Malevolent Designer News - How Bowel Cancer Is Designed To Outwit Our Imune System

Example hematoxylin and eosin (H&E) staining for polypoid cancer

Kayhanian, H., Cross, W., van der Horst, S.E.M. et al. (2024)

Bowel cancer turns genetic switches on and off to outwit the immune system | UCL News - UCL – University College London

You're creationism's favourite invisible designer and you want to make people suffer and die from bowel cancer. So, you design a tumour that grows, spreads, and destroys essential tissues and systems. All good so far.

But there is a problem: when you designed humans you gave them an immune system to protect them from the parasites you had designed to make them sick, and this immune system can detect the bowel cancer cells and kill them!

What do you do?

Well, obviously, you design the cancer cells so they outwit the immune system you designed, and since you designed it, you know exactly what its weaknesses and vulnerabilities are.

Easy peesy! You just design the cancer cells so they switch the immune system off!

What can you tell me about the aetiology of bowel cancer in humans? The aetiology of bowel cancer, also known as colorectal cancer, involves a combination of genetic, environmental, and lifestyle factors. Here's a detailed overview:

Genetic Factors

1. Hereditary Syndromes:
   • Familial Adenomatous Polyposis (FAP): Caused by mutations in the APC gene, leading to the development of numerous polyps in the colon and rectum, which can turn into cancer if not managed.
   • Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC): Caused by mutations in mismatch repair (MMR) genes (e.g., MLH1, MSH2), leading to a higher risk of colorectal cancer and other cancers.
2. Family History:
   • Individuals with a first-degree relative with colorectal cancer have a higher risk, suggesting a genetic predisposition even outside of known hereditary syndromes.
3. Genetic Mutations:
   • Sporadic mutations in genes such as KRAS, BRAF, and PIK3CA are common in colorectal cancer.
   • Microsatellite instability (MSI) and chromosomal instability (CIN) play roles in tumorigenesis.

Environmental and Lifestyle Factors

1. Diet:
   • High intake of red and processed meats has been associated with an increased risk.
   • Low fiber intake is also linked to higher incidence rates.
2. Physical Inactivity:
   • Sedentary lifestyle increases the risk, while regular physical activity is protective.
3. Obesity:
   • Increased body weight, particularly abdominal obesity, is a risk factor.
4. Alcohol Consumption:
   • High alcohol intake is associated with an increased risk of colorectal cancer.
5. Smoking:
   • Long-term tobacco use is a known risk factor.

Other Risk Factors

1. Age:
   • The risk increases with age, with most cases diagnosed in individuals over 50.
2. Inflammatory Bowel Disease (IBD):
   • Conditions like Crohn's disease and ulcerative colitis increase the risk of colorectal cancer due to chronic inflammation.
3. Diabetes:
   • Type 2 diabetes is associated with a higher risk of colorectal cancer.
4. Previous Cancer History:
   • Individuals with a history of colorectal cancer or adenomatous polyps are at increased risk for recurrence.

Molecular Pathways

1. Adenoma-Carcinoma Sequence:
   • Most colorectal cancers develop from adenomatous polyps through a series of genetic mutations and epigenetic changes.
2. Serrated Pathway:
   • Involves serrated polyps, which follow a different molecular pathway characterized by mutations in the BRAF gene and widespread DNA methylation (CIMP - CpG island methylator phenotype).
3. Microsatellite Instability (MSI):
   • A hallmark of Lynch syndrome and some sporadic cancers, involving defects in DNA mismatch repair.

Prevention and Early Detection

1. Screening:
   • Regular screening (e.g., colonoscopy, fecal occult blood test) can detect precancerous polyps and early-stage cancer, significantly reducing mortality.
2. Diet and Lifestyle:
   • A diet high in fruits, vegetables, and fiber, along with regular exercise, can reduce the risk.
   • Limiting alcohol consumption and avoiding smoking are also beneficial.

Understanding these factors is crucial for both prevention and early detection strategies, improving patient outcomes and reducing the burden of colorectal cancer.

Or that's what you would have to believe if you were an intelligent [sic] design creationist, because you believe there is only one designer capable of that degree of control over living organisms.

Yes, I know your guru, Michael J Behe tried to give you a work-around for the parasite/cancer problem by inventing the biologically nonsensical, but Bible-literalist consistent, notions of 'devolution' and 'genetic entropy', but anything which benefits the cells, in this case the cancer cells, can't be called 'devolutionary' nor the result of 'genetic entropy' from some initial perfection, because something better can't be less perfect than something worse.

So, what has this intelligent [sic] designer come up with to make its bowel cancer better at killing us in an especially nasty way?

Well, nothing actually, because what the researchers from University College London, UK (UCL) and the University Medical Centre, Utrecht, Holland, who investigated it found was that it had evolved naturally, with no evidence of magic or malevolent intent anywhere in the mindless, unplanned process.

What they found is the subject of an open access paper in Nature Genetics and a press release from UCL:

Bowel cancer turns genetic switches on and off to outwit the immune system

Bowel cancer cells have the ability to regulate their growth using a genetic on-off switch to maximise their chances of survival, a phenomenon that’s been observed for the first time by researchers at UCL and University Medical Center Utrecht.

The number of genetic mutations in a cancer cell was previously thought to be purely down to chance. But a new study, published in Nature Genetics, has provided insights into how cancers navigate an “evolutionary balancing act”.

The researchers found that mutations in DNA repair genes can be repeatedly created and repaired, acting as ‘genetic switches’ that take the brakes off a tumour’s growth or put the brakes back on, depending on what would be most beneficial for the cancer to develop.

Researchers say the findings could potentially be used in personalised cancer medicine to gauge how aggressive an individual’s cancer is so that they can be given the most effective treatment.

Cancer is a genetic disease caused by mutations in our DNA. DNA damage occurs throughout life, both naturally and due to environmental factors. To cope with this, cells have evolved strategies to protect the integrity of the genetic code, but if mutations accumulate in key genes linked to cancer, tumours can develop.

Bowel cancer is the fourth most common cancer in the UK, with around 42,900 cases a year. Though still predominantly a cancer that affects older people, cases among the under 50s have been increasing in recent decades.

Disruption of DNA repair mechanisms is a major cause of increased cancer risk. About 20% of bowel cancers, known as mismatch repair deficient (MMRd) cancers, are caused by mutations in DNA repair genes. But disrupting these repair mechanisms is not entirely beneficial to tumours. Though they do allow tumours to develop, each mutation increases the risk that the body’s immune system will be triggered to attack the tumour.

Cancer cells need to acquire certain mutations to circumvent mechanisms that preserve our genetic code. But if a cancer cell acquires too many mutations, it is more likely to attract the attention of the immune system, because it’s so different from a normal cell. We predicted that understanding how tumours exploit faulty DNA repair to drive tumour growth – whilst simultaneously avoiding immune detection – might help explain why the immune system sometimes fails to control cancer development.

Dr Marnix Jansen, senior author
UCL Cancer Institute
University College London, London, UK

In this study, researchers from UCL analysed whole genome sequences from 217 MMRd bowel cancer samples in the 100,000 Genomes Project database. They looked for links between the total number of mutations and genetic changes in key DNA repair genes.

The team identified a strong correlation between DNA repair mutations in the MSH3 and MSH6 genes, and an overall high volume of mutations.

The theory that these ‘flip-flop’ mutations in DNA repair genes might control cancer mutation rates was then validated in complex cell models, called organoids, grown in the lab from patient tumour samples.

Our study reveals that DNA repair mutations in the MSH3 and MSH6 genes act as a genetic switch that cancers exploit to navigate an evolutionary balancing act. On one hand, these tumours roll the dice by turning off DNA repair to escape the body’s defence mechanisms. While this unrestrained mutation rate kills many cancer cells, it also produces a few ‘winners’ that fuel tumour development.

The really interesting finding from our research is what happens afterwards. It seems the cancer turns the DNA repair switch back on to protect the parts of the genome that they too need to survive and to avoid attracting the attention of the immune system. This is the first time that we’ve seen a mutation that can be created and repaired over and over again, adding it or deleting it from the cancer’s genetic code as required.

Dr Suzanne E. M. van der Horst, co-author
University Medical Center Utrecht, Holland.

The DNA repair mutations in question occur in repetitive stretches of DNA found throughout the human genome, where one individual DNA letter (an A, T, C or G) is repeated many times. Cells often make small copying mistakes in these repetitive stretches during cell division, such as changing eight Cs into seven Cs, which disrupts gene function.

The degree of genetic disarray in a cancer was previously thought to be purely down to chance accumulation of mutations over many years. Our work shows that cancer cells covertly repurpose these repetitive tracts in our DNA as evolutionary switches to fine-tune how rapidly mutations accumulate in tumour cells.

Interestingly, this evolutionary mechanism had previously been found as a key driver of bacterial treatment resistance in patients treated with antibiotics. Like cancer cells, bacteria have evolved genetic switches which increase mutational fuel when rapid evolution is key, for example when confronted with antibiotics. Our work thus further emphasises similarities between evolution of ancient bacteria and human tumour cells, a major area of active cancer research.

Dr Hamzeh Kayhanian, first author
UCL Cancer Institute
University College London, London, UK

The researchers say that this knowledge could potentially be used to gauge the characteristics of a patient’s tumour, which may require more intense treatment if DNA repair has been switched off and there is potential for the tumour to adapt more quickly to evade treatment – particularly to immunotherapies, which are designed to target heavily mutated tumours.

A follow-up study is already underway to find out what happens to these DNA repair switches in patients who receive cancer treatment.

Overall our research shows that mutation rate is adaptable in tumours and facilitates their quest to obtain optimal evolutionary fitness. New drugs might look to disable this switch to drive effective immune recognition and, hopefully, produce better treatment outcomes for affected patients.

Dr Hugo J. G. Snippert, co-senior author
University Medical Center Utrecht, Holland.

This research was funded with grants from Cancer Research UK, the Rosetrees Trust, and Bowel Research UK.

Cancer’s evasion of immune system destruction is a key element of its ability to grow and spread. Understanding exactly how bowel cancers do this is crucial to optimising treatment for patients. Bowel Research UK are delighted that our funding has contributed to producing this exciting new data, and we look forward to seeing how these discoveries could change treatments for future patients.

Georgia Sturt
Research and Grants Manager at Bowel Research UK

Abstract
Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

Main
In human cells, DNA mismatch repair (MMR) is performed by protein complexes consisting of MutL homolog 1 (MLH1) and PMS1 homolog 2 (PMS2), known as MutL_α, and MutS homolog 2 (MSH2) and MutS homolog 6 (MSH6), known as MutS_α¹. Alternatively, MSH2 can pair with MutS homolog 3 (MSH3) in a complex called MutS_β. MutS_α and MutS_β each function as DNA mismatch detection modules with partially overlapping specificities, whereas MutL_α (MLH1/PMS2) executes MMR. Although the mutagenic impact of isolated MSH6 or MSH3 loss is relatively mild, combined MSH6/MSH3 inactivation in model systems drives a robust hypermutator phenotype². Importantly, while MMR had previously been treated as a single linear pathway focused on postreplicative mismatch correction, recent studies indicate that MutSα and MutSβ also participate in the repair of endogenous mutational processes during interphase (for example, due to 5-methylcytosine deamination or oxidative damage) independent of MLH1 (refs. ^3,4,5; Fig. 1a,b). Overall, these studies suggest that MutS cooperates with MutL during canonical postreplicative repair of misincorporated bases, while MutS can liaise with other partners such as MBD4 in the interphase noncanonical repair of endogenous DNA damage.

Fig. 1: Subclonal MSH6^F1088fs and MSH3^K383fs homopolymer frameshift mutations drive increased mutation burden in the MMRd CRC GEL WGS cohort.

a, MS-instable CRC. b, The MMR system safeguards genomic integrity by detecting and repairing replication-associated mismatches (left, blue). Recent studies indicate that MutS also participates in the repair of endogenous mutational damage independent of MLH1 (right, pink). c, Volcano plot showing the relationship between MS frameshifts in individual genes and total mutation burden in multiple linear regression analysis. For each independent variable, the P value of a two-sided t-test is plotted as −log₁₀(P). Two-sided F statistic (accounting for multiple independent variables in the regression model) P = 4.2 × 10⁻⁷. d, Pie charts showing mutation categories for MSH3 (top) and MSH6 (bottom). e, Cases with MSH6^F1088fs and/or MSH3^K383fs homopolymer frameshifts (in red), and cases without such mutations (in blue) ranked by mutation burden (n = 217). Clonal alterations in MMR genes MLH1, PMS2, MSH2 and MSH6, as well as subclonal MSH6^F1088fs and MSH3^K383fs frameshift status, are indicated below. Insets show MSH6^F1088fs and MSH3^K383fs mutation variant allele fraction. Extended Data Fig. 1a–c shows analysis restricted to BRAFV600E tumors. f–h, Number of SNV (f), number of InDel (g) and total mutation burden (h) according to MSH6^F1088fs and MSH3^K383fs mutation status. Median values are represented by horizontal black lines.

Loss of MMR proficiency occurs in about 15% of colorectal cancers (CRCs) resulting in the accumulation of single-nucleotide mismatches and frameshift variants due to short insertion and deletion (InDel) mutations in repetitive homopolymer sequences⁶. In most cases, this is due to sporadic MLH1 hypermethylation. The relentless accumulation of somatic variants renders MMR-deficient (MMRd) tumors immunogenic and provokes extensive immunoediting⁷. While many of the genetic targets associated with immune escape (for example, HLA (human leukocyte antigen) complex and B2M (beta-2 microglobulin) mutations) have been characterized, the evolutionary trajectories MMRd tumors take to navigate their immune selection landscape remain unknown⁸.

Here we visualize the clonal architecture of evolving MMRd tumors to allow joint analysis of individual tumor subclones and the immune microenvironment at clonal resolution. We find that subclonal MMRd lineages harness hypermutable homopolymer sequences in MSH6 and MSH3 to adapt cellular mutation rate and mutation bias to subclonal immune selection. This strategy allows MMRd tumor subclones to engage in an evolutionary arms race with the evolving immune system and efficiently explore immune adaptation solutions while minimizing the deleterious impact of prolonged genomic hypermutation on cellular fitness.

Kayhanian, H., Cross, W., van der Horst, S.E.M. et al.
Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01777-9

Copyright: © 2024 The authors.
Published by Springer Nature. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

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