History and molecular genetics of lynch syndrome in family G

A century later

Julie A. Douglas, Stephen B. Gruber, Karen A. Meister, Joseph Bonner, Patrice Watson, Anne J. Krush, Henry T. Lynch

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Context: In 1895, Aldred Scott Warthin, MD, PhD, initiated one of the most thoroughly documented and longest cancer family histories ever recorded. The unusually high incidence and segregation of cancers of the colon, rectum, stomach, and endometrium in Dr Warthin's family G was later followed up by his colleagues, most recently by Henry Lynch, MD. Described today as a Lynch syndrome family, family G was last documented in 1971, prior to the modern era of molecular diagnostics. Objective: To update family G. Design, Setting, and Participants: Historical prospective cohort study of family G members from 1895 to 2000. Main Outcome Measures: The primary outcomes were the frequencies and types of cancers, ages at diagnosis, and presence of the T to G transversion at the splice acceptor site of exon 4 of the mutS homolog 2, colon cancer, nonpolyposis type 1 (E coli) (MSH2) gene in family G members. A secondary analysis compared cancerspecific incidence rates in family G with published national and regional cancer incidence rates through the standardized incidence ratio (SIR). Results: Family G now has 929 known descendants of the original progenitor first reported in 1913. Cancers of the colon and rectum (SIR, 3.20; 95% confidence interval [CI], 2.39-4.19) and endometrium (SIR, 3.51; 95% CI, 1.92-5.89) continue to predominate in family G. Five of 40 tested members of family G carry the MSH2 T to G mutation; as a result, 15 of their living relatives are at increased risk of developing 1 or more colorectal or Lynch syndrome-associated cancers. In contrast, 97 living members of family G can now be excluded as mutation carriers. Conclusion: Within the last decade, molecular diagnostic testing has transformed the care of family G and other Lynch syndrome families in which a pathogenic mutation has been identified.

Original languageEnglish
Pages (from-to)2195-2202
Number of pages8
JournalJAMA - Journal of the American Medical Association
Volume294
Issue number17
DOIs
StatePublished - Nov 2 2005

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Hereditary Nonpolyposis Colorectal Neoplasms
Molecular Biology
History
Incidence
Colonic Neoplasms
Rectal Neoplasms
Endometrium
Mutation
Neoplasms
Molecular Diagnostic Techniques
Confidence Intervals
RNA Splice Sites
Molecular Pathology

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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History and molecular genetics of lynch syndrome in family G : A century later. / Douglas, Julie A.; Gruber, Stephen B.; Meister, Karen A.; Bonner, Joseph; Watson, Patrice; Krush, Anne J.; Lynch, Henry T.

In: JAMA - Journal of the American Medical Association, Vol. 294, No. 17, 02.11.2005, p. 2195-2202.

Research output: Contribution to journalArticle

Douglas, Julie A. ; Gruber, Stephen B. ; Meister, Karen A. ; Bonner, Joseph ; Watson, Patrice ; Krush, Anne J. ; Lynch, Henry T. / History and molecular genetics of lynch syndrome in family G : A century later. In: JAMA - Journal of the American Medical Association. 2005 ; Vol. 294, No. 17. pp. 2195-2202.
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abstract = "Context: In 1895, Aldred Scott Warthin, MD, PhD, initiated one of the most thoroughly documented and longest cancer family histories ever recorded. The unusually high incidence and segregation of cancers of the colon, rectum, stomach, and endometrium in Dr Warthin's family G was later followed up by his colleagues, most recently by Henry Lynch, MD. Described today as a Lynch syndrome family, family G was last documented in 1971, prior to the modern era of molecular diagnostics. Objective: To update family G. Design, Setting, and Participants: Historical prospective cohort study of family G members from 1895 to 2000. Main Outcome Measures: The primary outcomes were the frequencies and types of cancers, ages at diagnosis, and presence of the T to G transversion at the splice acceptor site of exon 4 of the mutS homolog 2, colon cancer, nonpolyposis type 1 (E coli) (MSH2) gene in family G members. A secondary analysis compared cancerspecific incidence rates in family G with published national and regional cancer incidence rates through the standardized incidence ratio (SIR). Results: Family G now has 929 known descendants of the original progenitor first reported in 1913. Cancers of the colon and rectum (SIR, 3.20; 95{\%} confidence interval [CI], 2.39-4.19) and endometrium (SIR, 3.51; 95{\%} CI, 1.92-5.89) continue to predominate in family G. Five of 40 tested members of family G carry the MSH2 T to G mutation; as a result, 15 of their living relatives are at increased risk of developing 1 or more colorectal or Lynch syndrome-associated cancers. In contrast, 97 living members of family G can now be excluded as mutation carriers. Conclusion: Within the last decade, molecular diagnostic testing has transformed the care of family G and other Lynch syndrome families in which a pathogenic mutation has been identified.",
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