REV ARGENT COLOPROCT | 2024 | VOL. 35, N

2 INVESTIGACIÓN TRASLACIONAL

COLORECTAL CANCER: DISORDERS OF DNA REPAIR MECHANISMS AND THEIR MEDICAL IMPLICATION. Soarez J, et al.

Colorectal cancer: Disorders of DNA repair mechanisms and their

medical implication.

Walter Hernán Pavicic

1,2

, Julieta Natalia Soarez

1,2

Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB) Hospital Italiano de Buenos Aires, Instituto Universitario Hospital Italiano de Buenos Aires,

Consejo Nacional de Investigaciones Científicas y Técnicas (HIBA-IUHI-CONICET), Ciudad Autónoma de Buenos Aires (CABA), Argentina.

Programa de Cáncer Hereditario (Pro.Can.He.), Hospital Italiano de Buenos Aires (HIBA), Ciudad Autónoma de Buenos Aires (CABA), Argentina.

ABSTRACT

All tumors, whether hereditary or sporadic, are characterized by

genetic instability (chromosomal or microsatellites instability) which

is a key mechanism that gives the cancer cell all its harmful charac-

teristics (growth advantage, migration, etc.). Although a DNA

repair-deficiency disorder that causes microsatellite instability has

historically been associated with Lynch Syndrome, this molecular

characteristic is also observed in sporadic tumors and determines

not only the prognosis but also just as relevant, the response to

new immunological therapies.

Keywords: colon cancer, Lynch Syndrome, MMR.

INTRODUCTION

DNA repair mechanisms maintain genome stability by

preventing the multiplication of genetic errors, which are

caused by intracellular processes and environmental factors.

Unrepaired damage can permanently alter the genome and

cellular functions, leading to, for example, malignant trans-

formation of the cell. Several DNA repair mechanisms are

necessary to ensure genomic stability and can be divided

according to the DNA damage they repair or the associated

genetic syndromes. Elucidating these mechanisms has been

important, and researchers who carried out pioneering work

were awarded the 2015 Nobel Prize in Chemistry.

When DNA damage occurs, both DNA strands can break,

causing a double-strand break, or it can be more restricted

and occur only on one DNA strand, affecting one or more

bases -nucleotides-. Due to their relevance in tumor devel-

opment, the two mechanisms studied in more detail are: (i)

homologous recombination (HR), and (ii) the mismatch

repair system (MMR). Mainly, they are associated with

hereditary syndromes that predispose to the development of

breast and ovarian cancer (HBOC) or colorectal cancer

(Lynch), respectively.

Repair of DNA replication errors

Although this type of error is common during DNA replica-

tion, the stability of the genetic code is ensured by the

specialized mismatch repair mechanism, called the “MMR

system.” Briefly, the process is detailed to denote the key

MMR genes involved: the repair is initiated by the MutSa

protein complex (MSH2 + MSH6 genes) that recognizes the

error. Then, MutLa (MLH1 + PMS2 genes), together with

the enzyme that synthesizes DNA (DNA polymerase)

correct the error. Germline genetic alterations affecting

MMR gene’s function, a single allele, is associated with

Lynch syndrome (LS), an autosomal dominant genetic

disorder, and the most common inherited cause of colorectal

cancer (CRC). Carriers of pathogenic or causal alterations in

these genes also have a higher risk of developing LS-

associated cancer. This includes cancers such as endometri-

um, small intestine, stomach, pancreas and bile ducts, ovary,

brain, upper urinary tract, and skin. The incidence rate in the

general population can be as high as 1:370 and it is estimat-

ed to cause around 3% of all colon and rectal cancers. On

the other hand, congenital alterations of both alleles cause a

rare cancer syndrome known by the acronym CMMRD

(constitutional mismatch repair deficiency). Furthermore,

the MMR mechanism is altered in approximately 15% of

CRC and other non-hereditary cancers, the most common

mechanism being deficiency in the MLH1 gene function,

caused by promoter region hypermethylation and, conse-

quently, silencing of gene expression. Tumors with a defi-

ciency MMR system are called “unstable tumors.”

Lynch Syndrome Diagnosis

The suspicion of LS can be based on clinical criteria (Am-

sterdam or Bethesda) or molecular criteria (immunohisto-

chemistry or microsatellite analysis by a PCR assay). Fur-

ther details of these complementary studies exceed the

editorial focus. However, it is important to note that current-

ly a definitive LS diagnosis requires identification of a

germline genetic alteration in the MMR or in the EPCAM

genes. The analysis should cover small sequence changes

and large rearrangements (which can be achieved by DNA

sequencing plus copy number variant analysis by, for exam-

ple, MLPA study). Currently, multigene panel sequencing

test (along with MLPA) has become the most widespread

assay, compared to traditional syndrome-specific gene

testing. Ultimately, this information allows alteration carri-

ers to be referred for follow-up or surveillance in pursuit of

cancer prevention or treatment.

Implications of molecular advances in Surveillance,

Prevention and Treatment of CRC Surveillance recom-

mendations.

Recent advances have allowed us to understand in more

detail the differences linked to each MMR gene and tumor

development risk. Therefore, clinical surveillance and

treatment guidelines have incorporated new specific rules

for each of these genes. For example, heterozygous PMS2

variant carriers show a low cumulative CRC incidence,

suggesting that colonoscopy surveillance might be less

stringent for this group. In both Europe and the US, new

colonoscopy surveillance recommendations for MSH6 and

PMS2 variant carriers suggest an onset at an older age.

Similarly, association of urothelial cancer with MSH2

variants is making urologic screening recommendations

more gene specific.

The authors declare no conflict of interest. Walter Pavicic: walter.pavicic@hospitalitaliano.org.ar

Pavicic W. ORCID:0000-0001-7840-4943

REV ARGENT COLOPROCT | 2024 | VOL. 35, N

2 INVESTIGACIÓN TRASLACIONAL

COLORECTAL CANCER: DISORDERS OF DNA REPAIR MECHANISMS AND THEIR MEDICAL IMPLICATION. Soarez J, et al.

Importance of DNA repair mechanisms defects and

cancer treatment. Immune system.

A functional or dysfunctional DNA repair mechanism can

predict both the course of the disease and the effectiveness

of drugs in cancer treatment, that is, it can act as a prognos-

tic and predictive marker. Patients with colon cancer whose

MMR system is altered, either congenitally (Lynch syn-

drome) or because of somatic MLH1 gene methylation

(sporadic cancer), have a better prognosis compared to

patients whose cancers have a normal MMR mechanism.

There are several possible explanatory factors. One of the

most accepted is that inadequate DNA errors repairs leads to

a higher number of genetic alterations and consequently to

an increased quantity of abnormal peptides (neoantigens) in

the cell. The strong immune defense reaction derived from

this could be a possible explanation for the better prognosis.

Repair mechanism deficiency: Prognostic and predictive

value.

For several decades, it has been observed that tumors with

deficiencies in DNA repair mechanisms (unstable tumors)

are associated with a more favorable long-term prognosis.

Furthermore, these tumors tend to be relatively resistant to

5-fluorouracil. Recent results from adjuvant or neoadjuvant

immunotherapy are especially encouraging for these tumors.

In fact, checkpoint inhibitors have displayed promising

responses compared to traditional regimens in metastatic

unstable tumors. In locally advanced rectal cancer with PD-

1 blockers such as dostarlimab showed significant levels of

complete clinical response without including irradiation.

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