Family Studies Explore the Causes of Cancer

For more than 30 years, NCI scientists have studied families in which multiple individuals have developed specific cancers. The research, now aided by new genomic technologies, is leading to the discovery of genes that affect cancer risk in families and the general population.

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Hereditary Syndromes

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Over the years, 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 determinates 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 NF2in 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 innevoid basal cell carcinoma syndrome (Hahn et al., 1996); SUFU inmedulloblastoma (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 forchronic 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).

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Learn about our current research on hereditary cancer syndromes