EVIDENCE FOR FAMILIAL AGGREGATION OF LUNG CANCER

Epidemiologic Cohort Studies Tokuhata and Lilienfeld
54,55 showed familial aggregation of lung cancer over
40 years ago. After accounting for personal smoking, their
results suggested the possible interaction of genes, shared
environment, and common lifestyle 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 an RR of 2.0 to 2.5 for mortality
because of lung cancer in cigarette-smoking relatives of cases
compared with smoking relatives of controls. Nonsmoking
relatives of lung cancer cases were also at higher risk when
compared with nonsmoking relatives of controls. Smoking
was a more important risk factor for men, but family history
was the more important risk factor for women. 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 resulting from noncancerous respiratory
diseases in relatives of patients compared with relatives of
controls, suggesting that the case relatives have a common
susceptibility to respiratory diseases. However, they found no
significant 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 smoking status
alone was used. Therefore, some of the familial aggregation
could be a result of familial correlation in smoking levels or age
at smoking initiation. However, nonsmoking relatives of cases
were at higher risk than nonsmoking relatives of controls.
At present, many other studies have shown evidence of familial
aggregation of lung cancer. In 1975, Fraumeni et al. 56
reported an increased risk of lung cancer mortality in siblings of
lung cancer probands. In 1982, Goffman et al. 57 reported families
with excess lung cancer of diverse histologic types. Lynch et
al. 58 reported evidence for increased risk of cancer at all anatomic
sites for relatives of lung cancer patients but no significant
increased risk for lung cancer alone in these relatives.
In southern Louisiana, case-control studies reported an
increased familial risk for lung cancer 59 and smoking-related
non–lung cancers 60 among relatives of lung cancer probands
(the index case leading the family to be studied) after allowing
for the effects of age, sex, occupation, and smoking. In these
two studies, familial aggregation analyses were performed on
a set of 337 lung cancer probands (cases), their spouse controls,
and the parents, siblings, half-siblings, and offspring of
both the probands and the controls. The probands were male
and female whites who died from lung cancer during the period
1976 to 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
cancer proband in the data set. A strong excess risk for lung
cancer was detected among first-degree relatives of probands
compared with 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
exposures. Parents of probands had a fourfold risk of having
developed lung cancer compared with parents of spouses, after
adjusting for the effects of age, sex, smoking, and occupational
exposures. Women greater than 40 years old who were relatives
of probands were at nine times higher risk than similar female
relatives of spouses, even among nonsmokers who had not reported
excessive exposure to hazardous occupations. Among
female heavy smokers who were relatives of probands, the risk
was increased from fourfold to sixfold. Overall, male relatives
of probands had a greater risk of lung cancer than their female
counterparts. After controlling for the confounding effects
of the measured environmental risk factors, relationship to a
proband remained a significant determinant of lung cancer,
with a 2.4 odds in favor of relatives of probands.
These same families were reanalyzed 60 to determine if
non–lung cancers exhibited similar familial aggregation. When
analyzing the number of cancers at any site that occurred in
a family, proband families were found to be 1.7 times more
likely than spouse families to have one family member (other
than the proband) with cancer, and 2.2 times more likely to
have two family members with cancer. Comparing case relatives
and control relatives, families that had three and four or
more cancers occurred with RRs of 3.7 and 5.0, respectively.
Each risk estimate was significant at the 0.01 level. The most
striking differences in cancer prevalence between proband
and control families were noted for cancer of the nasal cavity/
sinus, mid-ear, and larynx (odds ratio [OR] 4.6); trachea,
bronchus, and lung (OR 3.0); skin (OR 2.8); and uterus,
placenta, 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 non–lung cancer ( p 0.05) when
compared with relatives of spouse controls.
A family case-control study, drawn from a population-based
registry in Saskatchewan, Canada was reported by McDuffie. 61
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 history of neoplastic disease
exclusive of the proband (62% of patients’ families and 57% of
control families). However, the families of the lung cancer cases
were more likely (30%) to have two or more family members
affected with 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 primary tumors were lung
tumors (16.5%) in patients’ relatives compared with controls’
relatives (10%). The progression of increased risks for observing
1, 2, 3, and 4 affected relatives in case families versus control
families was less than that observed by Sellers et al.’s60 study but
showed the same type of progression.
Family history data from an incident case-control study
in Texas were analyzed for evidence of familial aggregation
by Shaw et al. 62 A total of 943 histologically confirmed lung
cancer cases and 955 age-, gender-, vital status-, and ethnicitymatched
controls 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, there
was a 1.8-fold OR associating lung cancer with having one or
more first-degree relatives 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
(ORs of 1.7 and 2.8 for one and two or more relatives with
lung cancer, respectively). Lung cancer was diagnosed at a significantly
younger age among cases who had first-degree relatives
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
examined histologic subtypes of lung cancer cases and found
that for each histologic type, there were significant risks associated
with having any relatives with lung cancer, with ORs of
2.1 for adenocarcinoma, 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. 63 examined the degree of relatedness
of all pairs of lung cancer patients in the Utah Population
Database (UPD). By comparing this with the degree of relatedness
in sets of matched controls, they showed that lung cancer
exhibited excess familiality, and three of four histological tumor
types still showed excess familiality when considered separately.
In the same population, but using different methodology,
Goldgar et al. 64 studied lung cancer probands and controls who
had died in Utah and their first-degree relatives. They found
that 2.55 times more lung cancers occurred in first-degree relatives
of lung cancer probands than expected (computing a familial
relative risk or FRR) 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) versus
male relatives of male probands (FRR 2.5). No adjustment
was made in these analyses for personal smoking or other
environmental risk factors, so these results may partly reflect
the familiality of smoking behaviors. However, the UPD is
derived from the Church of Latter-Day Saints records, which
is largely a nonsmoking population and Utah has the lowest
smoking rates of any state in the United States.
In 2000, Bromen et al., 65 in a population-based case-control
study in Germany, showed that lung cancer in parents or siblings
was significantly associated with an increased risk of lung cancer
and that this risk was much stronger in younger participants.
In 2003, Etzel et al. 66 evaluated whether first-degree relatives of
lung cancer cases were at increased 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 smoking history of patients and their relatives, there was
significant evidence for familial aggregation of lung cancer and
of smoking-related cancers. However, 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 67,68 both found, after adjusting for
age, sex, birth order, residence, family size, chronic obstructive
pulmonary disease (COPD), smoking, and cumulative index
of smoky coal exposure or occupational/industrial exposure
index, that first-degree relatives of lung cancer patients were at
significantly increased risk for lung cancer compared with the
same relatives of controls. They also observed that families of
the lung cancer patients were significantly more likely to have
three or more affected relatives than were control families.
A series of studies using the Swedish Family-Cancer
Database, 69–72 which totals over 10.2 million individuals,
found that a high proportion 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 significantly
increased risk of subsequent primary lung cancers. A recent
study 73 utilizing the Icelandic Cancer Registry calculated risk
ratios of lung cancer in first-, second-, and third- degree relatives
of 2756 lung cancer patients diagnosed between 1955
and 2002. RRs 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 a result of
the effects of smoking in all relative types, except for cousins
and spouses.
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, 74 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 increase 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,
data on personal smoking in relatives were not available.
A study of early onset white and African American lung
cancer cases and of 773 frequency-matched controls in Detroit,
Michigan, 75 showed that smokers with a family history of early
onset lung cancer had a higher risk of lung cancer with increasing
age than smokers without a family history, and that
relatives of African American cases were at higher risk than
relatives of white cases, after adjusting for age, sex, pack-years
of cigarette smoking, pneumonia, and COPD.
Studies of familial risk of lung cancer in nonsmokers 65,76–78
have also shown increased risk of lung cancer associated with a
family history of lung cancer. Schwartz et al. 76 found increased
risk of lung cancer among relatives of younger, nonsmoking
lung cancer cases compared with relatives of younger controls
after adjusting for smoking, occupational, and medical histories
of each family member, suggesting increased susceptibility
to lung cancer among relatives of early onset nonsmoking
lung cancer patients. Wu et al. 77 found an increased risk of
lung cancer in persons with a history of lung or aerodigestive
tract cancer in first-degree relatives after adjustment for ETS
exposure, which was significant for affected mothers and sisters.
Mayne et al. 78 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 positive history in first-degree relatives of
any cancer including lung cancer, aerodigestive tract cancer, or
breast cancer were each associated with significantly increased
risk of lung cancer.
Studies in Twins The number of lung cancers observed
in some twin studies have been too small to draw conclusions
regarding familiality of lung cancer, 79 although possible aggregation
of bronchoalveolar carcinoma has been suggested in
twins and family studies. 80,81 However, this effect may be a
result of aggregation of cigarette smoking because risk of this
cancer is linked to tobacco consumption. 82 In 1995, in a study
using a large twin registry, the National Academy of Sciences–
National Research Council Twin Registry, Braun et al. 83 reported
that the observed concordance rates of monozygous
(MZ) twins for death from lung cancer compared with that of
dizygous (DZ) twins was 1.1 (95% CI, 0.6 to 1.9), although
this did not adjust for smoking behaviors in the twins. These
results suggest that, as expected, on a population level, smoking
behavior is probably a much stronger risk factor than inherited
genetic susceptibility. Lichtenstein et al. 84 studied nearly
45,000 twins to identify clustering of excess risk in cotwins
of MZ versus DZ twins. Results showed a 7.7-fold increased
risk to MZ cotwins and a 6.7-fold increased risk to cotwins of
DZ twins. These risks reflect combined effects of environmental
and genetic determinants. Further modeling suggested that
26% of excess risk to MZ cotwins was attributed to heritable
factors, whereas 12% was attributed to shared environment in
the twins, and the remaining 62% was attributed to individual
environmental factors. Although a very large sample size of
twins was studied, the estimates still had very wide confidence
intervals reflecting the study of only 608 index twins who had
developed a lung cancer.
A review in 2005 by Matakidou et al. 85 of 28 case- control,
17 cohort, and seven twin studies of the relationship between
family history and risk of lung cancer and a metaanalysis of
risk estimates, concluded that the case-control and cohort
studies consistently show an 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 increased risk of disease in spouses highlighted
the importance of environmental risk factors, such as smoking,
in this disease.