A major lung cancer susceptibility locus maps to chromosome 6q23-25

Abstract

Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P=.007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.

Figure 1

Maximum two-point homogeneity LOD scores under the simple dominant low-penetrance model without inclusion of age and smoking exposure. Individual chromosomes are indicated at the top of the graph.

Figure 2

Two-point maximum HLOD scores on chromosome 6, under the Sellers et al. (1990) model (Env) that includes age and cigarette-smoking exposure and is used in LODLINK, compared with two-point HLOD scores under the simple dominant low-penetrance model without inclusion of age and smoking exposures (No Env). Inclusion of age and smoking exposure increases the evidence in favor of linkage on 6q.

Figure 3

Plot of chromosome 6 parametric multipoint HLOD scores (affected-only dominant model, no environmental covariates) calculated by SIMWALK2, in all 52 families (HLOD-All), in the 38 families with four or more affected individuals (HLOD-38), and in the 23 multigenerational families with five or more affected individuals (HLOD-23).

Figure 4

Plot of chromosome 6 nonparametric multipoint linkage analysis using the variance-components approach (binary option) and the mixed-effects Cox models with multipoint IBD sharing calculated by SIMWALK2, for the 23 multigenerational families with five or more affected individuals.

Figure 5

Minimum regions of chromosomal deletions of various tumor types, located within the 6q linkage region. The HLOD-score plot for the 23 families (fig. 3) is reproduced with the scale of the X-axis in physical distances (Mb) instead of cM. Horizontal lines denote regions of minimum chromosomal deletions for various tumor types. The number above each line denotes the reference in which the information about chromosomal deletions was obtained (see list of references below). Some of the studies detected two or more distinct regions of deletion and, thus, the same reference number may appear above more than one horizontal line. The numbers 1–4 on deletion lines represent minimal regions of deletion for breast cancer; 5 and 6, for ovarian cancer; 7, for mesothelioma; 8 and 9, for pancreatic cancer; 10, for SCC of oral cavity; 11, for melanoma; and 12, for Hodgkin lymphoma. Markers are indicated by the symbol “♦” and are placed from left to right: D6S474 (112.92 Mb), D6S1040 (130.97 Mb), D6S1009 (137.28 Mb), C6S1848 (147.95 Mb), D6S2436 (154.70 Mb), D6S1035 (159.94 Mb), D6S1277 (164.21 Mb), and D6S1027 (168.98 Mb). The references for each horizontal line are: (1) Noviello et al. ; (2) Utada et al. ; (3) Zeller et al. ; (4) Cesari et al. ; (5) Hansen et al. ; (6) Cesari et al. ; (7) Jensen et al. ; (8) Abe et al. ; (9) Barghorn et al. ; (10) Tong et al. ; (11) Millikin et al. ; and (12) Re et al. .