Gender-associated genomic differences in colorectal cancer: clinical insight from feminization of male cancer cells

Abstract

Gender-related differences in colorectal cancer (CRC) are not fully understood. Recent studies have shown that CRC arising in females are significantly associated with CpG island methylator phenotype (CIMP-high). Using array comparative genomic hybridization, we analyzed a cohort of 116 CRCs (57 males, 59 females) for chromosomal copy number aberrations (CNA) and found that CRC in females had significantly higher numbers of gains involving chromosome arms 1q21.2-q21.3, 4q13.2, 6p21.1 and 16p11.2 and copy number losses of chromosome arm 11q25 compared to males. Interestingly, a subset of male CRCs (46%) exhibited a "feminization" phenomenon in the form of gains of X chromosomes (or an arm of X) and/or losses of the Y chromosome. Feminization of cancer cells was significantly associated with microsatellite-stable CRCs (p-value 0.003) and wild-type BRAF gene status (p-value 0.009). No significant association with other clinicopathological parameters was identified including disease-free survival. In summary, our data show that some CNAs in CRC may be gender specific and that male cancers characterized by feminization may constitute a specific subset of CRCs that warrants further investigation.

Figure 1

aCGH analysis of 116 colorectal cancers showing chromosomal copy number aberrations in male and female patients. Gains are depicted in blue and deletions in red. (A) 1q21.2–q21.3 locus; (B) 4q13.2 locus; (C) 6p21.1 locus; (D) 11q25 locus; (E) aCGH analysis using GISTIC algorithm showing copy number profiles of the autosomes and X-chromosome. The grey bars indicate highly significant aberrations as detected by GISTIC. Asterisks (*) indicate CNAs previously obtained by Significance Testing for Aberrant Copy number (STAC) then confirmed here. Black circles indicate statistically significant CNAs observed in females only, while arrowheads pinpoint CNAs specific to males.

Figure 2

Sex-chromosome copy number aberrations in colorectal cancer cells by aCGH. Gains are depicted in blue and deletions in red. (A) Male cancers show extensive X chromosome gains while female cancers show equivalent frequencies of gains and losses; (B) Male cancers also show Y chromosome losses.

Figure 3

Morphology of a male colorectal cancer with feminization. (A) A hematoxylin and eosin stained histological section showing tumor on the right-hand side and normal colonic mucosa on the left; (B) Fluorescence in-situ hybridization of tumor cells (right-hand side) show multiple red centromeric enumeration probe (CEP) X signals indicating X chromosome gains and absence of green CEP Y signals indicating Y chromosome losses, while both red and green signals are present in non-neoplastic interstitial cells (left-hand side).

Figure 4

Allelotyping. (A) Normal DNA from a male patient showing X and Y peaks of equal height (arrow); (B) Tumor DNA from same patient showing X peak more than twice the height of the Y peak (arrow) indicating X gains.

Figure 5

aCGH analysis of the autosomes and the X-chromosome using GISTIC algorithm limited to: (A) 96 cases of Dukes’ B cancer; (B) 90 cases of MSS cancer; (C) 28 cases with sigmoid colon cancer; (D) 23 cases with rectal cancer; (E) 28 cases with right-sided colon cancer. Gains are depicted in blue and deletions in red. The grey bars indicate highly significant aberrations as detected by GISTIC. Asterisks (*) indicate CNAs previously obtained by STAC then confirmed here. Black circles indicate statistically significant (p < 0.05) CNA specific to females, while arrowheads pinpoint CNA specific to males.