history of neoplastic disease exclusive of the
proband (62%of patients’ families and 57%of con-
trol families). However, the families of the lung can-
cer cases were more likely (30%) to have two or
more familymembers affectedwith any cancer than
the families of the controls. The case families were
also significantly more likely to have two or more
relatives with lung cancer than were the control
families. In addition, a higher percentage of all pri-
mary tumors were lung tumors (16.5%) in patients’
relatives as compared to controls’ relatives (10%).
The progression of increased risks for observing 1,
2, 3, and 4+ affected relatives in case families ver-
sus control families was slightly smaller than in the
Sellers et al. study [55] but showed the same type of
progression.
Family history data froman incident case–control
study in Texaswere analyzed for evidence of familial
aggregation by Shaw et al. [57]. A total of 943 histo-
logically confirmed lung cancer cases and 955 age-,
gender-, vital-status-, and ethnicity-matched con-
trols were interviewed regarding smoking, alcohol
use, cancer in first-degree relatives, medical history,
and demographic characteristics. After adjusting for
personal smoking status, passive smoking exposure
(ever/never), and gender, participants with at least
one first-degree relativewith lung cancer had a lung
cancer risk of 1.8 compared to those with no rela-
tives with lung cancer. Lung cancer risk increased as
the number of relatives with cancer increased and
was highest when only relatives with lung cancer
were considered (odds ratios of 1.7 and 2.8 for one
and two or more relatives with lung cancer, respec-
tively). Lung cancer was diagnosed at a significantly
younger age among cases who had first-degree rel-
atives with lung cancer than among those who had
no relatives with lung cancer. However, no such age
difference was seen between cases who had first-
degree relatives with any cancer versus those who
had no relatives with cancer. This study also exam-
ined histologic subtypes of lung cancer cases and
found that for each histologic type, there were sig-
nificant risks associated with having any relatives
with lung cancer, with odds ratios of 2.1 for ade-
nocarcinoma, 1.9 for squamous cell carcinoma, and
1.7 for small cell lung cancer. Finally, in this study,
only current and former smokers had an increased
lung cancer risk associated with lung cancer in
relatives.
Cannon-Albright et al. [58] examined the degree
of relatedness of all pairs of lung cancer patients in
the Utah Population Database. By comparing this to
the degree of relatedness in sets ofmatched controls,
they showed that lung cancer exhibited excess fa-
miliality, and three of four histological tumor types
still showed excess familiality when considered sep-
arately. In the same population, but using different
methodology, Goldgar et al. [59] studied lung can-
cer probands and controls who had died in Utah
and their first-degree relatives. They found that 2.55
timesmore lung cancers occurred in first-degree rel-
atives of lung cancer probands than expected based
on rates in control relatives. When they stratified
by gender, they observed higher relative risks for
female relatives of female probands (FRR = 4.02)
versusmale relatives ofmale probands (FRR = 2.5).
No adjustment was made in these analyses for per-
sonal smoking or other environmental risk factors,
so these results may simply reflect the familiality of
smoking behaviors. However, this is a largely non-
smoking population and Utah has the lowest smok-
ing rates of any state in the United States.
The number of lung cancers observed in some
twin studies have been too small to draw con-
clusions regarding familiality of lung cancer [60]
although possible aggregation of bronchoalveolar
carcinoma has been suggested in twin and family
studies [61,62]. However, this effect may be due to
aggregation of cigarette smoking as risk of this can-
cer is linked to tobacco consumption [63]. In 1995,
a study using a large twin registry, the National
Academy of Sciences—National Research Council
Twin Registry, Braun et al. [64] reported that the
observed concordance rates of monozygotic (MZ)
twins for death from lung cancer compared to that
of dizygotic (DZ) twins was 1.1 (95% confidence
interval, 0.6–1.9) although this did not adjust for
smoking behaviors in the twins. These results sug-
gest that, as expected, on a population level, smok-
ing behavior is probably a much stronger risk factor
than inherited genetic susceptibility.
Studies of familial risk of lung cancer in non-
smokers [65–67] have also shown increased risk
of lung cancer associated with a family history of
lung cancer. The study by Schwartz et al. [65] found
increased risk of lung cancer among relatives of
younger, nonsmoking lung cancer cases as com-
paredwith relatives of younger controls after adjust-
ing for smoking, occupational and medical histories
of each family member, suggesting increased sus-
ceptibility to lung cancer among relatives of early-
onset nonsmoking lung cancer patients. Wu et al.
[66] found an increased risk of lung cancer in per-
sonswith a history of lung or aerodigestive tract can-
cer in first-degree relatives after adjustment for ETS
exposure, which was significant for affected moth-
ers and sisters. Mayne et al. [67], in a population-
based study of nonsmokers (45% never smokers
and 55% former smokers who had quit at least
10 years prior to diagnosis or interview; 437 lung
cancer cases and 437 matched population controls)
in New York State, found that after adjusting for age
and smoking status (yes, no) in the relatives, a posi-
tive history in first-degree relatives of any cancer or
lung cancer or aerodigestive tract cancer or breast
cancer were each associated with significantly in-
creased risk of lung cancer.
In 2000, Bromen et al. [68], in a population-based
case–control study in Germany, showed that lung
cancer in parents or siblings was significantly as-
sociated with an increased risk of lung cancer and
that this risk was much stronger in younger partic-
ipants. In 2003, Etzel et al. [69] evaluated whether
first-degree relatives of lung cancer caseswere at in-
creased risk for lung cancer and for other smoking-
related cancers (bladder, head and neck, kidney, and
pancreas). They studied 806 hospital-based lung
cancer patients and 663 controls matched on age,
sex, ethnicity, and smoking history, all from the
Houston, Texas, area. After adjustment for smok-
ing history of patients and their relatives, there
was significant evidence for familial aggregation of
lung cancer and of smoking-related cancers. How-
ever, they did not find increased aggregation in
the families of young onset (less than or equal to
age 55) lung cancer cases or in families of never-
smokers.
Two studies in China [70,71] found, after adjust-
ing for age, sex, birth order, residence, family size,
chronic obstructive pulmonary disease (COPD),
smoking and cumulative index of smoky coal ex-
posure or occupational/industrial exposure index,
that first-degree relatives of lung cancer patients
were at significantly increased risk for lung cancer
compared to the same relatives of controls. They
also observed that families of the lung cancer pa-
tientswere significantlymore likely to have three or
more affected relatives than were control families.
A series of studies using the Swedish Family-
Cancer Database [72–75], which totals over
10.2 million individuals, found that a high propor-
tion of lung cancers diagnosed before the age of 50
appear to be heritable, and that lung cancer patients
with a family history of lung cancer were at a sig-
nificantly increased risk of subsequent primary lung
cancers.
In the United Kingdom, a case–control study of
lung cancer prevalence in first-degree relatives of
1482 female lung cancer cases and 1079 female
controls [76] was performed, adjusting for age and
tobacco exposure (pack-years) in the cases and
controls. They found that lung cancer in any first-
degree relative was associated with a significant in-
crease in lung cancer risk, and that the increase in
risk was stronger in relatives of cases with onset less
than 60 years or cases with three or more affected
relatives. However, this study was not able to adjust
for personal smoking in the relatives since these data
were not available.
A study ofwhite and black relatives of early-onset
lung cancer cases and of 773 frequency-matched
controls in Detroit, Michigan [77], showed that
smokers with a family history of early-onset lung
cancer had a higher risk of lung cancerwith increas-
ing age than smokers without a family history, and
that relatives of black cases were at higher risk than
relatives of white cases, after adjusting for age, sex,
pack-years of cigarette smoking, pneumonia, and
COPD.
A recent study [78] utilizing the Icelandic Can-
cer Registry calculated risk ratios of lung cancer in
first-, second-, and third-degree relatives of 2756
lung cancer patients diagnosed between 1955 and
2002. Relative risks were significantly elevated for
all three classes of relatives, and this increased risk
was stronger in relatives of early-onset lung cancer
patients (age at onset less than or equal to 60 years).
The effect did not appear to be solely due to the
effects of smoking in all relative types, except for
cousins and spouses.
A review in 2005 by Matakidou et al. [79] of 28
case–control, 17 cohort and 7 twin studies of the re-
lationship between family history and risk of lung
cancer and a meta-analysis of risk estimates, con-
cluded that the case–control and cohort studies con-
sistently showan increased risk of lung cancer given
a family history of lung cancer, and that risk appears
to be increased given a history of early-onset lung
cancer or of multiple affected relatives. However,
the results of the twin studies and the observed in-
creased risk of disease in spouses highlighted the
importance of environmental risk factors, such as
smoking, in this disease.