History and Molecular Genetics of Lynch Syndrome in Family G

Abstract

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.

Association of Smoking and XPG, CYP1A1, OGG1, ERCC5, ERCC1, MMP2, and MMP9 Gene Polymorphisms with the early detection and occurrence of Laryngeal Squamous Carcinoma

“…The family comprised seven generations and total of 929 people as of 2002. The cancer incidence rate of this family was 12.4%, which was higher than that of the general population, and most of the affected individuals had colorectal or endometrial cancer 12 . In addition to identifying such family aggregation phenomena, researchers also found that the influences of environmental factors varied among individuals such that exposure to the same risk factors did not invariably lead to cancer 6 .…”

Sebaceous Skin Lesions as Clues to Hereditary Non-Polyposis Colorectal Cancer

“…One of the authors, a dermatopathologist, kindly advised us about his patient with MTS cutaneous signs and visceral cancer who, after considerable discussion, had stated that she was a member of a very large extended family, namely, "Family G of Warthin," which we were studying. This family has been under investigation for more than 100 years (Douglas et al, 2005;Lynch and Krush, 1971;Warthin, 1913). As far as we are aware, this report provided the first description of MTS in HNPCC (Lynch et al, 1981).…”

Direct contact in inviting high-risk members of hereditary colon cancer families to genetic counselling and DNA testing

“…In the well-known family G, first described by Warthin in 1913 and further revised by Henry Lynch et al , only 40 members have had predictive genetic testing to date, resulting in 5 mutation carriers among 665 living family members 32. Thus, the carrier status for the majority of family members has remained unknown.…”