FaCD Online Syndrome Fact Sheet

Last updated: 21 Dec 2010

Name: Lung Cancer, Familial Clustering of

Synonym: incl. Hereditary Lung cancer, Hereditary Non-Small Cell Lung cancer

Mode of Inheritance: multifact?/AD?

Genes

EGFR, mapped to 7p12.3-p12.1
LNCR1, mapped to 6q23-q25
RGS17/RGSZ2, mapped to 6q25.3

Tumor features

lung/bronchial cancer

Tumor features (possible)

cervical cancer
colorectal cancer
laryngeal cancer
nasopharyngeal cancer
oropharyngeal cancer
ovarian cancer (i.e. epithelial origin)

Comment

Familial Risks
A family history of lung cancer has been documented in approximately 12-23 % of lung cancer patients[1-3]. Having an affected relative clearly increases lung cancer risk[30]. A smoking-adjusted relative risk (RR) of 2.4 to develop lung cancer in general, and a RR of 4 to develop adenocarcinoma of the lung, has been estimated in first degree relatives of lung cancer patients[3;4]. A relative risk of 5.31 for offspring of lung cancer patients has been reported[5]. In an Icelandic study, risk increase was shown to extend beyond the nuclear family for second and third-degree relatives[36]. As expected, early age at diagnosis is associated with stronger increase in lung cancer risk for relatives[26]. Risk for multiple primary lung cancers is increased for patients with a family history of lung cancer[37]. Racial differences in risk exist. First-degree relatives of black individuals with early-onset lung cancer appear to have greater risk of lung cancer than their white counterparts, and these risks are further amplified by cigarette smoking[27].

Histology
Differences appear to exist between risks associated with the various histological types of lung cancer. However, studies on this subject are contradictive[2,6,7,34]. In a Japanese study[35], family history was more strongly associated with the risk of squamous cell carcinoma than with other histologic types, while no clear increase in risk was observed in adenocarcinoma and small cell carcinoma. A previous Japanese study[8] of 1188 patients with primary lung cancer had found that patients with adenocarcinoma reported a family history of colorectal cancer, and those with squamous cell cancer reported a family history of head and neck cancer more frequently than others. In a Swedish study[34], compared with the rate of lung cancers among persons without family history, a high risk by parental family history in adenocarcinoma and large cell carcinoma was found, and only a slightly lower risk was found among patients with squamous cell carcinoma and small cell carcinoma. Among siblings, an increased risk was shown for concordant adenocarcinoma and small cell carcinoma at all ages and for all histological types when cancer was diagnosed before age 50.
A rare type of neoplasm of the lung, pleuropulmonary blastoma[9] is discussed in a seperate database entry.

Smoking
There is evidence for a familial effect on lung cancer risk that is independent of the effect of tobacco smoke[10,29]. Having a first-degree relative with lung cancer has been shown to be associated with a RR of 6.1. among non-smokers in the 40-59 year old age group, after adjusting for environmental smoke exposures[1] and a RR of 1.5 to develop lung adenocarcinoma was found among non-smoking first-degree female relatives of lung cancer patients[11]. However, not all studies show an increase of lung cancer risk among non-smokers with a family history of lung cancer[12,28]. More general, a significant increase of risk has been observed in relatives of lung cancer probands for cancer at all anatomical sites [13] and smoking associated cancer in particular[14]. In addition to cancer of the respiratory tract these risks are particularly observed for cancer of the skin and female genital tract[15;16]. Data from the Iowa Women's Health Study demonstrated a RR of 2 for smoking associated lung cancer (small cell, squamous and large cell type) in women with a history of cervical cancer (also thought to be smoking-associated) in first-degree relatives[17]. In contrast, the risk for adenocarcinoma of the lung, which is generally more common in women and has the weakest association with smoking, was increased in women with first-degree relatives with ovarian cancer (RR 2), suggestive of shared hormonal risk factors. A Swedish study that tried to model the heritability of smoking in families of lung cancer patients suggested that most familial cases of lung cancer cannot be attributed to shared smoking habits[33].

Genetic Analysis
Genetic (segregation) analysis of smoking-associated malignancies suggests that Mendelian factors may influence the risk of cancers that are known to be smoking associated[18]. In this model, approximately 15 % of the population could be expected to carry a gene which increases their susceptibility to smoking associated cancer. Gene-carriers were estimated to have a mean age-of-onset of approximately 22 years earlier than non-carriers[18]. Segregation analysis of the Louisiana lung cancer dataset supported a high-risk allele frequency of 2% and carriers were estimated to have a RR of 17.3 to develop lung cancer[10]. In this dataset, the estimated percentage of lung cancer patients carrying a high-risk allele exceeded 90% for those diagnosed before the age of 61 years, and decreased to 10% for those diagnosed after age 79[19].

A genetic epidemiological study in the families of non-smoking lung cancer probands rejected all simple Mendelian models when trying to explain lung cancer aggregation in these families[20]. When that study population was re-examined for an age-at-diagnosis effect, it was shown that in the families of lung cancer patients diagnosed before the age of 60 years, a Mendelian codominant model with significant modifying effects of smoking and chronic bronchitis best explained the observed data. In contrast, no evidence for a major genetic effect was observed in the families of probands diagnosed after the age of 60[21]. Analyzing age-specific incidence rates of lung cancer lead Renan[22] to believe that indeed a small percentage (< 1 % ?) can be associated with heritable factors, a percentage likely to be much higher in the early-onset cases. Sellers et al[23] stressed that segregation analysis for lung cancer could be confounded by differences across generations in exposure to environmental risk factors (e.g. tobacco exposure). Twin studies did not indicate the existence of a strong genetic lung cancer predisposition in their population [24,25]. Data from a Swedish study suggested that 1.7% of lung cancers up to age 68 years were heritable and probably due to a high-penetrant recessive gene or genes that predispose to tobacco carcinogens[33].

A wide range of gene polymorphisms is associated with small to modest increases in lung cancer risk. Discussing those is beyond the scope of this review. A major locus for lung cancer, LNCR1, has been mapped to 6q[38]. RGS17 has been proposed as the likely candidate gene in this region[39]. Mutations in EGFR have been detected in a few families with lung adenocarcinoma[40-43].

Links

National Familial Lung Cancer Registry at The Johns Hopkins Medical Institutions 23 1 08

References

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