Evidence for familial aggregation of lung cancer

Tokuhata and Lilienfeld [48,49] provided epidemi-
ologic evidence for familial aggregation of lung can-
cer over 40 years ago. After accounting for personal
smoking, their results suggested the possible inter-
action of genes, shared environment, and common
life-style factors in the etiology of lung cancer. In
their study of 270 lung cancer patients and 270 age-,
sex-, race-, and location-matched controls and their
relatives, they found a relative risk of 2–2.5 formor-
tality due to lung cancer in cigarette-smoking rel-
atives of cases as compared to smoking relatives
of controls. Nonsmoking relatives of lung cancer
cases were also at higher risk when compared to
nonsmoking relatives of controls. Smoking was a
more important risk factor for males but family his-
tory was the more important risk factor for females.
They also noted a synergistic interaction between
familial and smoking factors on the risk of lung
cancer in relatives, with smoking relatives of lung
cancer patients having much higher risk of lung
cancer than either nonsmoking relatives of patients
or smoking relatives of controls. They observed a
substantial increase in mortality due to noncancer-
ous respiratory diseases in relatives of patients as
compared to relatives of controls, suggesting that
the case relatives have a common susceptibility to
respiratory diseases. However, they found no signif-
icant differences between the spouses of the lung
cancer cases and controls for lung cancer mortality,
mortality from noncancerous respiratory diseases,
or smoking habits.
The major weakness of this study was that smok-
ing status alonewas used, as nomeasures of amount
or duration of smoking in the relatives were avail-
able. Therefore, some of the familial aggregation
could be due to familial correlation in smoking lev-
els or age at starting smoking. However, nonsmok-
ing relatives of cases were at higher risk than non-
smoking relatives of controls.
Since this time, many other studies have shown
evidence of familial aggregation of lung cancer. In
1975, Fraumeni et al. [50] reported an increased
risk of lung cancer mortality in siblings of lung can-
cer probands. In 1982, Goffman et al. [51] reported
families with excess lung cancer of diverse histo-
logic types. Lynch et al. [52] reported evidence for
increased risk of cancer at all anatomic sites for rel-
atives of lung cancer patients but no significant in-
creased risk for lung cancer alone in these relatives.
Leonard et al. [53] reported that survivors of famil-
ial retinoblastoma may also be at increased risk for
small cell lung cancer.
In southern Louisiana, our retrospective case–
control studies reported an increased familial risk for
lung cancer [54] and nonlung cancers [55] among
relatives of lung cancer probands after allowing for
the effects of age, sex, occupation, and smoking.
In these two studies, familial aggregation analy-
ses were performed on a set of 337 lung cancer
probands (cases), their spouse controls, and the par-
ents, siblings, half-siblings, and offspring of both
the probands and the controls. The probands were
male and female Caucasians who died from lung
cancer during the period 1976–1979 in a 10-parish
(county) area of southern Louisiana, a region noted
for its high lung cancer mortality rates. There were
about 3.5 male probands to every female lung can-
cer proband in the dataset. A strong excess risk for
lung cancer was detected among first-degree rela-
tives of probands compared to relatives of spouse
controls, after adjusting for age, sex, smoking status,
total duration of smoking, cigarette pack-years, and
a cumulative index of occupational/industrial ex-
posures. Parents of probands had a fourfold risk of
having developed lung cancer as opposed to parents
of spouses, after adjusting for the effects of age, sex,
smoking, and occupational exposures. Females over
40 years old who were relatives of probands were
at nine times higher risk than similar female rela-
tives of spouses, even among nonsmokers who had
not reported excessive exposure to hazardous occu-
pations. Among female heavy smokers who were
relatives of probands, the risk was increased four-
to sixfold. Overall, male relatives of probands had a
greater risk of lung cancer than their female coun-
terparts. After controlling for the confounding ef-
fects of the measured environmental risk factors,
relationship to a proband remained a significant de-
terminant of lung cancer, with a 2.4 odds in favor
of relatives of probands.
These same families were reanalyzed [55] to de-
termine if nonlung cancers exhibited similar familial
aggregation.When analyzing the number of cancers
at any site that occurred in a family, proband fam-
ilies were found to be 1.67 times more likely than
spouse families to have one family member (other
than the proband)with cancer, and 2.16 timesmore
likely to have two family members with cancer. For
three cancers and four or more cancers, the relative
risk increased to 3.66 and 5.04, respectively. Each
risk estimate was significant at the 0.01 level. The
most striking differences in cancer prevalence be-
tween proband and control families were noted for
cancer of the nasal cavity/sinus, mid-ear, and lar-
ynx (odds ratio, OR = 4.6); trachea, bronchus and
lung (OR = 3.0); skin (OR = 2.8); and uterus, pla-
centa, ovary, and other female organs (OR = 2.1).
After controlling for age, sex, cigarette smoking, and
occupational/industrial exposures, relatives of lung
cancer probands maintained an increased risk of
nonlung cancer (p < 0.05) when compared to rel-
atives of spouse controls.
A family case–control study, drawn from
a population-based registry in Saskatchewan,
Canada, was reported by McDuffie [56]. A total
of 359 cases and 234 age- and gender-matched
community controls were included in the study.
Most families reported at least one member with a