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An evolutionary explanation for antibiotics’ association with increased Colon cancer risk

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More than 10 studies have confirmed the association of antibiotic overuse with colorectal cancer. The exact cause is unknown, but most authors hypothesize that disturbance of colon microbiota is the main culprit. In this commentary an evolutionary explanation is proposed. It is well known that antibiotics can induce antibiotic resistance in bacteria through selection of mutators—DNA mismatch repair deficient (dMMR) strains. Mutators have an increased survival potential due to their high mutagenesis rate. Antibiotics can also cause stress in human cells. Selection of dMMR colon cells may be advantageous under this stress, mimicking selection of bacterial mutators. Concomitantly, MMR deficiency is a common cause of cancer, this may explain the increased cancer risk after multiple cycles of oral antibiotics. This proposed rationale is described in detail, along with supporting evidence from the peer-reviewed literature and suggestions for testing hypothesis validity. Treatment schemes could be re-evaluated, considering toxicity and somatic selection mechanisms. LAY SUMMARY The association of antibiotics with colon cancer is well established but of unknown cause. Under an evolutionary framework, antibiotics may select for stress resistant cancerous cells that lack mechanisms for DNA mismatch repair (MMR). This mimics the selection of antibiotic resistant “mutators”- MMR deficient micro-organisms- highly adaptive due to their increased mutagenesis rate.
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An evolutionary explanation
for antibiotics’ association
with increased colon cancer
risk
Konstantinos Voskarides *
Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus
*Corresponding author. University of Nicosia Medical School, 21 Ilia Papakyriakou, 2414 Engomi, PO Box 24005, CY-1700
Nicosia, Cyprus. Tel: þ357-22-471-819; E-mail: voskarides.c@unic.ac.cy
Received 20 December 2021; revised version accepted 21 April 2022
ABSTRACT
More than 10 studies have confirmed the association of antibiotic overuse with colorectal cancer. The
exact cause is unknown, but most authors hypothesize that disturbance of colon microbiota is the
main culprit. In this commentary, an evolutionary explanation is proposed. It is well known that antibi-
otics can induce antibiotic resistance in bacteria through selection of mutators—DNA mismatch repair
deficient (dMMR) strains. Mutators have an increased survival potential due to their high mutagenesis
rate. Antibiotics can also cause stress in human cells. Selection of dMMR colon cells may be advanta-
geous under this stress, mimicking selection of bacterial mutators. Concomitantly, mismatch repair
deficiency is a common cause of cancer, this may explain the increased cancer risk after multiple cycles
of oral antibiotics. This proposed rationale is described in detail, along with supporting evidence from
the peer-reviewed literature and suggestions for testing hypothesis validity. Treatment schemes could
be re-evaluated, considering toxicity and somatic selection mechanisms.
Lay Summary: The association of antibiotics with colon cancer is well established but of unknown cause.
Under an evolutionary framework, antibiotics may select for stress-resistant cancerous cells that lack
mechanisms for DNA mismatch repair (MMR). This mimics the selection of antibiotic resistant ‘muta-
tors’—MMR-deficient micro-organisms—highly adaptive due to their increased mutagenesis rate.
KEYWORDS: natural selection; MSH2; MLH1; DNA repair; cancer evolution; adaptation
ASSOCIATION OF ANTIBIOTICS WITH
COLON CANCER
Multiple studies have found a positive association
between overuse of antibiotics and risk for
colorectal cancer, though the exact cause remains
unknown. In this article, a connection with DNA
mismatch repair (MMR) genes is speculated,
under the view of somatic selection. Below, a
V
CThe Author(s) 2022. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health. This is an Open
Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which per-
mits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
214
COMMENTARY
Evolution, Medicine, and Public Health [2022] pp. 214–220
https://doi.org/10.1093/emph/eoac018
Advance access date 29 April 2022
detailed description of the most significant studies that found
the antibiotics–cancer association is included. Studies are sum-
marized in Table 1.
Kilkkinen et al.[1], using a Finnish registry of 3 112 624 indi-
viduals, aged 30–79 years, found a positive association of antibi-
otics use with several cancer organ sites, including prostate,
breast, lung and colon. Wang et al.[2] surveyed 3593 colon can-
cer cases, 1979 rectal cancer cases and 22 288 controls, finding
that the use of any anti-anaerobic antibiotic was associated with
a higher risk of colon cancer (OR ¼2.31, 95% CI: 2.12–2.52)
and rectal cancer (OR ¼1.69, 95% CI: 1.50–1.90) but without
any obvious dose-dependent relationship. Boursi et al.[3]
studied a total of 20 990 cases and 82 054 controls. They found
an increased colorectal cancer risk with the use of penicillins,
an increase by OR of 1.04 (95% CI: 1.01–1.08) per one addition-
al treatment per year. No association was found with exposure
to anti-viral or anti-fungal therapy. Zhang et al.[4] found an
increased risk of colon cancer (UK cases) with antibiotics use in
a dose-dependent fashion (28 980 colorectal cancer cases and
137 077 controls, P<0.001). Along the same lines, Armstrong
et al.[5] found a dose-dependent association with colorectal
cancer for patients prescribed antibiotics in up to a 15-year
timeframe (OR ¼1.90, 95% CI: 1.61–2.19, P<0.001). Simin et
al.[6] in a huge meta-analysis (4.1 million individuals) found
increased pooled colorectal cancer risk for individuals with any
antibiotics exposure (OR ¼1.17, 95% CI: 1.05–1.30), with par-
ticularly higher risk for broad-spectrum antibiotics (OR ¼1.70,
95% CI: 1.26–2.30). Wan et al.[7] in a meta-analysis with
412 450 individuals in total found, after stratifying by type of
antibiotic, that participants with extensive use of penicillin and
anti-anaerobic antibiotics had 18% and 49% increased risk of
colorectal cancer, respectively. In another meta-analysis by Qu
et al., [8], more than 60 days of antibiotics use and five prescrip-
tions of antibiotics were significantly associated with an ele-
vated risk of colorectal cancer (OR ¼1.09, 95% CI: 1.02–1.17).
Sanyaolu et al.[9] searched MEDLINE, EMBASE and CINAHL
databases for published observational studies. The final ana-
lysis included a total of 3 408 312 patients and found a weak as-
sociation between antibiotic exposure and colorectal cancer
when exposure was assessed cumulatively by the number of
prescriptions (OR ¼1.204, 95% CI: 1.097–1.322, P<0.001) or
duration of antibiotic exposure (OR ¼1.168, 95% CI: 1.087–
1.256, P<0.001). The most recent studies were performed by
Lu et al.[10] and Aneke-Nash et al.[11]. In the Swedish study by
Lu et al.[10], 40 545 colorectal cancer cases and 202 720 con-
trols were included. A positive association between frequent
antibiotics use and colorectal cancer was found, especially for
the proximal colon (adjusted OR for very high use vs no
use ¼1.17, 95% CI: 1.05–1.31). The study by Aneke-Nash et al.
[11] was a meta-analysis of six papers. Individuals with high
antibiotic exposure had a 10% higher risk of colorectal neopla-
sia than those with the lowest exposure (OR ¼1.10, 95% CI:
1.01–1.18).
The association of antibiotics use and cancer is not restricted
to colorectal tumors. Indicatively, two studies are referred here.
The study of Kilkkinen et al.[1] found an association of
Table 1. Studies showing the association of antibiotics with colon or colorectal cancer
Study Type of study Type of cancer Antibiotics Odds ratio (CI) Number of
cases
[1]Nation-wide
cohort study
Colon Any 1.15 (1.04–1.26) 7513
[2]Case–control Colon Anti-anaerobic 2.31 (2.12–2.52) 3593
[3]Case–control Colorectal Penicillins 1.04 (1.01–1.08)
(per treatment)
20 990
[4]Case–control Colon Ampicillin/
amoxicillin
1.09 (1.05–1.13) 28 980
[5]Case–control Colorectal Any 1.90 (1.61–2.19) 35 214
[6]Meta-analysis Colorectal Broad-spectrum 1.70 (1.26–2.30) 73 550
[8]Meta-analysis Colorectal Any 1.09 (1.02–1.17) 4 853 289 (all
participants)
[9]Meta-analysis Colorectal Any 1.20 (1.10–1.32) 3 408 312
[10]Case–control Colon Any 1.17 (1.05–1.31) 40 545
[11]Meta-analysis Colorectal Any 1.10 (1.01–1.18) 73 405
[49]Case–control Colon Any 1.49 (1.07–2.07) 7903
CI, confidence intervals.
Somatic evolution and antibiotics-cancer association Voskarides | 215
antibiotics use with several forms of cancer. Boursi et al.[12]
reported similar findings with antibiotic use being associated
with several cancer types, studying 125 441 cases and 490 510
matched controls.
According to this vast amount of published data, there can
be little doubt that antibiotics overuse is associated with
increased colorectal cancer risk, often in a dose- or time-de-
pendent manner. Antibiotic type was usually not found to be a
significant parameter of this association; however, some stud-
ies agree on penicillin and anti-anaerobic antibiotics.
Association of antibiotics with other cancer types probably
needs further investigation. Is colorectal cancer–antibiotics a
causal relationship? The obvious explanation is the disturbance
of colon microbiota. This is the explanation that most authors
give for their results. In this perspective article, an alternative
evolutionary explanation will be discussed, related with the se-
lection of DNA MMR-deficient cells under antibiotic stress. I
would like to state here that I do not neglect the probable sig-
nificance of microbiota to cancer. DNA MMR deficiency is prob-
ably a part of a complicate equation that drives to cancer.
DNA MMR AND CANCER
DNA MMR is considered one of the most important mecha-
nisms of DNA damage repair and one of the most conserved
molecular mechanisms in all living organisms (Fig. 1). MMR
protein dimers recognize a variety of base–base and insertion–
deletion mismatches [13], while other auxiliary proteins remove
the wrong bases and DNA polymerase synthesizes the correct
DNA sequence [13].
In humans, seven DNA MMR genes/proteins (MLH1,MLH3,
MSH2,MSH3,MSH6,PMS1 and PMS2) have been identified.
For some of them, the exact function is not clear. Deficiencies
in the MMR pathway are a frequent cause of carcinogenesis.
Most cancer cases are associated with somatic mutations in
oncogenes and tumor suppressor genes. MMR genes are
considered as tumor suppressor genes. Inherited neoplasias
represent 5–10% of all cancer cases and usually follow an
autosomal dominant model of inheritance. Mutations in the
MMR genes are responsible for hereditary nonpolyposis colo-
rectal cancer/Lynch syndrome (HNPCC/LS), and other cancer-
predisposing Lynch variant syndromes. The majority of muta-
tions in HNPCC/LS occur in MSH2 and MLH1 genes; however,
mutations in other MMR genes are also implicated, such as
MSH6 and PMS2 [14]. Additionally, somatic mutations in MMR
genes are found in up to 15% of sporadic colorectal, gastric or
endometrial carcinomas [15]. Specifically for colorectal cancers,
15% of tumors are deficient in DNA MMR, commonly due to
loss of MLH1 (9.8%) [16,17]. Frequently, the defect found in
MLH1-associated tumors is not a gene mutation but hyperme-
thylation of the promoter. Promoter hypermethylation of MLH1
is found in at least nine more cancer sites including gastric can-
cer (21.6%) [18] and oral squamous cell carcinoma (76%) [19].
Microsatellite instability (MSI) is considered the classical
method for detecting MMR pathway deficiency in colorectal or
other tumors. Microsatellites are short tandem repeats (STRs)
that are found throughout the genome. The most common
ones in the human genome are the dinucleotide repeats, espe-
cially (AC)n. In case of a deficient MMR pathway, genetic in-
stability is detected as presence of multiple alleles (instead of
two) per each analyzed STR in tumors’ DNA [20]. The National
Cancer Institute Workshop agreed on five microsatellite
markers for MSI testing, two mononucleotides and three dinu-
cleotides: BAT25, BAT26, D2S123, D5S346 and D17S250 [21].
Tumors are defined as: MSI-High (two or more microsatellites
are unstable), MSI-Low (one microsatellite out of five is un-
stable) and microsatellite stable [15,21]. MSI testing has great
clinical significance for cancer prevention, prognosis and treat-
ment. For example, prognosis is good for many MSI-High colo-
rectal cancer patients [22] and aspirin can prevent MSI in
patients with germline mutations in MSH2 and MLH1 genes
[23]. Treatment with 5-fluorouracil seems to be not effective in
Figure 1. MLH1 gene tree. MLH1 orthologues exist in all five life kingdoms. Protein sequences were derived from Ensembl. Maximum-likelihood phylogeny
method was used for the gene tree construction (CLC Main Workbench 21).
216 | Voskarides Evolution, Medicine, and Public Health
MSI-High patients [24], despite a report showing some benefit
for stage IV MSI-High patients [25]. Immunotherapy has had
promising results for MSI-High or MMR-deficient patients,
which led the FDA to recently approve treatment regimens with
the immunotherapeutic agent Keytruda (pembrolizumab), a
PD-1 inhibitor [26].
DNA MMR AND MUTATOR MICROORGANISMS
MMR gene mutations are observed in monocellular as well as
multicellular organisms. In multicellular organisms, these
mutations can cause cancer. In monocellular organisms, these
mutations can offer an adaptive advantage through the ‘muta-
tor’ phenomenon. Eucaryotic somatic cells with MMR gene
mutations may have also increased fitness under the concept of
‘mutator’ cells. By virtue of the MMR mutation that may in-
crease their fitness, mutator cells are also potentially cancerous
cells.
The term ‘mutator’ is used for cells that have increased muta-
genesis rate, which contributes to their survival under demand-
ing or hostile environments. Most of the knowledge we have of
this phenomenon comes from antibiotic-resistant bacteria or
other drug-resistant microorganisms. Commonly, mutator micro-
organisms’ strains have a defective MMR pathway [27,28].
Escherichia coli mutators were among the first that were studied
[29]. In these cases, a partially defective MMR system is compat-
ible with life and in fact may have beneficial effects for survival. If
more mutations emerge after each cell division, then the prob-
ability increases for the appearance of a beneficial mutation
which would allow the population to escape extinction. In evolu-
tionary terms, antibiotics are catastrophic and highly selective for
bacterial populations. If a mutator strain exists inside the popula-
tion, this allows for tremendous adaptive capacities to increase
replication after antibiotic treatment.
There are several examples of mutator strains. Studies show
that MMR-deficient Pseudomonas aeruginosa is antibiotic-resist-
ant and has increased virulence [3032]. This has been a major
problem for cystic fibrosis patients given that P. aeruginosa
lung infections are a life-threatening condition for these
patients. Generally, mutator multidrug-resistant bacterial
strains are common in chronic infections, like cystic fibrosis or
urinary tract infections. Patients in these cases receive multiple
antibiotic cycles and bacteria are continuously under positive
selection for antibiotic resistance [31,33]. Antibiotic-resistant
Salmonella strains have also been identified with mutations in
MMR genes [29,34]. Fungi is not an exception: MMR gene
mutations have been found in Cryptococcus,Candida and
Aspergillus genus, all of which are characterized by increased
mutagenesis rates and rapid adaptation to antifungal drugs
[28,35].
ANTIBIOTIC STRESS AND SOMATIC EVOLUTION
Somatic evolution favors cancer mutations in healthy
tissues
Recent advances in genomic analysis of somatic tissues chal-
lenge the standard knowledge that somatic mutations in onco-
genes and tumor suppressor genes are always pathogenic.
Mutations in oncogenes and tumor suppressor genes can lead
to clonal expansions and adaptation in cells harboring these
mutated genes. Martincorena et al.[36] found thousands of
mutations in esophageal tissue from healthy individuals, includ-
ing mutations in 14 well-known cancer genes. Most of the
mutations were on the NOTCH1 and TP53 genes, the most fre-
quently mutated ones in esophageal cancer. NOTCH1 muta-
tions in normal esophagus were several times higher than in
esophageal cancers. Similar results were published soon after
for many other healthy human tissues like endometrial, colorec-
tal and liver [3739]. Many ‘driver’ mutations in cancer genes in
those healthy tissues were found to be under positive selection.
It remains unknown why these individuals do not develop can-
cer. As such, it is obvious that the external environment drives
selection and evolution even in normal somatic cells. The hy-
pothesis offered in this perspective is that cells that are resist-
ant to apoptosis or have a high mutagenesis rate have an
evolutionary advantage under stressful conditions, such as
those conferred by drugs (e.g. antibiotics), poisons, oxidative
stress, starvation, cold, etc. This may be the way that our cells
survive under diverse and challenging conditions.
Antibiotics may induce somatic selection for mutator cells
Intestinal epithelial cells with mutator capabilities have an
adaptive advantage under stressful conditions, e.g. anticancer
therapy [40]. MMR-deficient intestinal cells probably experience
positive selective pressures in such stressful environments.
This is a procedure that mimics selection of MMR-deficient bac-
teria or other monocellular organisms under harsh conditions.
As it was described in the previous sections, antibiotics cause
an intense evolutionary pressure, benefiting mutator selection.
Pharmacokinetic studies show that 20–60% of the orally admin-
istered tetracyclines’ dose is excreted through the feces [41]. As
a result, oral treatment exposes gastrointestinal cells to a high
antibiotic concentration for a prolonged time. This exposure
can potentially cause stress to colon mucosa cells. Antibiotics
have a high specificity for bacterial proteins or nucleic acids,
but this is not absolute. The low-grade affinity of antibiotics
with human biomolecules can cause significant cell toxicity, es-
pecially if given in multiple treatment cycles (or for a prolonged
time). The following antibiotic categories are of high concern:
antibiotics that bind the bacterial large 50S ribosomal unit (e.g.
macrolides), antibiotics that bind the bacterial small 30S
Somatic evolution and antibiotics-cancer association Voskarides | 217
ribosomal unit (e.g. aminoglycosides), antibiotics that inhibit
bacterial tRNA biogenesis or function (e.g. tetracyclines). The
bacterial large and small ribosomal units are not completely un-
related with the human ones. Similarities exist and these antibi-
otics can potentially inhibit protein synthesis and become toxic
for human cells [42,43]. Enzymes that participate in bacterial
tRNA biosynthesis or function also share some homology with
the human versions. Again, tRNA antibiotics can potentially be
toxic for humans, by inhibiting protein synthesis [44].
Under repeated antibiotic courses, MMR-deficient colon mu-
cosa cells can be selected as in the case of bacteria. These evolu-
tionary pressures probably affect colon crypt stem cells, which are
small clonal units occupying intestinal spaces referred to as crypts.
Mutations in non-stem cells usually do not accumulate since they
havelimitedlifespans,whilethestemcellsareresponsibleforcell
proliferation of the crypt. Despite stem cells being quite resistant
to mutagenesis, inevitably mutations appear during ageing [45].
Crypt stem-cells may increase their stress-tolerance with or without
mutations but in the latter case, MMR pathway can be involved
simply through downregulation of MMR gene expression. Russo
et al.[46] showed that this is the case with colon cancer cells under
anticancer therapy stress. EGFR inhibition induced a negative
regulation of MMR gene expression. MMR mutations or expres-
sion inhibition is a possible explanation for the association of anti-
biotics use with colon cancer.
TESTING THE HYPOTHESIS—CONCLUSION
Studies have reported a gut microbiome imbalance (dysbiosis) in
patients with colorectal cancer, showing an increase of the popula-
tion of ‘bad’ microbes compared to a decrease of ‘good’ microbes
[47]. In light of these studies, the association of antibiotics with
colon cancer has been attributed to microbiome imbalance.
According to the perspective offered here, an evolutionary explan-
ation must be considered as playing a significant role in the car-
cinogenic potential of antibiotics. However, other explanations
may exist as well. Inflammation caused by infection is also a cause
of cancer. Obviously, patients who needed treatment by antibiotics
have suffered by an infection. It is known that inflammation is
accompanied by immune cells infiltration, fibroblast recruitment
and activation, and extracellular matrix remodeling. These proce-
dures involve cell proliferation, increased cell mobility and
increased cell penetrance. Subsequently, carcinogenesis probabil-
ities are increasing, especially on the background of genetic var-
iants on tumor suppressor genes or oncogenes [48]. Additionally,
people who take antibiotics frequently may have less effective im-
mune systems. Immune system is responsible for eliminating can-
cer cells in our body. People with weak immune systems, e.g. HIV
infected people, are highly predisposed for cancer. Many other fac-
tors can also to be considered, like diet and other drugs taken to-
gether with antibiotics. A specific diet could be associated with
cancer if some of its components are chemically interfering with
antibiotics. Patients frequently taking antibiotics may also take fre-
quently other kind of drugs. These can add on their risk for cancer.
Despite the fact that most of the studies have considered parame-
ters like smoking and alcohol, residual confounding may be pre-
sent, e.g. units of alcohol consumed, number of packs per year for
smokers, etc. [49]. Of course, it is extremely difficult for a study to
adjust for all these parameters. Figure 2 summarizes the major
factors discussed here that can drive to cancer.
The MMR genes’ hypothesis could be tested by multiple
ways. A population-based study would be ideal, by arranging
prospective cohorts of patients treated frequently with antibiot-
ics. Steps: (i) Patients undergo once a year colonoscopy exam-
ination, checking for any alterations in their colon mucosa, (ii)
biopsies must be taken from any abnormal forms of tissue, like
polyps or cancer-like malformations, (iii) DNA from those tis-
sues will be tested for MSI, (iv) exome sequencing can be per-
formed in polyp DNA or tumor DNA, looking for mutations in
MMR genes or other implicated genes, (v) groups of cancer
patients with an already MSI-tested biopsy, can be examined for
a previous history of multiple antibiotic treatments, comparing
the MSI-positive and the MSI-negative ones.
The weakness of testing this hypothesis in humans is the
need of colonoscopy. Colonoscopy is considered an invasive
method, and this may be problematic under a research proto-
col. Additionally, biopsy testing cannot differentiate between
direct and indirect effects of antibiotics. An alternative way to
test this hypothesis is the use of animal models. Mice and
zebrafish can be used as well. Steps: (i) Antibiotics can be
administered in mice or zebrafish for a prolonged time, (ii)
After some months (multiple time points can be used), DNA
from multiple cell types, including intestinal cells, could be
checked for any MMR gene pathogenic mutations, (iii) Results
must be compared with antibiotic-free animals of the same age.
Experiments can be designed to be more complicated, e.g. by
performing comparisons between microbiota-free animals vs
normal microbiota animals. Additionally, cancer incidence
must be estimated, between treated and non-treated animals.
Similar experiments can be performed in cell cultures, prefer-
ably colon cell tissue cultures. Cultured cells treated for a pro-
longed time with antibiotics and antibiotic-free cells can be
tested for MMR gene mutations. More advanced technology
can be used like organ-on-a-chip models as well. Microfluidic
organ-on-a-chip models of human intestine are available [50].
Chip experiments can be performed as described above, fol-
lowed by MMR gene re-sequencing. Again, appropriate compar-
isons must be designed, e.g. intestine cell chips treated with
antibiotics vs antibiotic-free chips, microbiota intestine cell
chips vs microbiota-free intestine cell chips, etc.
The above suggestions can confirm or reject the hypothesis
of MMR-deficient mutator cell selection. In addition, it would
218 | Voskarides Evolution, Medicine, and Public Health
be important to consider whether extensive use of antibiotics by
cancer patients could be risky as MSI-negative tumors can be
transformed to MSI-positive after exposure to a harsh micro-
environment. These tumors are more aggressive than the previ-
ous ones. It is probably wise for cancer patients to carefully con-
sider antibiotic treatments or generally drugs that can increase
death resistance of their cells.
In conclusion, an evolutionary explanation is proposed for
the association of antibiotics with colorectal cancer, which has
been revealed in multiple large-scale population-based studies.
Testing this hypothesis is feasible, especially in national cancer
reference centers, where large cohorts of patients exist. Somatic
selection is the key for the understanding of many conditions
related with human disease.
acknowledgements
I thank Dr Jason S. Gill for linguistic improvement of this paper.
Conflict of interest: None declared.
references
1. Kilkkinen A, Rissanen H, Klaukka T et al. Antibiotic use predicts an
increased risk of cancer. Int J Cancer 2008;123:2152–5.
2. Wang JL, Chang CH, Lin JW et al. Infection, antibiotic therapy and risk
of colorectal cancer: a nationwide nested case-control study in patients
with Type 2 diabetes mellitus. Int J Cancer 2014;135:956–67.
3. Boursi B, Haynes K, Mamtani R et al. Impact of antibiotic exposure on
the risk of colorectal cancer. Pharmacoepidemiol Drug Saf 2015;24:
534–42.
4. Zhang J, Haines C, Watson AJM et al. Oral antibiotic use and risk of
colorectal cancer in the United Kingdom, 1989-2012: a matched case-
control study. Gut 2019;68:1971–8.
5. Armstrong D, Dregan A, Ashworth M et al. The association between
colorectal cancer and prior antibiotic prescriptions: case control study.
Br J Cancer 2020;122:912–7.
6. Simin J, Fornes R, Liu Q et al. Antibiotic use and risk of colorectal can-
cer: a systematic review and dose–response meta-analysis. Br J Cancer
2020;123:1825–32.
7. Wan QY, Zhao R, Wang Y et al. Antibiotic use and risk of colorectal can-
cer: a meta-analysis of 412 450 participants. Gut 2020;69:2059–60.
8. Qu G, Sun C, Sharma M et al. Is antibiotics use really associated with
increased risk of colorectal cancer? An updated systematic review and
meta-analysis of observational studies. Int J Colorectal Dis 2020;35:
1397–412.
9. Sanyaolu LN, Oakley NJ, Nurmatov U et al. Antibiotic exposure and the
risk of colorectal adenoma and carcinoma: a systematic review and
meta-analysis of observational studies. Color Dis 2020;22:858–70.
10. Lu SSM, Mohammed Z, Ha¨ggstro¨m C et al. Antibiotics use and subse-
quent risk of colorectal cancer: a Swedish nationwide population-based
study. JNCI J Natl Cancer Inst 2022;114:38–46.
11. Aneke-Nash C, Yoon G, Du M et al. Antibiotic use and colorectal neo-
plasia: a systematic review and meta-analysis. BMJ Open Gastroenterol
2021;8:e000601.
12. Boursi B, Mamtani R, Haynes K et al. Recurrent antibiotic exposure
may promote cancer formation—another step in understanding the
role of the human microbiota? Eur J Cancer 2015;51:2655–64.
13. Iyer RR, Pluciennik A, Burdett V et al. DNA mismatch repair: functions
and mechanisms. Chem Rev 2006;106:302–23.
14. Rustgi AK. The genetics of hereditary colon cancer. Genes Dev 2007;21:
2525–38.
15. Yamamoto H, Imai K. Microsatellite instability: an update. Arch Toxicol
2015;89:899–921.
16. Truninger K, Menigatti M, Luz J et al. Immunohistochemical analysis
reveals high frequency of PMS2 defects in colorectal cancer.
Gastroenterology 2005;128:1160–71.
17. Hissong E, Crowe EP, Yantiss RK et al. Assessing colorectal cancer mis-
match repair status in the modern era: a survey of current practices
and re-evaluation of the role of microsatellite instability testing. Mod
Pathol 2018;31:1756–66.
18. Li Y, Yang Y, Lu Y et al. Predictive value of CHFR and MLH1 methyla-
tion in human gastric cancer. Gastric Cancer 2015;18:280–7.
19. Gonza´lez-Ram
ırez I, Ram
ırez-Amador V, Irigoyen-Camacho ME et al.
HMLH1 promoter methylation is an early event in oral cancer. Oral
Oncol 2011;47:22–6.
20. Nojadeh JN, Sharif SB, Sakhinia E. Microsatellite instability in colorec-
tal cancer. EXCLI J 2018;17:159–68.
21. Boland CR, Goel A. Microsatellite instability in colorectal cancer.
Gastroenterology 2010;138:2073–87.e3.
22. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite in-
stability and colorectal cancer prognosis. J Clin Oncol 2005;23:609–18.
Figure 2. Possible ways that inflammation or antibiotic use can predispose to cancer. ECM, extracellular matrix.
Somatic evolution and antibiotics-cancer association Voskarides | 219
23. Leenders EKSM, Westdorp H, Bru¨ggemann RJ et al. Cancer prevention
by aspirin in children with Constitutional Mismatch Repair Deficiency
(CMMRD). Eur J Hum Genet 2018;26:1417–23.
24. Sun BL. Current microsatellite instability testing in management of
colorectal cancer. Clin Colorectal Cancer 2021;20:e12–20.
25. Liang JT, Huang KC, Lai HS et al. High-frequency microsatellite instabil-
ity predicts better chemosensitivity to high-dose 5-fluorouracil plus leu-
covorin chemotherapy for stage IV sporadic colorectal cancer after
palliative bowel resection. Int J Cancer 2002;101:519–25.
26. FDA grants accelerated approval to pembrolizumab for first tissue/site
agnostic indication. Case Med Res 2017. DOI: 10.31525/fda1-ucm
560040.htm.
27. Chopra I, O’Neill AJ, Miller K. The role of mutators in the emergence of
antibiotic-resistant bacteria. Drug Resist Updat 2003;6:137–45.
28. Healey KR, Zhao Y, Perez WB et al. Prevalent mutator genotype identi-
fied in fungal pathogen Candida glabrata promotes multi-drug resist-
ance. Nat Commun 2016;7:11128.
29. LeClerc JE, Li B, Payne WL et al. High mutation frequencies among
Escherichia coli and Salmonella pathogens. Science 1996;274:1208–11.
30. Khil PP, Chiang AD, Ho J et al. Dynamic emergence of mismatch repair
deficiency facilitates rapid evolution of ceftazidime-avibactam resistance
in Pseudomonas aeruginosa acute infection. mBio 2019;10:e01822.
31. Mena A, Mac
ıa MD, Borrell N et al. Inactivation of the mismatch repair
system in Pseudomonas aeruginosa attenuates virulence but favors
persistence of oropharyngeal colonization in cystic fibrosis mice.
J Bacteriol 2007;189:3665–8.
32. Hogardt M, Schubert S, Adler K et al. Sequence variability and function-
al analysis of MutS of hypermutable Pseudomonas aeruginosa cystic fi-
brosis isolates. Int J Med Microbiol 2006;296:313–20.
33. Couce A, Alonso-Rodriguez N, Costas C et al. Intrapopulation variability
in mutator prevalence among urinary tract infection isolates of
Escherichia coli.Clin Microbiol Infect 2016;22:566.e1–7.
34. Sheng H, Huang J, Han Z et al. Genes and proteomes associated with
increased mutation frequency and multidrug resistance of naturally
occurring mismatch repair-deficient Salmonella hypermutators. Front
Microbiol 2020;11:770.
35. dos Reis TF, Silva LP, de Castro PA et al. The Aspergillus fumigatus mis-
match repair MSH2 homolog is important for virulence and azole re-
sistance. mSphere 2019;4:e00416.
36. Martincorena I, Fowler JC, Wabik A et al. Somatic mutant clones colon-
ize the human esophagus with age. Science 2018;362:911–7.
37. Suda K, Nakaoka H, Yoshihara K et al. Clonal expansion and diversifica-
tion of cancer-associated mutations in endometriosis and normal
endometrium. Cell Rep 2018;24:1777–89.
38. Brunner SF, Roberts ND, Wylie LA et al. Somatic mutations and clonal
dynamics in healthy and cirrhotic human liver. Nature 2019;574:
538–42.
39. Lee-Six H, Olafsson S, Ellis P et al. The landscape of somatic mutation
in normal colorectal epithelial cells. Nature 2019;574:532–7.
40. Damia G, D’Incalci M. Genetic instability influences drug response in
cancer cells. Curr Drug Targets 2010;11:1317–24.
41. Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics
of the tetracyclines including glycylcyclines. J Antimicrob Chemother
2006;58:256–65.
42. Jospe-Kaufman M, Siomin L, Fridman M. The relationship between the
structure and toxicity of aminoglycoside antibiotics. Bioorganic Med
Chem Lett 2020;30:127218.
43. Bo¨ttger EC, Springer B, Prammananan T et al. Structural basis for se-
lectivity and toxicity of ribosomal antibiotics. EMBO Rep 2001;2:
318–23.
44. Francklyn CS, Mullen P. Progress and challenges in aminoacyl-tRNA
synthetase-based therapeutics. J Biol Chem 2019;294:5365–85.
45. Kang H, Shibata D. Direct measurements of human colon crypt stem
cell niche genetic fidelity: the role of chance in non-Darwinian mutation
selection. Front Oncol 2013;3:264.
46. Russo M, Crisafulli G, Sogari A et al. Adaptive mutability of colorec-
tal cancers in response to targeted therapies. Science 2019;366:
1473–80.
47. Abdulla MH, Agarwal D, Singh JK et al. Association of the microbiome
with colorectal cancer development (Review). Int J Oncol 2021;58:17.
48. Foster DS, Jones RE, Ransom RC et al. The evolving relationship of
wound healing and tumor stroma. JCI Insight 2018;3:e99911.
49. McDowell R, Perrott S, Murchie P et al. Oral antibiotic use and early-
onset colorectal cancer: findings from a case-control study using a na-
tional clinical database. Br J Cancer 2022;126:957–11.
50. Bein A, Shin W, Jalili-Firoozinezhad S et al. Microfluidic organ-on-a-
chip models of human intestine. Cell Mol Gastroenterol Hepatol 2018;5:
659–68.
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