DCEG research on hereditary syndromes and cancer has made a significant impact in the following areas:
DCEG researchers have identified genes and mutations responsible for hereditary cancer syndromes. These findings have had a significant impact on the clinical management of these and related conditions, as well as informed research on the genetic determinants of cancer in general. Examples include the discovery of Li-Fraumeni syndrome and the role of p53 (Li and Fraumeni, 1969, 1982; Li et al., 1988; Malkin et al., 1990) and the roles of NF2 in neurofibromatosis type 2 (Rouleau et al., 1993; Trofatter et al., 1993); CDKN2A, CDK4, MITF, and POT1 in hereditary melanoma (Hussusian et al., 1994; Zuo et al., 1996; Yokoyama et al., 2011; Shi et al., 2014); PTCH in nevoid basal cell carcinoma syndrome (Hahn et al., 1996); SUFU in medulloblastoma (Taylor et al., 2002); and T (brachyury) duplication in familial chordoma (Yang et al., 2009).
Detailed clinical studies of neurofibromatosis type 2 carried out by DCEG investigators revealed heterogeneity of the disease phenotype, changed its clinical management, and informed genetic counseling guidelines (Kaiser-Kupfer et al., 1989; Parry et al., 1994, 1996; Ruttledge et al., 1996).
DCEG researchers identified the PTCH gene as the cause of nevoid basal cell carcinoma syndrome after discovering a novel chromosome 9q deletion in a patient with the syndrome and conducting genetic linkage and fine-mapping studies (Gailani et al., 1992; Hahn et al., 1996; Chidambaram et al., 1996). This work set in motion a research effort that recently culminated in the first U.S. Food and Drug Administration-approved biological agent (vismodegib) to target the Hedgehog signaling pathway, a novel therapy for locally advanced and metastatic basal cell carcinoma of the skin.
DCEG researchers and colleagues published the Concise Handbook of Familial Cancer Susceptibility Syndromes, which has provided a useful reference for clinical recognition and management of these rare but important disorders (Lindor and Greene, 1998; Lindor et al., 2008).
DCEG researchers observed that patients with dyskeratosis congenita (DC) have extremely short telomeres and that approximately 60 percent of DC patients have a germline mutation in a telomere biology gene. These discoveries led to the development of telomere length as a diagnostic test for DC and new criteria for evaluating potential bone marrow donors (Alter et al., 2007; Savage et al., 2008).
DCEG studies of monoclonal B-cell lymphomatosis established the condition as a precursor for chronic lymphocytic leukemia (CLL) in high-risk families and in the general population, facilitating the development of screening for early diagnosis of CLL (Landgren et al., 2009; Goldin et al., 2010).