Cross-Cancer Analysis Reveals Novel Pleiotropic Associations—Letter
Authors: Lei Quan, Alan Hutson, Peter Demant
Journal: Cancer Research (2017)

Meta-analysis of genome-wide association (GWA) studies of cancer susceptibility by Fehringer and colleagues (1) revealed four susceptibility loci with cross-cancer effects: 1q22 (lung and breast cancer), 2q33.1 (breast and prostate cancer), 9p21.3 (lung and breast cancer), and 13q13.1 (breast, lung, and ovarian cancer). Such pleiotropic loci may reveal important carcinogenic pathways common to different tumors, but their frequency in humans has yet to be established (1).Unexpectedly, we found previously that cross-cancer susceptibility for colon and lung is very frequent in mice (2). We mapped in completely separate studies susceptibility to lung cancer (Sluc) genes and susceptibility to colon cancer (Scc) genes (3), using for each cancer type a different carcinogen, different cancer induction schedule, and different mouse strains (2, 3). Surprisingly, we found that 12 of 12 Scc loci mapped close to a Sluc locus. Moreover, 5 of 7 rat colon cancer susceptibility loci and 9 of 11 human colon cancer susceptibility loci (published before 2009) mapped close to a Sluc locus (2).The publication of Fehringer and colleagues (1) led us to reinvestigate the association of lung and colon cancer susceptibility loci by including all detected mouse lung cancer loci (3, 4) and 31 previously unanalyzed human colon cancer susceptibility loci listed in the most recent NCI GWA database (5). For 24 of these 31 human colon cancer loci, their mouse orthologous sites were previously screened for lung cancer susceptibility (4). Twenty-three of them mapped to a human region orthologous to a mouse region carrying a lung cancer locus. We defined operationally 27 colon–lung cancer susceptibility gene clusters where mouse lung and mouse, rat, and/or human colon cancer susceptibility gene were mapped within 10 cM (centiMorgan; Table 1). This formal definition of a cluster allowed us to provide an unbiased overall description of the genetic regions that affect both cancers rather than presenting only the tightest examples, which nevertheless were most frequent. The average length of a cluster was 5.4 ± 4.4 cM, median 3.0 cM. Nine of 27 clusters were ≤2.0 cM long, which is similar or shorter than the MHC; 14 of 27 (52%) were ≤3.0 cM long. Several clusters contained one gene at a larger distance from the remainder of genes in the cluster, which were mutually very tightly linked in a much shorter subcluster. Including these subclusters, we detected 16 groups ≤2.0 cM long containing both lung and colon cancer susceptibility genes. Some clusters may actually indicate a single pleiotropic gene, others may be complexes of linked evolutionally or functionally related genes possibly affecting also other cancers, and still others may be accidental linkages without biological significance. However, the bulk of the data suggest that a very significant number of lung and colon cancer susceptibility loci are identical or related, possibly because the mammalian respiratory system develops from an embryonic pharyngeal branch.Although analyses of Fehringer and colleagues did not detect any colocalizations with colon cancer susceptibility, several suggestive loci affecting more than one cancer that they reported (1) do fall into the lung–colon clusters: 1p36.33 cluster 7, 10q26.13 cluster 11, and 10q26.12 cluster 27. Moreover, the mouse orthologs for the human loci 1q22 and 13q13.1 are on mouse chromosomes 3 and 5, respectively; these chromosomes were not polymorphic in the strains we used, so mouse colon cancer loci in the corresponding positions cannot be excluded. The lung cancer susceptibility loci reported in ref. 1 do not colocalize with known mouse Sluc or colon cancer loci, but four lung cancer loci listed in ref. 5 do: 10q26.13 (Cluster 7, Sluc19, Scc2), 10q25.2 (Cluster 27, Sluc35, human colon 10q25.2 and 10q26.12), 7p15.3 (Cluster 19, Sluc12, rat colon rCcr5), and 15q15 (Cluster 4, Sluc31, Scc1, human colon 15q13.3). It has to be established to what extent susceptibility genes for other cancers map frequently to the colon–lung clusters, whether cross-cancer susceptibility can exhibit clusters affecting other cancers than the mouse lung–colon cancer, and whether there may be function-related overlaps between such groups. Analysis of susceptibility genes with and without cross-cancer specificity may reveal important differences in their functions.Although cross-cancer susceptibility genes may be frequent in humans, their complete detection may exceed the statistical power of the current GWA studies (1). Focusing the search for human cross-cancer genetic elements to the human orthologs of the mouse genomic cross-cancer regions could reduce the burden of multiple testing and facilitate detection of novel human multifunctional cancer susceptibility loci and identification of possible genetic elements with pleiotropic function. New techniques of genome manipulation in animals may help to achieve molecular resolution and elucidation of the functional effects of these cross-cancer susceptibility loci by altering the different polymorphic residues that are likely contained in each locus. Such analysis would be particularly interesting in elucidating the nature of polymorphisms in the regions of cross-cancer colocalization that are conserved across three distant genera (human, rat, and mouse).See the Response, p. 6045No potential conflicts of interest were disclosed.This work was supported by the NCI grant 1R01 CA115158, and by an institutional grant from the Roswell Park Cancer Institute (to P. Demant), by NCI grant P30CA016056 to the Roswell Park Cancer Institute supporting the use of its Biostatistics and Genomic Shared Resources, and by the grant 16JCYBJC42900 from the Natural Science Foundation of Tianjin City and Tianjin Thousand Young Talents Plan (to L. Quan).