Colorectal Cancer Genomic Differences in Patients with African and European Ancestry
Written by Vered Smith, Science Writer
Scientists have published an article in Cancer Discovery, highlighting the difference between the genetics of colorectal cancers of African descended patients (AFR) and European descended patients (EUR).
The scientists sequenced key genes often mutated in colorectal cancer (CRC) in over 39,000 patients and compared how the two groups differed. This has uncovered new knowledge of the molecular mechanisms involved in CRC in AFR, which can be used to improve medical treatment and design new drugs.
In the United States, Black patients have higher rates of colorectal cancer (CRC) than any other ethnic group. Moreover, they have a worse overall mortality rate, and a younger age of onset with more advanced disease. This can partly be explained by factors such as higher obesity rates, less exercise, and less CRC screening. However, these factors alone do not sufficiently explain the differences observed in the clinic. The genetic contribution to these differences is inadequately understood, because there are not many genomic studies of ethnic minority groups.
In this study, the researchers used genomic ancestry markers to categorise patients as descending from African ancestry (AFR) or European ancestry (EUR). They then investigated the genomic differences between AFR and EUR colorectal cancer cases, and determined if genomic ancestry was associated with specific mutations that could explain the different survival rates. They did this by profiling genomic alterations of key CRC genes in the two groups and assessing differences in mutations associated with tumour location and age of onset.
CRC Genomic Differences in AFR and EUR
AFR had significantly more mutations in KRAS than EUR. This is important because KRAS mutations are a predictive biomarker of resistance to anti-EGFR therapies, such as cetuximab and panitumumab. The most common KRAS mutation in both AFR and EUR was G12D, but AFR had more G12D and G13 mutations than EUR. The researchers suggested that it may be beneficial to develop drugs targeting these mutations, and to enroll AFR in clinical trials for specific KRAS inhibitors.
AFR had more frequent mutations in genes coding for proteins in the MAP kinase pathway (ARAF, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, RAF1), and the PI3K pathway (AKT, MTOR, PIK3CA/B, PIK3R1/2, PTEN, TSC1/2). They also had more PIK3CA mutations. However, both AFR and EUR had similar rates of KRASWT/ PIK3CAmut tumours.
AFR had more frequent mutations in the Wnt signalling pathway (APC, CTNNB1, GSK3B, AXIN1, LRP6, as well as FAM123B). They also had co-mutations APCmut/KRASmut and APCmut/KRASmut/TP53mut more frequently. Developing inhibitors that target Wnt pathway protein overexpression might be able to change the tumour microenvironment, and increase CRC susceptibility to immunotherapies.
Additionally, AFR had fewer BRAF mutations. They also had a lower frequency of microsatellite instability high (MSI-H) tumours, so would benefit less from being treated with checkpoint inhibitors.
There were no significant differences in actionable kinase driver alterations between EUR and AFR.
Analysis by Age of Diagnosis
AFR were more likely to be diagnosed with CRC than EUR when younger than 50 years old. AFR with early-onset CRC had more frequent KRAS mutations, whereas EUR with early-onset CRC had more frequent BRAF mutations.
In both groups, TP53 mutations were more common in younger people, but FAM123B mutations were more common in older people. Interestingly, mutations in APC were more common in younger EUR than older EUR, but more common in older AFR than younger AFR. Since tumours with wildtype APC have worse overall survival, this may contribute to the higher death rate in young AFR with CRC.
Lessons for Future Research
This study landscaped the genomic profile of CRC in AFR and provided targetable changes that could affect clinical treatment. It highlighted the need for conducting genomic research on ethnic minorities to identify opportunities to provide personalised medicine that would otherwise be missed. However, the scientists stressed that social determinants of health still account for the premature death of AFR with CRC, and this needs to be incorporated into further genomic research.
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