Field cancerization

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Longitudinally opened freshly resected colon segment showing a cancer and four polyps. Plus a schematic
diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of
cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the
tumors.

Field cancerization (also termed field change, field change cancerization, field
carcinogenesis, cancer field effect orpremalignant field defect) is a biological process in which
large areas of cells at a tissuesurface or within an organ are affected by acarcinogenic alteration(s).
The process arises from exposure to an injurious environment, often over a lengthy period.[1]

How field cancerization arises[edit]

The initial step in field cancerization is associated with various molecular lesions such as
acquired genetic mutations and epigeneticchanges, occurring over a widespread, multi-focal
"field".[2][3][4][5][6][7][8] These initial molecular changes may subsequently progress
tocytologically recognizable premalignant foci ofdysplasia, and eventually to carcinoma in situ(CIS)
or cancer.[1][5] The image of a longitudinally opened colon resection on this page shows an area of a
colon resection that likely has a field cancerization or field defect. It has one cancer and four
premalignant polyps.
Field cancerization can occur in any tissue.[1] Prominent examples of field cancerization include
premalignant field defects in head and neck cancer,[9] lung cancer,[2][3] colorectal cancer,[10]Barrett's
esophagus,[11][12][13] skin,[4][6][8] breast ducts[7][14] and bladder.[1][15] Field cancerization has implications for
cancer surveillance and treatment.[3][4][8][11][14][16] Despite adequate resection and
being histologically normal, the remaining locoregional tissue has an increased risk for developing
multiple independent cancers, either synchronously or metachronously.[1][9][17]

Common early carcinogenic alterations[edit]

A common carcinogenic alteration, found in many cancers and in their adjacent field defects from which
the cancers likely arose, is reduced expression of one or more DNA repair enzymes. Since reduced
DNA repair expression is often present in a field cancerization or a field defect, it is likely to have been
an early step in progression to the cancer.

FrequencyoffindingepigeneticreductionsinproteinexpressionofDNArepairgenesinsporadic
cancersandinadjacentfielddefects
Cancer

Gene

FrequencyinCancer

FrequencyinFieldDefect

Ref.

Colorectal

MGMT

46%

34%

[18]

Colorectal

MGMT

47%

11%

[19]

Colorectal

MGMT

70%

60%

[20]

Colorectal

MSH2

13%

5%

[19]

Colorectal

ERCC1

100%

40%

[21]

Colorectal

PMS2

88%

50%

[21]

FrequencyoffindingepigeneticreductionsinproteinexpressionofDNArepairgenesinsporadic
cancersandinadjacentfielddefects
Cancer

Gene

FrequencyinCancer

FrequencyinFieldDefect

Ref.

Colorectal

XPF

55%

40%

[21]

HeadandNeck

MGMT

54%

38%

[22]

HeadandNeck

MLH1

33%

25%

[23]

HeadandNeck

MLH1

31%

20%

[24]

Stomach

MGMT

88%

78%

[25]

Stomach

MLH1

73%

20%

[26]

Esophagus

MLH1

77%100%

23%79%

[27]

Field defects associated with gastrointestinal tract cancers also commonly displayed reduced apoptosis
competence, aberrant proliferation and genomic instability.[28] Field defects of the gastrointestinal tract
that show those common faults occurred in the oropharynx, esophagus, stomach, bile duct, pancreas,
small intestine and colon/rectum.

Pattern of alterations in a field defect[edit]

A colon cancer resection, 22 cm long, had 6 tissue samples evaluated for expression of 3 DNA repair proteins,
KU86, ERCC1 and PMS2. All 3 proteins are expressed at near 100% in colon tissue from a person without any
colonic neoplasia, but adjacent to a colon cancer, in this instance, there is a field of more than 20 cm in which
ERCC1 and PMS2 have reduced expression.

The field defect adjacent to a colon cancer consists of the inner surface of the colon (the epithelium)
that has about 1 million crypts (indentations in the surface of the epithelium).[21] Each crypt has about
5,000 cells in the shape of a test-tube and all 5,000 cells of the crypt are generated from the few stem
cells at the base of the crypt. The stem cells at the base of the crypt can undergo "crypt conversion"
where a stem cell with a selective advantage takes over the stem cell niche, and all cells of that crypt
display consistent expression (high or low) of a protein being evaluated.
The diagram shows results obtained by Facista et al.[21] A particular colon resection from a colon cancer
patient was evaluated for expression of 3 different DNA repair enzymes: KU86 (active in the nonhomologous end joining pathway), ERCC1 (active in the nucleotide excision DNA repair pathway) and
PMS2 (active in the mismatch DNA repair pathway). The percent of crypts in 6 tissue samples taken
within the field defect were evaluated for frequency of high levels of expression of each of the repair
proteins. Almost every crypt in all tissue samples from this patient showed high expression of KU86.
However, the majority of crypts in all 6 tissue samples were reduced or absent in protein expression of
ERCC1 and PMS2. The crypts with reduced or absent expression of ERCC1 or PMS2 usually occurred
in large patches of adjacent crypts. Both ERCC1 and PMS2, in these tissue samples, were thought to
be deficient due to epigenetic alterations.