Cancer Mortality in Relatives of Retinoblastoma Patients2

Abstract

The risk of other cancers in relatives of retinoblastoma (RTB) patients was determined by a survey of the mortality experience of siblings, parents, parental siblings, and grandparents of all U.S. or Canadian RTB patients referred to The University of Texas M.D. Anderson Hospital and Tumor Institute between 1944 and 1980. Expected mortality was ascertained by the application of age-, sex-, race-, and calendar year-specific U.S. mortality rates to the observed person-years. Among 607 relatives of 33 unilateral-sporadic RTB probands, no excess in cancer deaths was observed (observed/expected = 18/22). Among 733 relatives of 47 bilateral-familial RTB probands, a slight excess in cancer deaths was observed (41/31). A significant excess in cancer deaths was occurred in relatives under age 55 years (18/9) and in fathers (7/1) of the bilateral RTB probands. To determine whether the cancer excess was related to some unique allele associated with second tumors in RTB survivors, the cancer mortality of 203 relatives of the 14 RTB patients with second tumors was examined, and no excess was observed (11/11). To determine whether the excess might be attributable to an unexpressed RTB gene or precursor, the mortality experience was examined in 6 kindreds in which parents, unaffected by RTB, had more than 1 child with RTB. Among these 72 relatives a significant excess in cancer deaths was observed (8/2). The findings demonstrate a modest overall cancer excess in relatives of hereditary RTB patients and suggest it may be attributable to an unexpressed RTB gene or precursor in a small number of kindreds. Mechanisms for an apparent "precursor" might involve a delayed mutation, genetic mosaicism, or a submicroscopic balanced chromosomal translocation.

Rb family proteins differentially regulate distinct cell lineages during epithelial development

“…Epidemiological studies show that carriers of a mutant Rb allele are 15 times more likely to die from lung cancer than the general population (Sanders et al, 1989). Moreover, the tumors that arise in these patients are predominantly SCLC and develop at a younger age than in the general population (Leonard et al, 1988;Sanders et al, 1989;Strong et al, 1984). The mouse model generated for these studies therefore provides evidence that genetically engineered mice can be used to model human lung disease resulting from Rb deficiency.…”

“…However, germline Rb mutations would be predicted to predispose individuals to neuroendocrine tumors, specifically to SCLC. Indeed, multiple studies have now established that germ line Rb mutations in humans confer an increased risk to lung cancer (Kleinerman et al, 2000;Leonard et al, 1988;Sanders et al, 1989;Strong et al, 1984). Epidemiological studies show that carriers of a mutant Rb allele are 15 times more likely to die from lung cancer than the general population (Sanders et al, 1989).…”

Second primary neoplasms in patients with retinoblastoma

“…These may include an increased risk of osteosarcoma in apparently unaffected gene carriers (Gordon, 1974;Francois, 1977a), and a generally increased risk of cancer in relatives of patients with retinoblastoma (Gordon, 1974;Bonaiti-Pellie & Briaid-Guillemot, 1980;Fedrick & Baldwin, 1978;Strong et al, 1984).…”

Abnormal Gene Expression Profiles in Unaffected Parents of Patients with Hereditary-Type Retinoblastoma

“…However, parental mosaicism of a mutation arising during early embryonic development of the zygote may also occur (4). Among Rb patients with high-penetrance, new germ line mutations, no known genetic abnormalities have as yet been identified in the somatic cells of their parents, although a statistically significant increase in the incidence of cancer has been reported (5)(6)(7).…”