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A mechanistic link between red meat consumption and colorectal cancer (CRC) has been identified in the form of an alkylating mutational signature, according to investigators.
This is the first time a colorectal mutational signature has been associated with a component of diet, which demonstrates the value of large-scale molecular epidemiologic studies and suggests potential for early, precision dietary intervention, reported lead author Carino Gurjao, MSc, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues.
“Red meat consumption has been consistently linked to the incidence of colorectal cancer,” the investigators wrote in Cancer Discovery. “The suggested mechanism is mutagenesis through alkylating damage induced by N-nitroso-compounds (NOCs), which are metabolic products of blood heme iron or meat nitrites/nitrates. Nevertheless, this mutational damage is yet to be observed directly in patients’ tumors.”
To this end, the investigators turned to three long-term, large-scale, prospective cohort studies: the Nurses’ Health Studies I and II, and the Health Professionals Follow-up Study. These databases include nearly 300,000 individuals with follow-up dating back as far as 1976. The investigators identified 900 cases of primary, untreated CRC with adequate tissue for analysis, then, for each case, performed whole exome sequencing on both tumor tissue and normal colorectal tissue.
This revealed an alkylating mutational signature previously undescribed in CRC that was significantly associated with consumption of red meat prior to diagnosis, but not other dietary or lifestyle factors. The signature occurred most frequently in tumors and normal crypts in the distal colon and rectum.
According to the investigators, the presence of the alkylating signature in normal colorectal crypts “suggests that mutational changes due to such damage may start to occur early in the path of colorectal carcinogenesis.”
Further analysis showed that tumors harboring common KRAS and PIK3CA driver mutations had the highest levels of alkylating damage, with higher levels predicting worse survival.
“These results ... further implicate the role of red meat in CRC initiation and progression,” the investigators concluded.
Early findings, important implications
Cosenior author Kana Wu, MD, PhD, principal research scientist in the department of nutrition at Harvard School of Public Health, Boston, noted that these are early findings, although they may pave the way toward new dietary recommendations and methods of food production.
“While more detailed analysis needs to be conducted, and our results need to be confirmed in other studies, this study is a promising first step to better understand the biological mechanisms underlying the role of red and processed meats in colorectal cancers,” Dr. Wu said in an interview. “It is important to gain more insight into the biological mechanisms so we can improve dietary guidelines for cancer prevention and guide food reformulation efforts to lower cancer risk.”
For now, Dr. Wu predicted that standing dietary recommendations will remain unchanged.
“This study will not alter current diet recommendations to limit intake of red and processed meats,” Dr. Wu said, referring to similar recommendations across several organizations, including the American Heart Association, the World Cancer Research Fund/American Institute for Cancer Research, and the American Cancer Society.
“For example,” Dr. Wu said, “the WCRF/AICR recommends limiting consumption of red and processed meat to ‘no more than moderate amounts [12-18 ounces per week] of red meat, such as beef, pork, and lamb, and [to] eat little, if any, processed meat.’”
Possible biomarker?
According to Patricia Thompson-Carino, PhD, deputy director of the Stony Brook (N.Y.) Cancer Center, the study provides convincing evidence linking red meat consumption with development of CRC.
“Higher frequency of the signature in the distal colon is compelling for its consistency with epidemiologic evidence,” Dr. Thompson-Carino said in an interview. “Combined with the observed worse survival in patients harboring the signature and association with oncogenic KRAS and PIK3CA driver mutations, this study significantly elevates the biological plausibility that red meat is a modifiable source of NOC mutagenicity and carcinogenesis in humans.”
The signature could be used as a biomarker to detect exposure to NOCs, and susceptibility to CRC, she added.
Still, Dr. Thompson-Carino suggested that more work is needed to fully elucidate underlying mechanisms of action, which are needed to accurately shape dietary guidance.
“Key to advancing red meat dietary recommendations will be understanding the relationships between the new mutation signature and the NOCs derived from red meat and their source, whether endogenous [for example, intestinal N-nitrosation] or exogenous [for example, chemical preservation or charring],” she said. The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (coadministered by the American Association for Cancer Research), the Project P Fund, and others. The investigators, Dr. Wu, and Dr. Thompson-Carino reported no conflicts of interest related to this study.
A mechanistic link between red meat consumption and colorectal cancer (CRC) has been identified in the form of an alkylating mutational signature, according to investigators.
This is the first time a colorectal mutational signature has been associated with a component of diet, which demonstrates the value of large-scale molecular epidemiologic studies and suggests potential for early, precision dietary intervention, reported lead author Carino Gurjao, MSc, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues.
“Red meat consumption has been consistently linked to the incidence of colorectal cancer,” the investigators wrote in Cancer Discovery. “The suggested mechanism is mutagenesis through alkylating damage induced by N-nitroso-compounds (NOCs), which are metabolic products of blood heme iron or meat nitrites/nitrates. Nevertheless, this mutational damage is yet to be observed directly in patients’ tumors.”
To this end, the investigators turned to three long-term, large-scale, prospective cohort studies: the Nurses’ Health Studies I and II, and the Health Professionals Follow-up Study. These databases include nearly 300,000 individuals with follow-up dating back as far as 1976. The investigators identified 900 cases of primary, untreated CRC with adequate tissue for analysis, then, for each case, performed whole exome sequencing on both tumor tissue and normal colorectal tissue.
This revealed an alkylating mutational signature previously undescribed in CRC that was significantly associated with consumption of red meat prior to diagnosis, but not other dietary or lifestyle factors. The signature occurred most frequently in tumors and normal crypts in the distal colon and rectum.
According to the investigators, the presence of the alkylating signature in normal colorectal crypts “suggests that mutational changes due to such damage may start to occur early in the path of colorectal carcinogenesis.”
Further analysis showed that tumors harboring common KRAS and PIK3CA driver mutations had the highest levels of alkylating damage, with higher levels predicting worse survival.
“These results ... further implicate the role of red meat in CRC initiation and progression,” the investigators concluded.
Early findings, important implications
Cosenior author Kana Wu, MD, PhD, principal research scientist in the department of nutrition at Harvard School of Public Health, Boston, noted that these are early findings, although they may pave the way toward new dietary recommendations and methods of food production.
“While more detailed analysis needs to be conducted, and our results need to be confirmed in other studies, this study is a promising first step to better understand the biological mechanisms underlying the role of red and processed meats in colorectal cancers,” Dr. Wu said in an interview. “It is important to gain more insight into the biological mechanisms so we can improve dietary guidelines for cancer prevention and guide food reformulation efforts to lower cancer risk.”
For now, Dr. Wu predicted that standing dietary recommendations will remain unchanged.
“This study will not alter current diet recommendations to limit intake of red and processed meats,” Dr. Wu said, referring to similar recommendations across several organizations, including the American Heart Association, the World Cancer Research Fund/American Institute for Cancer Research, and the American Cancer Society.
“For example,” Dr. Wu said, “the WCRF/AICR recommends limiting consumption of red and processed meat to ‘no more than moderate amounts [12-18 ounces per week] of red meat, such as beef, pork, and lamb, and [to] eat little, if any, processed meat.’”
Possible biomarker?
According to Patricia Thompson-Carino, PhD, deputy director of the Stony Brook (N.Y.) Cancer Center, the study provides convincing evidence linking red meat consumption with development of CRC.
“Higher frequency of the signature in the distal colon is compelling for its consistency with epidemiologic evidence,” Dr. Thompson-Carino said in an interview. “Combined with the observed worse survival in patients harboring the signature and association with oncogenic KRAS and PIK3CA driver mutations, this study significantly elevates the biological plausibility that red meat is a modifiable source of NOC mutagenicity and carcinogenesis in humans.”
The signature could be used as a biomarker to detect exposure to NOCs, and susceptibility to CRC, she added.
Still, Dr. Thompson-Carino suggested that more work is needed to fully elucidate underlying mechanisms of action, which are needed to accurately shape dietary guidance.
“Key to advancing red meat dietary recommendations will be understanding the relationships between the new mutation signature and the NOCs derived from red meat and their source, whether endogenous [for example, intestinal N-nitrosation] or exogenous [for example, chemical preservation or charring],” she said. The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (coadministered by the American Association for Cancer Research), the Project P Fund, and others. The investigators, Dr. Wu, and Dr. Thompson-Carino reported no conflicts of interest related to this study.
A mechanistic link between red meat consumption and colorectal cancer (CRC) has been identified in the form of an alkylating mutational signature, according to investigators.
This is the first time a colorectal mutational signature has been associated with a component of diet, which demonstrates the value of large-scale molecular epidemiologic studies and suggests potential for early, precision dietary intervention, reported lead author Carino Gurjao, MSc, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues.
“Red meat consumption has been consistently linked to the incidence of colorectal cancer,” the investigators wrote in Cancer Discovery. “The suggested mechanism is mutagenesis through alkylating damage induced by N-nitroso-compounds (NOCs), which are metabolic products of blood heme iron or meat nitrites/nitrates. Nevertheless, this mutational damage is yet to be observed directly in patients’ tumors.”
To this end, the investigators turned to three long-term, large-scale, prospective cohort studies: the Nurses’ Health Studies I and II, and the Health Professionals Follow-up Study. These databases include nearly 300,000 individuals with follow-up dating back as far as 1976. The investigators identified 900 cases of primary, untreated CRC with adequate tissue for analysis, then, for each case, performed whole exome sequencing on both tumor tissue and normal colorectal tissue.
This revealed an alkylating mutational signature previously undescribed in CRC that was significantly associated with consumption of red meat prior to diagnosis, but not other dietary or lifestyle factors. The signature occurred most frequently in tumors and normal crypts in the distal colon and rectum.
According to the investigators, the presence of the alkylating signature in normal colorectal crypts “suggests that mutational changes due to such damage may start to occur early in the path of colorectal carcinogenesis.”
Further analysis showed that tumors harboring common KRAS and PIK3CA driver mutations had the highest levels of alkylating damage, with higher levels predicting worse survival.
“These results ... further implicate the role of red meat in CRC initiation and progression,” the investigators concluded.
Early findings, important implications
Cosenior author Kana Wu, MD, PhD, principal research scientist in the department of nutrition at Harvard School of Public Health, Boston, noted that these are early findings, although they may pave the way toward new dietary recommendations and methods of food production.
“While more detailed analysis needs to be conducted, and our results need to be confirmed in other studies, this study is a promising first step to better understand the biological mechanisms underlying the role of red and processed meats in colorectal cancers,” Dr. Wu said in an interview. “It is important to gain more insight into the biological mechanisms so we can improve dietary guidelines for cancer prevention and guide food reformulation efforts to lower cancer risk.”
For now, Dr. Wu predicted that standing dietary recommendations will remain unchanged.
“This study will not alter current diet recommendations to limit intake of red and processed meats,” Dr. Wu said, referring to similar recommendations across several organizations, including the American Heart Association, the World Cancer Research Fund/American Institute for Cancer Research, and the American Cancer Society.
“For example,” Dr. Wu said, “the WCRF/AICR recommends limiting consumption of red and processed meat to ‘no more than moderate amounts [12-18 ounces per week] of red meat, such as beef, pork, and lamb, and [to] eat little, if any, processed meat.’”
Possible biomarker?
According to Patricia Thompson-Carino, PhD, deputy director of the Stony Brook (N.Y.) Cancer Center, the study provides convincing evidence linking red meat consumption with development of CRC.
“Higher frequency of the signature in the distal colon is compelling for its consistency with epidemiologic evidence,” Dr. Thompson-Carino said in an interview. “Combined with the observed worse survival in patients harboring the signature and association with oncogenic KRAS and PIK3CA driver mutations, this study significantly elevates the biological plausibility that red meat is a modifiable source of NOC mutagenicity and carcinogenesis in humans.”
The signature could be used as a biomarker to detect exposure to NOCs, and susceptibility to CRC, she added.
Still, Dr. Thompson-Carino suggested that more work is needed to fully elucidate underlying mechanisms of action, which are needed to accurately shape dietary guidance.
“Key to advancing red meat dietary recommendations will be understanding the relationships between the new mutation signature and the NOCs derived from red meat and their source, whether endogenous [for example, intestinal N-nitrosation] or exogenous [for example, chemical preservation or charring],” she said. The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (coadministered by the American Association for Cancer Research), the Project P Fund, and others. The investigators, Dr. Wu, and Dr. Thompson-Carino reported no conflicts of interest related to this study.
FROM CANCER DISCOVERY