Inherited predisposition to early onset lung cancer according to histological type

Abstract

The role of hereditary factors in lung cancer is less well understood than in many other human neoplastic diseases. We used a nation-wide family dataset to search for evidence for a genetic predisposition in lung cancer. The Swedish Family-Cancer Database includes all Swedes born in 1932 and later (0-to 68-year-old offspring) with their parents, totaling over 10.2 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry up to year 2000. Standardized incidence ratios (SIR) and 95% confidence limits (CI) were calculated for age-specific familial risks in offspring by parental or sibling proband, separately. A Kappa test was used to examine the association between familial risk and histology. Compared to the rate of lung cancers among persons without family history, a high risk by parental family history in adenocarcinoma (2.03) and large cell carcinoma (2.14) was found, and only a slightly lower risk was found among patients with squamous cell carcinoma (1.63) and small cell carcinoma (1.55). 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. At young age, risks between siblings were higher than those between offspring and parents. The present data suggest that a large proportion of lung cancers before age 50 years appears to be heri- Lung cancer is the most common fatal cancer in the world, 1,2 and in Sweden it ranks fourth in incidence after prostate, colorectal and squamous cell skin cancer in men and after breast, colorectal and endometrial cancer in women. 3 Cigarette smoking is attributable to approximately 85-90% of all lung cancer, and certain environmental and occupational exposures, such as asbestos and radon, have also been linked to lung cancer development. 4,5 The incidence of lung cancer is rising in women and declining in men as a result of changed smoking behavior. 6 The changing histological patterns in lung cancer probably relate to changes in the composition of cigarettes. 7,8 As only 10% of cigarette smokers develop lung cancer, 9 it is suggested that genetic factors may be a contributing factor. Segregation analysis of lung cancer also supports the existence of heritable effects. 10 -12 In families of smoking probands, the data have suggested Mendelian dominant or codominant effects; in families of nonsmoking probands either no Mendelian or, particularly in lung cancers diagnosed before age 60 years, Mendelian codominant models have provided the best fits.Studies in molecular biology have elucidated the role of genetic factors in modifying an individual's risk for lung cancer. 13,14 There is increasing evidence that genes coding for carcinogen metabolism and DNA repair contribute to familial aggregation of lung cancer. [15][16][17][18] The early reports on genetic influences in lung cancer susceptibility appeared in the early 1980s and showed that firstdegree nonsmoking relatives of lung cancer patients had an increased risk of lung cance...

Family history and risk of lung cancer: age-at-diagnosis in cases and first-degree relatives

“…Bromen et al (2000) reported a 4.75-fold increase in risk of lung cancer among relatives of probands who were diagnosed with lung cancer before the age of 50 years. Li and Hemminki (2004) used a Swedish register of families to estimate standardised incidence ratio for offspring and siblings of cases of lung cancer, and found a substantially increased risk of disease before the age of 50 years in relatives of cases. In an alternative analysis to quantify the lifetime risk of lung cancer in first-degree relatives of earlyonset cases diagnosed before the age of 50 years, Cote et al (2005) reported a 1.91-fold increased risk of lung cancer for relatives of early-onset cases compared to affected relatives in a control population.…”

“…Biological theory and the experience of other cancers, including breast (Hopper et al, 1999), pancreas (James et al, 2004) and colon (Strate and Syngal, 2005), suggest that tumours associated with genetic factors tend to occur early in life. Numerous lung cancer studies have investigated the numbers of affected relatives and ageat-onset, with greatest risk seen in families with early-onset lung cancer compared with those whose onset of lung cancer occurred at older ages (Kreuzer et al, 1998;Bromen et al, 2000;Gauderman and Morrison 2000;Li and Hemminki, 2004;Cote et al, 2005). However, information on familial risk by age-at-onset of both the proband and the affected relatives is rare in lung cancer studies.…”

Parental lung cancer as predictor of cancer risks in offspring: Clues about multiple routes of harmful influence?

“…7,20 Thus in covering familial cases, by definition, the present subjects were sensitive to tobacco-related lung and other cancers, increasing the likelihood of observing effects. The SIRs measured between parental lung cancers and any offspring cancers would be elevated if there were genuine heritable causes for cancer susceptibility between the 2 sites.…”

“…It is likely that the familial risk for lung cancer, which is about 2.0, is partially explained by shared smoking habits among family members. 7 Thus, in analyzing cancer risks for offspring, we have no possibility to exclude the effects of their active smoking. However, we use age of onset and the relative magnitude of the effect in relation to lung cancer risks as reference points for possible inferences about cancer causation in offspring.…”

Circulating DNA as a Biomarker for Early Detection of Cancer: A Brief Update with an Emphasis on Lung Cancer~!2010-06-09~!2010-08-03~!2010-09-06~!

“…Even so, the role of this oncogene in the development of lung caner remains nebulous. In this regard, the findings reported by Li and Hemminki [68] may shed some light on this issue in that they describe an inherited predisposition to early-onset lung cancer due to mutations in the EGFR oncogene in a familial clustering with several cases of NSCL. KRAS belonging to the EGFR pathway genes is known to have mutated into various kinds of human tumors.…”