likelihood of identifying a Lynch syndrome-associated germline mutation in MLH1, MSH2, and MSH6.

Original languageEnglish (US)
Pages (from-to)5158-5164
Number of pages7
JournalJournal of Clinical Oncology
Volume25
Issue number33
DOIs
StatePublished - Nov 20 2007

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Hereditary Nonpolyposis Colorectal Neoplasms
Endometrial Neoplasms
Germ-Line Mutation
Mutation
Body Mass Index
Microsatellite Instability
Neoplasms
Prospective Studies
Age of Onset
Colonic Neoplasms
Multicenter Studies
Immunohistochemistry
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lu, K. H., Schorge, J. O., Rodabaugh, K. J., Daniels, M. S., Sun, C. C., Soliman, P. T., ... Broaddus, R. R. (2007). Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. Journal of Clinical Oncology, 25(33), 5158-5164. https://doi.org/10.1200/JCO.2007.10.8597

Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. / Lu, Karen H.; Schorge, John O.; Rodabaugh, Kerry J.; Daniels, Molly S.; Sun, Charlotte C.; Soliman, Pamela T.; White, Kristin G.; Luthra, Rajyalakshmi; Gershenson, David M.; Broaddus, Russell R.

In: Journal of Clinical Oncology, Vol. 25, No. 33, 20.11.2007, p. 5158-5164.

Research output: Contribution to journalArticle

Lu, KH, Schorge, JO, Rodabaugh, KJ, Daniels, MS, Sun, CC, Soliman, PT, White, KG, Luthra, R, Gershenson, DM & Broaddus, RR 2007, 'Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer', Journal of Clinical Oncology, vol. 25, no. 33, pp. 5158-5164. https://doi.org/10.1200/JCO.2007.10.8597
Lu, Karen H. ; Schorge, John O. ; Rodabaugh, Kerry J. ; Daniels, Molly S. ; Sun, Charlotte C. ; Soliman, Pamela T. ; White, Kristin G. ; Luthra, Rajyalakshmi ; Gershenson, David M. ; Broaddus, Russell R. / Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. In: Journal of Clinical Oncology. 2007 ; Vol. 25, No. 33. pp. 5158-5164.
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title = "Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer",
abstract = "Purpose: Age younger than 50 years at the time of colon cancer diagnosis is often used as a screening criterion for Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). The purpose of this study was to determine the prevalence of MLH1, MSH2, and MSH6 mutations in an unselected cohort of women diagnosed with endometrial cancer at age younger than 50 years. Methods: A prospective, multicenter study was performed at three institutions. After written consent was obtained, germline mutation testing by full sequencing and large deletion analysis of the MLH1, MSH2, and MSH6 genes was performed. Tumor studies included immunohistochemistry of MLH1, MSH2, and MSH6; microsatellite instability analysis; and hypermethylation of the MLH1 promoter. Results: Of the 100 women, nine (9{\%}; 95{\%} CI, 4.2 to 16.4) carried a deleterious germline mutation: seven women with mutations in MSH2, one woman with a mutation in MLH1, and one woman with a mutation in MSH6. Two additional women had molecular studies consistent with the diagnosis of Lynch syndrome. The mean body mass index (BMI) for the entire cohort was 34.4, which is significantly higher than 29.2, the mean BMI for the mutation carriers. Predictors of finding a germline mutation included having a first-degree relative with a Lynch syndrome-associated cancer, endometrial tumor with loss of MSH2 expression, tumors with high microsatellite instability, and lower BMI. Conclusion: In this prospective study of endometrial cancer patients younger than age 50 years, 9{\%} were found to carry germline Lynch syndrome-associated mutations. In addition to young age of onset, family history, BMI, and molecular tumor studies can improve the likelihood of identifying a Lynch syndrome-associated germline mutation in MLH1, MSH2, and MSH6.",
author = "Lu, {Karen H.} and Schorge, {John O.} and Rodabaugh, {Kerry J.} and Daniels, {Molly S.} and Sun, {Charlotte C.} and Soliman, {Pamela T.} and White, {Kristin G.} and Rajyalakshmi Luthra and Gershenson, {David M.} and Broaddus, {Russell R.}",
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T1 - Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer

AU - Lu, Karen H.

AU - Schorge, John O.

AU - Rodabaugh, Kerry J.

AU - Daniels, Molly S.

AU - Sun, Charlotte C.

AU - Soliman, Pamela T.

AU - White, Kristin G.

AU - Luthra, Rajyalakshmi

AU - Gershenson, David M.

AU - Broaddus, Russell R.

PY - 2007/11/20

Y1 - 2007/11/20

N2 - Purpose: Age younger than 50 years at the time of colon cancer diagnosis is often used as a screening criterion for Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). The purpose of this study was to determine the prevalence of MLH1, MSH2, and MSH6 mutations in an unselected cohort of women diagnosed with endometrial cancer at age younger than 50 years. Methods: A prospective, multicenter study was performed at three institutions. After written consent was obtained, germline mutation testing by full sequencing and large deletion analysis of the MLH1, MSH2, and MSH6 genes was performed. Tumor studies included immunohistochemistry of MLH1, MSH2, and MSH6; microsatellite instability analysis; and hypermethylation of the MLH1 promoter. Results: Of the 100 women, nine (9%; 95% CI, 4.2 to 16.4) carried a deleterious germline mutation: seven women with mutations in MSH2, one woman with a mutation in MLH1, and one woman with a mutation in MSH6. Two additional women had molecular studies consistent with the diagnosis of Lynch syndrome. The mean body mass index (BMI) for the entire cohort was 34.4, which is significantly higher than 29.2, the mean BMI for the mutation carriers. Predictors of finding a germline mutation included having a first-degree relative with a Lynch syndrome-associated cancer, endometrial tumor with loss of MSH2 expression, tumors with high microsatellite instability, and lower BMI. Conclusion: In this prospective study of endometrial cancer patients younger than age 50 years, 9% were found to carry germline Lynch syndrome-associated mutations. In addition to young age of onset, family history, BMI, and molecular tumor studies can improve the likelihood of identifying a Lynch syndrome-associated germline mutation in MLH1, MSH2, and MSH6.

AB - Purpose: Age younger than 50 years at the time of colon cancer diagnosis is often used as a screening criterion for Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). The purpose of this study was to determine the prevalence of MLH1, MSH2, and MSH6 mutations in an unselected cohort of women diagnosed with endometrial cancer at age younger than 50 years. Methods: A prospective, multicenter study was performed at three institutions. After written consent was obtained, germline mutation testing by full sequencing and large deletion analysis of the MLH1, MSH2, and MSH6 genes was performed. Tumor studies included immunohistochemistry of MLH1, MSH2, and MSH6; microsatellite instability analysis; and hypermethylation of the MLH1 promoter. Results: Of the 100 women, nine (9%; 95% CI, 4.2 to 16.4) carried a deleterious germline mutation: seven women with mutations in MSH2, one woman with a mutation in MLH1, and one woman with a mutation in MSH6. Two additional women had molecular studies consistent with the diagnosis of Lynch syndrome. The mean body mass index (BMI) for the entire cohort was 34.4, which is significantly higher than 29.2, the mean BMI for the mutation carriers. Predictors of finding a germline mutation included having a first-degree relative with a Lynch syndrome-associated cancer, endometrial tumor with loss of MSH2 expression, tumors with high microsatellite instability, and lower BMI. Conclusion: In this prospective study of endometrial cancer patients younger than age 50 years, 9% were found to carry germline Lynch syndrome-associated mutations. In addition to young age of onset, family history, BMI, and molecular tumor studies can improve the likelihood of identifying a Lynch syndrome-associated germline mutation in MLH1, MSH2, and MSH6.

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