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A Century Later

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

JAMA. 2005;294:2195-2202.

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 cancer-specific 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.

Author Affiliations: Departments of Human Genetics (Drs Douglas and Gruber), Epidemiology (Dr Gruber), and Internal Medicine (Dr Gruber, Ms Meister, and Mr Bonner), University of Michigan Medical School, Ann Arbor; Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Neb (Drs Lynch and Watson); and Department of Internal Medicine and Human Genetics, Johns Hopkins University School of Medicine, Baltimore, Md (Ms Krush).

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