History and molecular genetics of Lynch syndrome in family G: a century later.


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.

To update family G.

Historical prospective cohort study of family G members from 1895 to 2000.

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).

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.

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.

  • Bonner J
  • Douglas JA
  • Gruber SB
  • Krush AJ
  • Lynch HT
  • Meister KA
  • Watson P
PubMed ID
Appears In
JAMA, 2005, 294 (17)