Our study included an additional 41 families since our first report in 2004 (9
), and we performed OSA to examine evidence for linkage on each chromosome. Our results further confirm previous evidence for linkage on 6q with genome-wide significance and provide suggestive evidence for linkage on 12q in an identified subset of families with age at onset ≥78. We also observed several other suggestive linkages (LOD > 2.0) on chromosomes 5q, 14q, and 16q in subsets of families who were etiologically more homogeneous as defined by trait-related covariates. There was weak evidence for linkage (LOD > 1.0) on chromosomes 1q, 2p, 6q, 13p, and 17p if we sorted on risks for breast cancer, bladder cancer, digestive cancer or leukemia, but the exact mechanism of the relationship between diverse cancers and lung cancer remains to be determined in the future study. Of note, the region on chromosome 17p that showed the greatest evidence for linkage in families with the highest incidence of breast cancer includes p53 gene, suggesting that perhaps a subset of the families contains p53 variants. Two families that contain multiple primary cancers (family #21 had 6 lung, 5 breast, 2 colon, 1 lymphoma and 1 brain cancer; family #104 had 1 synovial sarcoma, 1 brain, 1 melanoma, 7 lung, 1 tonsil and 1 uterine cancers) previously underwent sequencing of exons 4-9 of the p53 gene and no variants were identified.
A genome-wide linkage study performed by Bailey-Wilson et al
) successfully mapped a major susceptibility locus to chromosome 6q23-25 in families with four or more individuals affected with lung cancer. The HLOD score in 38 families that included four or more affected cases in two or more generations increased from 3.47 to 4.26 in the 23 families with five or more affected members. A follow-up study by Amos et al
) that included 50 families with five or more affected individuals found a HLOD score of 4.69 on chromosome 6q at 158cM. These findings provided further evidence that a region of chromosome 6q was associated with lung cancer risk.
You et al
) identified RGS17
as a candidate familial lung cancer susceptibility gene for the locus at 158 cM on chromosome 6q through epidemiologic and biologic studies. RGS17
was found to have opioid receptor function and act as a potential oncoprotein, promoting tumor cell growth. In our study, OSA identified a peak LOD of 3.66 at this region in the 51 families with more than 4 affected lung cancer cases in each family. We also observed a maximum LOD of 4.19 at 168.2cM on 6q in 53 families with lowest proportion of smokers. This finding is consistent with findings from the study of Amos et al
) showing high risks for lung cancer in never and light smokers from families that link to chromosome 6q. The 1-LOD down support intervals of the regions for the subsets of families identified by these two covariates overlapped, suggesting that those two regions might share the same lung cancer susceptibility locus.
Our results on chromosome 12q showed a nearly significant linkage at the genome-wide significance level of linkage score 3.3 (23
) in 30 families with the highest maximum age of onset, and the increase of linkage relative to the overall sample was significant after correction for multiple comparisons. This was the largest linkage score of lung cancer on 12q yet reported (9
), and to some degree our OSA suggested linkage between the late onset of lung cancer and chromosome 12q. The support interval under this peak encompasses ~33 cM, in which one candidate gene - insulin-like growth factor-1(IGF-1
) at 114.24 cM was found to be involved with lung cancer because high plasma levels of IGF-I were associated with an increased risk of lung cancer (OR = 2.06) and a significant lower survival among patients(25
signaling is important for cancer development and progression because it is involved in cell proliferation, differentiation, migration and death (27
helps cells to pass the G1-S checkpoint in the cell cycle, and effects of overexpression of IGF-1
receptors are also important in tumorigenesis (25
). Raised concentrations of IGF-1
were also reported to increase the risk of several other cancers such as prostate cancer, premenopausal breast cancer and colorectal cancer (28
On three chromosomes—5q, 14q, and 16q—OSA produced a suggestive linkage score of greater than 2.0 in ordered subsets and the increase of LOD scores was significant compared with the whole sample. Such a suggestive linkage was previously reported only at 14q by Bailey-Wilson et al
) in a subset of families with five or more affected cases, but no candidate genes have been identified on this chromosome thus far. For the peak linkage region on 16q24.2-q24.3, previous evidence for linkage has not been demonstrated. Our results show an increased LOD score among families with early onset lung cancer. A candidate gene in this region is cadherin13 (CDH13
), which encompasses the marker D16S3091 at 111cM. CDH13
was reported to be inactivated in lung cancer by Sato et al
), who found that chromosomal deletion accompanied by hypermethylation inactivated the CDH13
gene in a considerable number of lung cancer specimens. The gene locus was also observed to be hypermethylated or deleted in breast cancer (32
) and ovarian cancer (33
). This particular cadherin is a putative regulator of cell-to-cell interaction in the heart and may function as a negative guiding molecule in neural cell growth (34
). The CDH13
gene was mapped to chromosome 16q, in which allelic loss in patients with lung cancer was also reported (35
Although the OSA yielded subsets of families with significant evidence for linkage on chromosome 6p (3.35 at 63 cM) and suggestive evidence for linkage on chromosome 20p (2.20 at 34.8 cM), neither of them were significantly increased from the overall baseline(P
>0.05). Evidence suggestive of linkage at these two regions has been previously noted by our colleagues (9
), but no candidate genes have been demonstrated to be associated with lung cancer on these chromosomes thus far.
A strong evidence for linkage to lung cancer was observed at 159cM on 6q in 61 families with the lowest digestive cancer incidence rate. Allelic losses were reported on bands 6q16, 6q21-22, and 6q27 in gastric carcinoma (36
) and on 6q25 in lung cancer (37
), but this observation can’t explain why the subset of families with low digestive cancer risk had high linkage to lung cancer. The roles of some other genes or environmental factors in the development of both digestive and lung cancers need to be further verified.
The OSA with breast-cancer risk-defined subsets produced a significant increase in LOD scores on chromosomes 1q23 (LOD = 2.24). On chromosome 1q21, the MUC1
gene was more strongly expressed in neoplastic lung tissues than in normal counterparts (38
), and it was highly overexpressed in breast carcinomas (39
In summary, our OSA results strongly support the previous evidence for linkage on 6q and provide nearly significant evidence for linkage on 12q in a subset of families defined by trait-related covariates. Several other regions suggestive of linkage with LOD scores greater than 2.0 were detected in the OSA. Genetic variants at one region that confer inherited susceptibility to lung cancer could be risk factors for other cancers. But we should also notice that common environmental factors may play in the development of both lung cancer and other cancers, for which an elevated LOD score for lung cancer can also be obtained when using other cancer risk as a covariate in OSA. Although our results provide a clue of utilizing disease-related covariates to identify potential linkage heterogeneity in genomic scans of lung cancer, confirmation of the linkage in another study with a larger sample size may be necessary to further reinforce our findings.