HIGH-RISK SYNDROMES CONFERRING AN INCREASED RISK FOR LUNG CANCERS

Leonard et al. 86 reported that survivors of familial retinoblastoma
may also be at increased risk for small cell lung cancer. The
standard mortality ratio for small cell lung cancer is estimated
to be 15-fold increased. 87,88 Kleinerman 89 reported that lung
cancer developing among those with germline retinoblastoma
mutations had the heaviest smoking histories. Retinoblastoma
survivors smoke less than the general population, suggesting
that targeted counseling to avoid this risky behavior in this
high-risk population may be effective. 90 The RB gene is inactivated
in 90% of small cell lung cancers, indicating the relevance
of this gene to small cell lung cancer etiology. 91
Mutations in the p53 gene cause Li-Fraumeni syndrome.
Individuals with this syndrome are at greatly increased risks
for many cancers, including breast and lung cancers, sarcomas,
leukemias and lymphomas, and adrenocortical tumors. The
standard incidence ratio for lung cancer was estimated to be 38,
using a prospectively followed cohort of carriers of p53 mutations.
92 Cigarette smoking further increased risk threefold.
Mutations in the epidermal growth factor receptor (EGFR)
locus are often found in adenocarcinomas of the lung arising in
nonsmoking women, particularly among Asian populations 93
(see Chapter 49). One family with multiple adenocarcinomas
was found to be segregating a mutation in the EGFR, indicating
that rarely inherited mutations of this locus can increase
the risk for lung cancer. 94 However, a study 95 of 237 familial
lung cancer cases occurring in individuals with three or more
relatives affected by lung cancer including 45 bronchoalveolar
lung cancers failed to find any mutations of EGFR, suggesting
that mutations of this gene are uncommon in the general
North American population.