Biomarkers Tied to Colorectal Cancer in Smokers

SAN FRANCISCO — Older women who smoke have an elevated risk of colorectal cancer, but they have a particularly high risk of cancers containing certain molecular features, a large prospective study has found.

Former and current smokers were much more likely than never smokers to develop colorectal cancers associated with a CpG island methylator phenotype and/or a BRAF mutation in the analysis of data and tissue samples from 37,399 women enrolled in the Iowa Women's Health Study.

“Existing observational data support a positive association between cigarette smoking and incident colorectal cancer,” lead author Dr. David Limsui said at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. “However, the molecular mechanisms underlying cigarette smoking-induced colorectal carcinogenesis remain incompletely defined.”

Studies have implicated hypermethylation of CpG islands, genome regions rich in CpG dinucleotides, noted Dr. Limsui, of the Mayo Clinic in Rochester, Minn. Patients having widespread methylation in these regions are said to have a CpG island methylator phenotype (CIMP). This phenotype has been associated with mutation of BRAF, a gene involved in cell signaling and cell growth.

Dr. Limsui and his coinvestigators analyzed data and tissue samples from women who were aged 55–69 years at baseline, had never had cancer, and reported their smoking status; 4% of the women developed colorectal cancer during a follow-up of 18 years.

Never smokers contributed 68% of 603,671 person-years of follow-up, former smokers contributed 19%, and current smokers contributed 13%.

The investigator assessed formalin-fixed, paraffin-embedded tumor specimens, available for 555 women with cancer, for CIMP status and the presence of BRAF mutation.

In a multivariate analysis among the entire cohort adjusted for potential confounders (age, body mass index, waist-to-hip ratio, physical activity, alcohol consumption, hormone replacement therapy use, and dietary factors), former and current smokers had 1.15 and 1.25 times the risk of any colorectal cancer, compared with never smokers.

The findings were similar when cumulative smoking was considered. Specifically, relative to their never-smoking peers, women having 1–19, 20–39, and 40 or more pack-years of exposure had 1.13, 1.11, and 1.38 times the risk, respectively, of any colorectal cancer.

The risk of CIMP-negative cancer did not vary by smoking status or exposure, but the risk of CIMP-positive cancer did. Compared with never smokers, former and current smokers had 1.21 and 1.85 times the risk of CIMP-positive cancer, respectively—increases that were more striking than those for colorectal cancer generally, Dr. Limsui commented.

The risk for CIMP-positive cancer among women with 1–19, 20–39, and 40 or more pack-years of smoking exposure was 1.32, 1.24, and 1.79, respectively, compared with never smokers.

Similarly, the risk of cancer without BRAF mutation did not vary by smoking status or exposure, but the risk of BRAF-mutated cancer did, he said. Compared with never smokers, former and current smokers had relative risk of 1.36 and 1.89—values again higher than those for colorectal cancer generally.

The relative risk for BRAF-mutated cancer among women with 1–19, 20–39, and 40 or more pack-years of smoking exposure was 1.58, 1.24, and 1.90, compared with never smokers.

Dr. Limsui reported that he had no conflicts of interest in association with the study.

SAN FRANCISCO — Older women who smoke have an elevated risk of colorectal cancer, but they have a particularly high risk of cancers containing certain molecular features, a large prospective study has found.

Former and current smokers were much more likely than never smokers to develop colorectal cancers associated with a CpG island methylator phenotype and/or a BRAF mutation in the analysis of data and tissue samples from 37,399 women enrolled in the Iowa Women's Health Study.

“Existing observational data support a positive association between cigarette smoking and incident colorectal cancer,” lead author Dr. David Limsui said at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. “However, the molecular mechanisms underlying cigarette smoking-induced colorectal carcinogenesis remain incompletely defined.”

Studies have implicated hypermethylation of CpG islands, genome regions rich in CpG dinucleotides, noted Dr. Limsui, of the Mayo Clinic in Rochester, Minn. Patients having widespread methylation in these regions are said to have a CpG island methylator phenotype (CIMP). This phenotype has been associated with mutation of BRAF, a gene involved in cell signaling and cell growth.

Dr. Limsui and his coinvestigators analyzed data and tissue samples from women who were aged 55–69 years at baseline, had never had cancer, and reported their smoking status; 4% of the women developed colorectal cancer during a follow-up of 18 years.

Never smokers contributed 68% of 603,671 person-years of follow-up, former smokers contributed 19%, and current smokers contributed 13%.

The investigator assessed formalin-fixed, paraffin-embedded tumor specimens, available for 555 women with cancer, for CIMP status and the presence of BRAF mutation.

In a multivariate analysis among the entire cohort adjusted for potential confounders (age, body mass index, waist-to-hip ratio, physical activity, alcohol consumption, hormone replacement therapy use, and dietary factors), former and current smokers had 1.15 and 1.25 times the risk of any colorectal cancer, compared with never smokers.

The findings were similar when cumulative smoking was considered. Specifically, relative to their never-smoking peers, women having 1–19, 20–39, and 40 or more pack-years of exposure had 1.13, 1.11, and 1.38 times the risk, respectively, of any colorectal cancer.

The risk of CIMP-negative cancer did not vary by smoking status or exposure, but the risk of CIMP-positive cancer did. Compared with never smokers, former and current smokers had 1.21 and 1.85 times the risk of CIMP-positive cancer, respectively—increases that were more striking than those for colorectal cancer generally, Dr. Limsui commented.

The risk for CIMP-positive cancer among women with 1–19, 20–39, and 40 or more pack-years of smoking exposure was 1.32, 1.24, and 1.79, respectively, compared with never smokers.

Similarly, the risk of cancer without BRAF mutation did not vary by smoking status or exposure, but the risk of BRAF-mutated cancer did, he said. Compared with never smokers, former and current smokers had relative risk of 1.36 and 1.89—values again higher than those for colorectal cancer generally.

The relative risk for BRAF-mutated cancer among women with 1–19, 20–39, and 40 or more pack-years of smoking exposure was 1.58, 1.24, and 1.90, compared with never smokers.

Dr. Limsui reported that he had no conflicts of interest in association with the study.

SAN FRANCISCO — Older women who smoke have an elevated risk of colorectal cancer, but they have a particularly high risk of cancers containing certain molecular features, a large prospective study has found.

Former and current smokers were much more likely than never smokers to develop colorectal cancers associated with a CpG island methylator phenotype and/or a BRAF mutation in the analysis of data and tissue samples from 37,399 women enrolled in the Iowa Women's Health Study.

“Existing observational data support a positive association between cigarette smoking and incident colorectal cancer,” lead author Dr. David Limsui said at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. “However, the molecular mechanisms underlying cigarette smoking-induced colorectal carcinogenesis remain incompletely defined.”

Studies have implicated hypermethylation of CpG islands, genome regions rich in CpG dinucleotides, noted Dr. Limsui, of the Mayo Clinic in Rochester, Minn. Patients having widespread methylation in these regions are said to have a CpG island methylator phenotype (CIMP). This phenotype has been associated with mutation of BRAF, a gene involved in cell signaling and cell growth.

Dr. Limsui and his coinvestigators analyzed data and tissue samples from women who were aged 55–69 years at baseline, had never had cancer, and reported their smoking status; 4% of the women developed colorectal cancer during a follow-up of 18 years.

Never smokers contributed 68% of 603,671 person-years of follow-up, former smokers contributed 19%, and current smokers contributed 13%.

The investigator assessed formalin-fixed, paraffin-embedded tumor specimens, available for 555 women with cancer, for CIMP status and the presence of BRAF mutation.

In a multivariate analysis among the entire cohort adjusted for potential confounders (age, body mass index, waist-to-hip ratio, physical activity, alcohol consumption, hormone replacement therapy use, and dietary factors), former and current smokers had 1.15 and 1.25 times the risk of any colorectal cancer, compared with never smokers.

The findings were similar when cumulative smoking was considered. Specifically, relative to their never-smoking peers, women having 1–19, 20–39, and 40 or more pack-years of exposure had 1.13, 1.11, and 1.38 times the risk, respectively, of any colorectal cancer.

The risk of CIMP-negative cancer did not vary by smoking status or exposure, but the risk of CIMP-positive cancer did. Compared with never smokers, former and current smokers had 1.21 and 1.85 times the risk of CIMP-positive cancer, respectively—increases that were more striking than those for colorectal cancer generally, Dr. Limsui commented.

The risk for CIMP-positive cancer among women with 1–19, 20–39, and 40 or more pack-years of smoking exposure was 1.32, 1.24, and 1.79, respectively, compared with never smokers.

Similarly, the risk of cancer without BRAF mutation did not vary by smoking status or exposure, but the risk of BRAF-mutated cancer did, he said. Compared with never smokers, former and current smokers had relative risk of 1.36 and 1.89—values again higher than those for colorectal cancer generally.

The relative risk for BRAF-mutated cancer among women with 1–19, 20–39, and 40 or more pack-years of smoking exposure was 1.58, 1.24, and 1.90, compared with never smokers.

Dr. Limsui reported that he had no conflicts of interest in association with the study.