Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
Molecular disparities in colorectal cancer: a study of race and ethnic groups
April 2024—Personalized medicine is revolutionizing cancer therapy, with targeted treatments customized to a person’s cancer-specific mutational profile leading to substantially improved health outcomes. Personalized medicine can also be applied to cancer prevention for high-risk groups based on genetic predisposition or lifestyle factors. However, there is a significant gap in cancer research resulting from a lack of equitable representation of racial and ethnic groups in cancer databases. Most research data are derived from white patients in the United States and Europe, creating racial disparities in understanding cancer development and therapies. The underrepresentation of patients of African, Asian, and Native American descent in observational, translational, and clinical cancer studies is particularly notable. Moreover, patients in these underrepresented groups may experience cancer differently. For example, it is well known that African American (AA) patients (ages 18–50 years) with colorectal cancer have lower five-year survival rates than Hispanics and non-Hispanic white patients in the same age group. The authors conducted a study in which they investigated molecular disparities in colorectal cancer among Alabama AAs, Oklahoma American Indians (AIs), and white people from Alabama and Oklahoma. They hypothesized that differences at the molecular level may contribute to the observed disparities in colorectal cancer incidence and mortality. The study showed that compared with the white patients, the Alabama AAs with colorectal cancer had higher expression of cytokines, genes related to the immune system, and vesicle trafficking. Although higher expression of immune signature genes is associated with immune activation and infiltration, and therefore a better prognosis, higher expression of vesicle trafficking may lead to AA colorectal cancers being able to evade host immunity. Compared with the white patients, the Oklahoma AIs with colorectal cancer had higher expression of PTGS2/COX2 and splicing regulators but lower expression of tumor suppressors and motility suppressors. Interestingly, differences in expression patterns were also seen in the benign colonic tissue of the various ethnic groups. The white patients had higher expression of IL22RA1, for which there is targeted therapy, while the AA colorectal cancer patients had higher expression of CCL4, which is associated with tumor infiltration by pro-tumor macrophages. This finding implies that therapy targeting the IL22RA1 pathway may not be as effective in AAs, and this group may instead benefit from CCL4 inhibitors. Overall, this study emphasized the importance of considering social constructs, dietary habits, geographical location, and cultural practices when analyzing biological patterns in ethnic and racial groups. Molecular disparities identified in this study, pertaining to the roles of COX2, splicing misregulation, and decreased tumor-suppressor activities, may contribute to the differences in the biology of CRCs among Alabama AAs and Oklahoma AIs. The study also has important implications for drug development, raising awareness of the need for race- and ethnicity-optimized therapy and colorectal cancer prevention strategies.
Yamada HY, Xu C, Jones KL, et al. The molecular disparities in colorectal cancers among white Americans, Alabama African Americans, and Oklahoma American Indians. NPJ Precis Oncol. 2023;7(1):79. doi:10.1038/s41698-023-00433-5
Correspondence: Dr. Hiroshi Yamada at yamada@ouhsc.edu
Epigenetic regulation of nuclear genome associated with mitochondrial dysfunction in LHON
Mitochondrial DNA is inherited exclusively from the mother. This unusual pattern of inheritance leads to mutational frequencies varying across geographic locations—a phenomenon known as mtDNA haplogroup. Leber’s hereditary optic neuropathy (LHON) is a mitochondrial genetic condition characterized by mutations in complex I of the electron transport chain, located on mitochondrial DNA (mtDNA). Complex I is a multi-subunit protein complex situated in the inner mitochondrial membrane of human cells, with some protein subunits encoded by mtDNA and others by nuclear DNA. Genetic and epigenetic alterations in any of these genes in mtDNA can result in electron transport impairment and mitochondrial disease. People with LHON typically present with painless dulling or blurring in one or both eyes, which progresses to loss of color perception due to degeneration of the retinal ganglion layer and optic nerve. The three most common point mutations associated with LHON are m.3460G>A (MTND1), m.11778G>A (MTND4), and m.14484T>C (MTND6). These mutations are necessary but not sufficient by themselves to result in disease manifestation, as disease penetrance can vary between families that have the same mutation. A team of researchers in India hypothesized that histone modification (acetylation or methylation, or both) may impact the expression of NDUFS4, another protein in complex I, thereby facilitating the progression of LHON. They examined cell lines with MTND4, the most common mutation in the Indian population, as well as normal cell lines and peripheral blood mononuclear cells (PBMC) from patients suspected or known to have LHON, along with PBMC from healthy people. All affected people were confirmed to have MTND4 through Sanger sequencing. To assess differences in histone modification between patients and the control group, the researchers employed chromatin immunoprecipitation-qRT PCR. This technique uses antibodies against acetylated or methylated forms of key amino acids on histone H3 and histone H4. Immunoprecipitated regions were then amplified using NDUFS4 primers. Significant histone modification enrichment was observed between LHON patients and the control group, consistent with findings in LHON and normal cell lines. Methylation of histone H3 on lysine 4 (H3K4Me3) and lysine 27 (H3K27Me3), as well as acetylation of H3 on lysine 27 (H3K27Ac), were enriched in patients’ PBMC. Similarly, enrichment of H3K27Me3 and H3K27Ac was observed in MTND4 cell lines. The authors’ research suggests that histone modifications, and epigenetic changes more generally, may contribute to the variable penetrance and clinical presentation of inherited diseases such as LHON.
Nair AP, Selvakumar A, Gopalarethinam J, et al. Epigenetic regulation of the nuclear genome associated with mitochondrial dysfunction in Leber’s hereditary optic neuropathy (LHON). Hum Genome Var. 2024;11(6). doi:10.1038/s41439-023-00258-5
Correspondence: Dr. Mohana Devi Subramaniam at geneticmohana@gmail.com