The Cancer Resolution?

Fungal infections are clearly associated with cancer. There's some research into its possible carcinogenic role in at least some cancers. There's a strong consensus that certain viruses can, but usually don't, cause cancer. Personally, it seems like a perfectly reasonable hypothesis that fungal infections can play an interactive causal role in driving some cancers.  In general, the consensus is you typically need at least two breakdowns of the numerous mechanisms that regulate the cell cycle and cell death for cancer to occur.

I'm a PhD student in the cancer space, focusing on epigenetics and cancer. Basically, this is the field where we try to explain both normal cellular diversity (where DNA mutations are definitely not the cause except in very specialized contexts like V(D)J recombination) and cancers apparently not driven by somatic mutations in protein-coding genes.

Mutations not in protein-coding genes are not necessarily inert. RNA can be biologically active. Noncoding DNA serves as docking sites for proteins, which can then go on to affect transcription of genes into mRNA. The proteome can also be affected by alternative splicing of mRNA. Non-coding mutations can potentially affect any of these processes and thereby affect the RNA and protein landscape within a cell.

In 2024, our ability to detect mutations varies widely across the genome, due both to the way we obtain sequencing data in the first place and the way we attempt to make sense of it. NGS sequencing involves breaking the genome into short fragments and reading around 150 base pairs on either end of the fragments, then trying to map it back to a reference genome. Mapping quality will suffer or completely degrade both if the patient has substantial genetic difference from the reference genome or in regions that are highly repetitive within the genome, such as centromeres. When I work with genetic data, there are regions spanning multiple megabasis that are completely blank, and a large percentage of our reads have to be thrown out because we can't unambiguously map them to a particular location on the genome. This will be partially overcome in the future as we start to use more long-read sequencing, but this technology is still in its early stages and I'm not sure it will completely replace NGS for the foreseeable future.

In the epigenetics space, we focus on several aspects of cell biochemistry apart from DNA mutations. The classic example is DNA methylation, which is a methyl group (basically a carbon atom) present on about 60% of cytosines (C) that are immediately followed by guanine (G). The CpG dinucleotide is heavily underrepresented relative to what you'd expect by chance, and its heavily clustered in gene promoters. Methylated CpG islands in promoters are associated with "off genes". The methylation mark is preserved across mitosis. It's thought to be a key mechanism by which cell differentiation is controlled. We also study things like chromatin accessibility (whether DNA is tightly packaged up and relatively inaccessible to protein interactions or loose and open) and chromatin conformation (the 3D structure of DNA, which can control things like subregion localization into a particular biochemical gradient or adjacency of protein-docking DNA regions to gene promoters).

These epigenetic alterations are also thought to be potentially oncogenic. Epigenetic alterations could potentially occur entirely due to random events localized to the cell in which the alterations occur, or could be influenced by intercellular signaling, physical forces, or, yes, infection. If fungal infections control cells like puppets and somehow cause cancer, my guess is that it would be through some sort of epigenetic mechanism (I don't know if there are any known fungi that can transmit their DNA to human cells).

Epigenetics research is mainstream, but the technology and data analysis is comparatively immature. One of the reasons it's not more common is that it's much harder to gather data on and interpret than it is to study DNA mutations. Most of our epigenetics methods involve sequencing DNA that has undergone some extra-fancy processing of one kind or another, so it's bound to be strictly more expensive and difficult to execute than plain ol' DNA sequencing alone. Compounding this, the epigenetic effects we're interested in are typically different from cell to cell, meaning that not only do you have these extra-challenging assays, you also need to aim for single-cell resolution, which is also either extremely expensive (like $30/cell, isolating individual nuclei using a cell sorter and running reactions on each individually, leading to assays that can cost millions of dollars to produce) or difficult (like using a hyperactive transposase to insert DNA barcodes into intact nuclei that give a cell-specific label the genetic fragments originating from each cell, bringing assay costs down to a mere $50,000-$100,000 driven mainly by DNA sequencing rather than cell processing costs). This data is then very sparse (because there's a finite amount of genetic information in each cell), very large, and very difficult to interpret. We also have extremely limited technologies to cause specific epigenetic changes, whereas we have a wide variety of tools for precisely editing DNA.

For potentially oncogenic infections, fungal or otherwise, you'd want to show things like:

• We can give organisms cancer by transferring the pathogen to them
• We can slow or prevent cancer by suppressing the putatively oncogenic pathogen.
• The pathogen is found in cancer biosamples at an elevated rate
• There are differences between the cancer-associated pathogens and non-cancer-associated pathogens, or cellular changes that make them more susceptible to oncogenesis through their interactions with the pathogen

All of this seems like a perfectly respectable research project, just difficult. I can't imagine anybody I work with having a problem with it. Where they probably would have a problem would be if the argument was that "fungal infections are the sole cause of cancer, and DNA mutations or epigenetic alterations are completely irrelevant to oncogenesis."

There's an angle I've neglected in this post until now, which is the perspective from evolutionary theory. it's more common to refer to this in explaining how cancer evolves within an individual. But it's also relevant to consider how it bears on the Peto paradox. Loosely, species tend to evolve such that causes of reproductive unfitness (including death) tend to balance out in terms of when they occur in the life cycle. Imagine a species under evolutionary pressure to grow larger, perhaps because it will allow it to escape predation or access a new food source. If the larger number of cells put it at increased risk of cancer, then at some point there would be an equilibrium where the benefit of increased size was cancelled by the cost of increased oncogenesis risk. This also increases adaptive pressure to stabilize new oncopreventative mechanisms in the population that weren't present before. This may facilitate additional growth to a new equilibrium.

This helps explain why cancer isn't associated with larger size: adaptive pressure to develop new oncopreventative mechanisms increases in proportion to the risk to reproductive fitness posed by cancer.

My first significant thought (which came up a bit in the AIs' output) is that it would seem that, if fungi cause cancer, then the fungi would at least sometimes be transmitted from one person to another, and if you weren't aware of the fungi, then this would look like cancer being transmitted from one to the other.  Yet I think this has basically never been observed.^[1]

One could try supposing that each fungus is only rarely able to infect people—only the few individuals that are unusually vulnerable to it.  But, well.  I imagine that would generally include anyone whose immune system is crippled.  Surely there have been enough cases of people with cancer next to old, immunocompromised people in a hospital, with sufficient mistakes in hygiene that the one would have infected the other.  Maybe there are additional requirements for an individual to be infected (the fungus has a favorite temperature? Acidity? Salt level?)... but even taking that into account, I think there should have been enough cases that we would have noticed.  (If the chance of an individual being infectable by a given fungus is so low that we never see transmission, then how is it that, er, 1/6th of all deaths are caused by cancer?  There would have to be zillions of different fungi, each of which is able to infect only a tiny number of people... which surely would have led to natural selection for much better infectivity by now?)

Incidentally, I think it is known that there are some viruses (like HPV) that cause (or greatly heighten the risk of) cancer.  It's plausible that fungi play a significantly larger role of this type than people realize.  But for it to be the primary cause seems implausible.

The strongest evidence is that they found cancers that seem to have no mutations.

This seems worth digging into.

1. ^{^}

   There are a few cases of cancers where it's known that the actual cancer cells themselves go from organism to organism: https://en.wikipedia.org/wiki/Clonally_transmissible_cancer 

If you're willing to take my rude and unfiltered response (and not complain about it) here it is:

Otherwise (written in about half an hour):

1. Fungal infections would lead to the vast majority of cancers being in skin, gut, lung i.e. exposed tissue. These are relatively common, but this does not explain the high prevalence of breast and prostate cancers. It also doesn't explain why different cancers have such different prognoses, etc.
2. Why do different cancer subtypes change in prevalence over the course of a person's life if they're tied to infection?
   https://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/age#heading-One
3. Around half of cancers have a mutation in p53, which is involved in preserving the genome. Elephants have multiple copies of p53 and very rarely get cancer. People with de novo mutations in p53 get loads of cancer. The random spread of DNA damage is downstream of the DNA damage causing cancer: once p53 is deactivated (or the genome is otherwise unguarded) mutations can accumulate all over the genome, drowning out the causal ones.
   https://en.wikipedia.org/wiki/P53
4. If it was infection-based, then you'd expect immunocompromised patients to get more of the common types of cancer. Instead they get super weird exotic cancers not found in people with normal immune systems.
   https://www.hopkinsmedicine.org/health/conditions-and-diseases/hiv-and-aids/aidsrelated-malignancies
5. Chemotherapy, does work? I don't know what to say on this one, chemotherapy works, are all the RCTs which show it works supposed to be fake? Do I need to cite them:
   https://pubmed.ncbi.nlm.nih.gov/30629708/
   https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00285-4/fulltext
   https://www.redjournal.org/article/S0360-3016(07)00996-0/fulltext
   I feel like a post which uncritically repeats someone's recommendation to not take chemotherapy has the potential to harm readers. You should at least add an epistemic status warning readers they might become stupider reading this.
6. Antifungals are relatively easy to get ahold of. Why hasn't this man managed to run a single successful trial? Moreover, cryptococcal meningitis is a fungal diseas which is fatal if untreated and, from the CDC:
   Each year, an estimated 152,000 cases of cryptococcal meningitis occur among people living with HIV worldwide. Among those cases, an estimated 112,000 deaths occur, the majority of which occur in sub-Saharan Africa.
   Which implies 40,000 people are successfully treated with strong antifungals every single year. These are HIV patients, who are more likely to get cancer and under this theory would be more likely than anyone else to have fungal-induced cancer. How come nobody has pointed out the miraculous curing of hundreds or thousands of patients by now?
7. Scientific consensus is an extremely powerful tool.
   https://slatestarcodex.com/2017/04/17/learning-to-love-scientific-consensus/

I think the fungal theory is basically completely wrong. Perhaps some obscure couple of percent of cancers are caused by fungi. I cannot disprove this, though I think it's very unlikely.

Very interesting. Thank you for sharing this theory.

I had two thoughts. The first is: "Doesn't radiation cause cancer? Isn't this effect well established with evidence?". Because if radiation does cause cancer then that is strong evidence that the DNA theory is true of at least some cancers. (Because radiation cannot spread a fungus).

My second thought (which I agree is in some tension with the radiation one), is that, even if I subscribe to a DNA theory of cancer, I don't have to imagine that every tumour has a mutation (relative to the rest of the organism), or that tumour cells are unable to produce healthy embryos without a cancer. To use a software analogy, lets imagine we have a piece of software with a bug. We have all played a computer game where things are basically fine but there is that one time you ended up halfway inside a wall because of some collision error thing. You never worked out quite what did it that time, but the game was usually fine.

When a piece of software shows that collision bug, we don't need to assume that a cosmic ray has flipped a bit in the software. We can check that the code is the same before and after we saw the collision error. This doesn't mean we are going to see collision errors every single time we play that computer game, it just means that the game has a bug that can appear in some limited situations. Similarly, I can imagine that many organisms contain "bugs" in their DNA (the DNA they were born with, undamaged) and that some of these bugs only express themselves rarely, when specific circumstances arise, and sometimes the result of the "glitch" is cancer. In this model the tumours are not mutated. This model is consistent with the idea that radiation and so on can make cancer more likely, as flipping a bunch of bits in a piece of software is much more likely to introduce more bugs than to reduce the number. But it also seems consistent with some tumours being genetically identical to the rest of the organism. The main prediction of this sort of model would be a strong inherited tendency for certain cancers, especially for identical twins.

As a final thought. If the fungus theory is correct, it doesn't seem like it would be impossibly hard for someone to find some of the fungus cells in mouse A. Look at them under a microscope, "Yes, fungus all right." and then use them to give cancer to a bunch of other mice. So the fungus theory (unlike my speculations above) has the great advantage of seeming to be very testable.

I want to take a look at the epistemics of this post, or rather, whether this post should have been written at all.

In 95% of cases someone tearing down the orthodoxy of a well established field is a crank. In another 4% of cases they raise some important points, but are largely wrong. In 1% of cases they are right and the orthodoxy has to be rewritten from scratch.

Now these 1% of cases are extremely important! It's understandable why the rationalist community, which has a healthy skepticism of orthodoxy would be interested in finding them. And this is probably a good thing.

But you have to have the expertise with which to do so. If you do not have an extremely solid grasp of cancer research, and you highlight a book like this, 95% of the time you are highlighting a crank, and that doesn't do anyone any good. From what I can make out from this post (and correct me if I'm wrong) you do not have any such expertise.

Now there are people on LessWrong who do have the necessary expertise, and I would value it if they were to either spend 10 seconds looking at the synopsis and saying "total nonsense, not even worth investigating" Vs "I'll delve into that when I get the time". But for anyone who doesn't have the expertise, your best bet is just to go with the orthodoxy. There's an infinite amount of bullshit to get through before you find the truth, and a book review of probable bullshit doesn't actually help anyone.

This comment describes some relevant research.

From Somatic Mutation Theory - Why it's Wrong for Most Cancers:

It should come as no surprise, therefore, that somatic mutations are questioned as representing "the" cause for the majority of cancers [10,11] and it should be noted that some cancers are not associated with any mutations whatsoever.

Importantly, a detailed analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies [48] revealed that "the vast majority, if not all, of aberrations that were observed in the cancer-affected cohort were also seen in cancer-free subjects, although at lower frequency" [47]. Thus, the notion that somatic mutations are necessarily harmful and can lead to cancer is not borne out by this study and further affirms the hypothesis that mutations observed in cancers are not the triggering event but more likely a means for the clonal replication of already transformed cancer cells.

From Speciation Theory of Carcinogenesis Explains Karyotypic Individuality and Long Latencies of Cancers:

However, despite 65 years of research on the mutation theory, there is still no proof for even one set of mutations that is able to convert a normal cell to a cancer cell.

Because the prevailing mutation theory has dominated the search for the genetic causes of cancer since the discovery of gene mutation in 1927 [111], consistent mutations or consistent karyotypic abnormalities with specific mutations were expected [15,21,22]. Instead, individual mutations [43,44] and individual karyotypes [2,9,112,113] were found, of which over 68,000 are listed in the NCI-Mitelman database of cancers [6].

The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory

From Cancer Treatment: A Systems Approach

When the first results of The Cancer Genome Project were reported, many scientists were shocked to learn that most patients, including those with the same type of cancer, did not share the same cancer-related mutations.

The DNA Theory predicts that cancer will be more common in cells that replicate more frequently and/or in organs that have more cells. Lintern's theory suggests more cancer in organs that have more surface area that are accessible by fungi. I think the evidence favors Lintern here, but probably not very strongly.

Itraconazole therapy in a pancreatic adenocarcinoma patient: A case report: an example of a patient with a terminal cancer diagnosis recovering in apparent response to getting an anti-fungal drug.

Case studies with salvestrol treatment: a class of natural anti-fungals helped cure some "terminal" cancer patients. 6 more case studies. New clinical study with phytonutrients (phytoalexins) a randomized controlled trial.

Fungal diseases mimicking primary lung cancer: radiologic--pathologic correlation: cancer and fungal infections look similar. Somehow, this is rarely taken as evidence that they're the same thing.

How a plant's anti-fungal defence may protect against cancer.

From Finding the "Missing 50%" of Invasive Candidiasis:

Blood cultures are limited for diagnosing invasive candidiasis by poor sensitivity and slow turn-around time.

Almost as important is that the mutations that are found seem more randomly distributed than would be expected if they caused consistent types of malfunctions.

Can you expand on this? I can't help but think of performance problems caused by software extensions as an analogy; these are often quite randomly distributed, with there being many different kinds of extensions that can cause program activity to expand uncontrolledly. Shouldn't we expect the same with mutations?

Here are some conversations that I had with AIs, mainly Claude 3.5 Sonnet:

Perplexity, in response to "arguments against Mark Lintern's theory that fungal infections are the primary cause of cancer?":

6. Effectiveness of current treatments: Many existing cancer treatments that do not specifically target fungal infections have shown efficacy in treating various types of cancer, which may contradict the theory that fungi are the primary cause [1].

That stands out as strange. The "effectiveness" of current cancer treatments is what led me to search for what is wrong with cancer research.

me: What are the strongest arguments against Mark Lintern's claim that fungal infections are the primary cause of cancer?

Claude:

Mark Lintern's claim that fungal infections are the primary cause of cancer is not widely accepted in the scientific community. While it's important to consider alternative hypotheses, there are several strong arguments against this claim:

1. Lack of robust scientific evidence: - There is a scarcity of peer-reviewed, well-designed studies supporting the fungal infection hypothesis as a primary cause of cancer. - The vast majority of cancer research points to genetic mutations, environmental factors, and other well-established risk factors.

2. Inconsistency with epidemiological data: - Cancer incidence patterns and risk factors observed in large-scale population studies don't align well with patterns of fungal infections. - Known risk factors like smoking, UV radiation, and certain chemicals have much stronger correlations with cancer incidence.

3. Cancer genomics: - Extensive genomic studies, such as The Cancer Genome Atlas, have identified numerous genetic mutations and alterations in cancer cells that are not explained by fungal infections. - These genetic changes are often directly linked to cancer-related processes.

4. Mechanism of action: - While some fungi can produce carcinogenic compounds, there's no clear mechanism by which fungi could consistently cause the specific genetic alterations observed in various types of cancer.

5. Immunocompromised patients: - Patients with compromised immune systems are highly susceptible to fungal infections. If fungi were the primary cause of cancer, we would expect to see much higher cancer rates in these populations, which is not the case.

6. Treatment efficacy: - Cancer treatments targeting cellular mechanisms and genetic alterations have shown significant efficacy, which would be unlikely if fungi were the primary cause.

7. Experimental evidence: - Laboratory studies inducing cancer in animal models through genetic alterations or carcinogen exposure don't require fungal involvement.

8. Tissue culture studies: - Cancer cells can be grown and studied in sterile laboratory conditions without any fungal presence, demonstrating that fungi are not necessary for cancer cell survival or proliferation.

9. Hereditary cancers: - The existence of hereditary cancer syndromes, where specific genetic mutations dramatically increase cancer risk, is difficult to explain with a fungal infection hypothesis.

10. Cellular and molecular biology: - Our understanding of cancer at the cellular and molecular level, including oncogene activation and tumor suppressor inactivation, doesn't require fungal involvement to explain cancer development.

11. Inconsistency across cancer types: - Different cancers have distinct molecular profiles and risk factors. A single cause (fungi) is unlikely to explain this diversity.

12. Successful prevention strategies: - Many cancer prevention strategies (e.g., smoking cessation, sun protection) are effective without addressing fungal infections.

13. Lack of fungal signatures: - Sophisticated genomic analyses of tumors have not revealed consistent fungal genetic material or signatures across cancer types.

14. Evolutionary perspective: - Cancer is observed across many animal species, including those with very different susceptibilities to fungal infections than humans.

15. Clinical observations: - Clinicians and pathologists routinely examine cancer tissues and rarely report finding evidence of widespread fungal involvement.

While it's true that some fungi can produce carcinogenic compounds and that certain fungal infections (like chronic candidiasis) have been associated with slightly increased risk of specific cancers, the evidence overwhelmingly suggests that fungi are not the primary cause of most cancers. The scientific consensus supports a multifactorial model of cancer causation, involving genetic, environmental, and lifestyle factors, with somatic mutations playing a central role in most cases.

It's important to approach such claims critically and rely on well-established scientific evidence and consensus when considering cancer causes and treatments.

Most of Claude's points seem weak, often assuming a rather controversial belief that fungi are reliably detected when they're present. The point that looks strongest to me is the one about Immunocompromised patients.

me: What's the best source of evidence for cancer rates in immunocompromised patients?

Claude:

To find the best evidence for cancer rates in immunocompromised patients, we should look at large-scale epidemiological studies, systematic reviews, and meta-analyses. Some of the most reliable sources include:

1. HIV/AIDS patient cohorts: The HIV/AIDS Cancer Match Study, conducted by the National Cancer Institute, is one of the most comprehensive sources. It links HIV/AIDS and cancer registry data in the United States.

Key resource: Engels, E. A., et al. (2008). Trends in cancer risk among people with AIDS in the United States 1980--2002. AIDS, 22(16), 2101-2108.

2. Transplant recipient studies: The Transplant Cancer Match Study, also by the National Cancer Institute, is an authoritative source for cancer incidence in organ transplant recipients.

Key resource: Engels, E. A., et al. (2011). Spectrum of cancer risk among US solid organ transplant recipients. JAMA, 306(17), 1891-1901.

3. Systematic reviews and meta-analyses: These provide comprehensive overviews of multiple studies.

Example: Grulich, A. E., et al. (2007). Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. The Lancet, 370(9581), 59-67.

4. Large national databases: Countries with comprehensive health registries, like the Nordic countries, often provide valuable data.

Example: Vajdic, C. M., & van Leeuwen, M. T. (2009). Cancer incidence and risk factors after solid organ transplantation. International Journal of Cancer, 125(8), 1747-1754.

5. Collaborative international studies: The International Immunocompromised Host Society (ICHS) often publishes comprehensive data.

6. Specific immunodeficiency disorder studies: For rare immunodeficiency disorders, studies like the USIDNET (United States Immunodeficiency Network) can be valuable.

7. World Health Organization (WHO) reports: The WHO occasionally publishes comprehensive reports on cancer in immunocompromised populations.

8. Centers for Disease Control and Prevention (CDC): The CDC maintains databases and publishes reports on cancer incidence in HIV-infected individuals.

When evaluating these sources, consider: - Sample size - Duration of follow-up - Methodology for cancer detection and classification - Adjustment for confounding factors - Recency of the data

It's important to note that cancer rates can vary depending on the specific cause and nature of immunosuppression, so looking at multiple sources covering different immunocompromised populations can provide a more comprehensive picture.

me: What does the Somatic Mutation Theory of cancer predict about the kinds of mutations seen in the DNA of cancer cells? What kind of evidence concerning those mutations would falsify the theory?

Claude:

The Somatic Mutation Theory (SMT) of cancer makes several predictions about the kinds of mutations seen in the DNA of cancer cells. Here are the key predictions and the types of evidence that could potentially falsify the theory:

Predictions of the Somatic Mutation Theory:

1. Accumulation of mutations: SMT predicts that cancer cells will have accumulated multiple mutations over time.

2. Driver mutations: Some mutations (called driver mutations) will be causally implicated in cancer development, affecting genes that control cell growth, division, or death.

3. Passenger mutations: Other mutations (called passenger mutations) will be present but not directly contributing to cancer development.

4. Clonal expansion: Cells with advantageous mutations will undergo clonal expansion, leading to a population of cancer cells with shared mutations.

5. Heterogeneity: Different areas of a tumor may have different sets of mutations due to ongoing mutation and selection processes.

6. Specific gene types: Mutations will often affect proto-oncogenes (promoting cell growth) and tumor suppressor genes (inhibiting cell growth).

7. Functional changes: Mutations will lead to functional changes in proteins that drive cancer-related processes (e.g., increased proliferation, evading apoptosis).

Evidence that could potentially falsify the theory:

1. Lack of mutations: If cancer cells consistently showed no increase in mutations compared to normal cells, this would challenge SMT.

2. Random distribution: If mutations in cancer cells were completely random and showed no enrichment in cancer-related genes, this would be contrary to SMT predictions.

3. Reversibility without genetic changes: If advanced cancers could be consistently and permanently reversed to normal cells without altering their genetic material, this would challenge SMT.

4. Lack of clonality: If cancer cells within a tumor showed no evidence of clonal relationships, this would be inconsistent with SMT.

5. Identical mutations across cancer types: If all cancers, regardless of tissue origin or type, always had the exact same set of mutations, this would be difficult to explain with SMT.

6. Non-genetic transmission: If cancer could be reliably transmitted between individuals or cells without any transfer of genetic material or induction of new mutations, this would challenge SMT.

7. Perfect correlation with environmental factors: If cancer incidence was perfectly explained by environmental factors alone, with no role for random mutations or genetic susceptibility, this would be inconsistent with SMT.

8. Lack of genomic instability: If cancer cells showed no signs of genomic instability or increased mutation rates compared to normal cells, this would be contrary to many versions of SMT.

9. Mutations without consequences: If the identified mutations in cancer cells could be shown to have no functional consequences at all, this would challenge a key aspect of SMT.

It's important to note that while these findings would challenge SMT, they would need to be consistently replicated and thoroughly verified before the theory would be considered falsified. Many of these potential falsifying observations have not been seen; instead, the accumulating evidence has generally supported the main tenets of the Somatic Mutation Theory, though it has also led to refinements and expansions of the theory over time.

me: What does the Cancer Genome Atlas say about whether mutations in cancer cells tend to be in cancer-related genes?

Claude:

The Cancer Genome Atlas (TCGA) has provided extensive data on the genomic characteristics of various cancer types, offering significant insights into the patterns of mutations in cancer cells. Regarding your specific question about whether mutations in cancer cells tend to be in cancer-related genes, TCGA data strongly supports this notion. Here's a summary of key findings:

1. Enrichment in cancer-related genes: TCGA data shows that mutations in cancer cells are indeed enriched in cancer-related genes. These include:

• Oncogenes (e.g., KRAS, BRAF) - Tumor suppressor genes (e.g., TP53, PTEN) - DNA repair genes (e.g., BRCA1, BRCA2) - Cell cycle regulators (e.g., RB1, CDKN2A)

2. Recurrent mutations: Certain genes are found to be recurrently mutated across multiple cancer types, suggesting their importance in cancer development. For example, TP53 is mutated in a high percentage of various cancers.

3. Cancer-type specific patterns: While some genes are commonly mutated across cancer types, TCGA has also revealed cancer-type specific mutation patterns. For instance: - BRAF mutations are common in melanoma

• APC mutations are frequent in colorectal cancer - EGFR mutations are often seen in certain lung cancers

4. Pathway-level alterations: TCGA data shows that even when specific genes are not mutated, the pathways they belong to are often altered. This supports the idea that cancer-related processes are being targeted by mutations.

5. Driver vs. passenger mutations: TCGA analyses have helped distinguish between driver mutations (in cancer-related genes) and passenger mutations. Driver mutations are less common but more impactful, often occurring in cancer-related genes.

6. Mutational signatures: TCGA has revealed mutational signatures that are associated with specific cancer types or carcinogenic exposures, many of which affect cancer-related genes more frequently.

7. Fusion genes: TCGA has identified numerous fusion genes in various cancers, often involving known cancer-related genes, further supporting the concentration of impactful mutations in cancer-relevant genomic regions.

8. Copy number alterations: Beyond point mutations, TCGA data shows that copy number alterations (amplifications and deletions) also frequently affect cancer-related genes.

9. Epigenetic alterations: While not mutations per se, TCGA has shown that epigenetic changes (like DNA methylation) often affect the expression of cancer-related genes.

10. Mutual exclusivity: TCGA data has revealed patterns of mutual exclusivity among mutations in certain cancer-related genes, suggesting that altering one component of a pathway is often sufficient for cancer development.

It's important to note that while TCGA data strongly supports the concentration of mutations in cancer-related genes, it also reveals the complexity of cancer genomics:

• Not all mutations in cancer cells are in known cancer-related genes. - The functional impact of many mutations is still not fully understood. - There's significant heterogeneity both within and between cancer types. - Some cancers show a high mutational burden across the genome, while others have fewer, more specific alterations.

In conclusion, TCGA data provides robust evidence that mutations in cancer cells tend to be enriched in cancer-related genes, supporting key aspects of the Somatic Mutation Theory of cancer. However, it also highlights the complexity of cancer genomics and the need for continued research to fully understand the role of various genetic alterations in cancer development and progression.

me: I've seen reports (via Mark Lintern) that a number of cancers involve no mutations. How do supporters of the Somatic Mutation Theory respond to such claims?

Claude:

The claim that some cancers involve no mutations is indeed a challenge to the Somatic Mutation Theory (SMT) of cancer. This topic has been a subject of debate in the cancer research community. Here's how supporters of SMT typically respond to such claims:

1. Questioning the methodology: - SMT supporters often argue that the studies claiming "mutation-free" cancers may have limitations in their detection methods. - They suggest that more sensitive techniques or broader genomic analyses might reveal mutations that were initially missed.

2. Epigenetic alterations: - Some SMT proponents argue that while there might not be detectable DNA sequence mutations, epigenetic changes (which can alter gene expression without changing the DNA sequence) could be present. - They consider epigenetic alterations as an extension of the mutation concept, still fitting within a broader interpretation of SMT.

3. Inherited genetic factors: - In some cases, cancer might develop due to inherited genetic factors rather than new somatic mutations. SMT supporters argue this still fits within the genetic basis of cancer.

4. Chromosomal abnormalities: - Some cancers might have large-scale chromosomal abnormalities (like aneuploidy) rather than point mutations. These are still genetic changes consistent with SMT.

5. Viral oncogenesis: - In cancers caused by viruses, the viral genes might drive cancer development without new mutations in the host genome. SMT supporters argue this still involves genetic alterations, albeit from an external source.

6. Rare exceptions: - SMT proponents often argue that even if some cancers truly lack mutations, these are likely rare exceptions that don't invalidate the theory for the vast majority of cancers.

7. Limitations of current knowledge: - They might argue that our current understanding of cancer-related genes is incomplete, and mutations in yet-unknown cancer-related genes might be present.

8. Challenging the "mutation-free" claim: - Some supporters question whether truly "mutation-free" cancers exist, suggesting that more comprehensive analyses would likely reveal some level of genetic alteration.

9. Fusion genes and other structural variations: - Some genetic alterations, like gene fusions, might not be detected by methods looking for point mutations but still represent genetic changes consistent with SMT.

10. Mosaicism and low-frequency mutations: - They argue that some mutations might be present in only a small subset of cells or at very low frequencies, making them difficult to detect with standard methods.

11. Expanding the definition of "mutation": - Some researchers propose broadening the definition of mutations to include other types of genetic and epigenetic alterations, thus maintaining the core of SMT while accommodating new findings.

12. Integrating with other theories: - Many SMT supporters advocate for an integrated view of cancer development, incorporating aspects of other theories (like the metabolic theory or tissue organization field theory) while maintaining the central role of genetic alterations.

It's worth noting that the cancer research community continues to debate and refine theories based on new evidence. While SMT remains a dominant paradigm, many researchers acknowledge that it may not fully explain all aspects of cancer development and progression. The field is moving towards more nuanced and integrated models of cancer biology that can account for the complex and diverse nature of the disease.