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Molecular Oncology, Markers, Clinical Correlates |
Department of Pathology, Mayne Medical School, University of Queensland, Herston, Queensland 4006, Australia [A-E. B-H., M. D. W., J. R. J.]; Mater Medical Research Institute, Mater Misericordiae Hospital, South Brisbane, Queensland 4101, Australia [M. A. M.]; and Conjoint Gastroenterology Laboratory, Royal Brisbane Hospital, Herston QLD 4029, Australia [L. A. S., J. Y., B. A. L.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A second genetic pathway is driven by a defect in DNA repair caused by the inactivation of DNA mismatch repair genes. This has been described as the "mutator" pathway because of the widespread accumulation of mutations in repetitive genomic sequences (2 , 5 , 6) . Tumor suppressor genes are also targets in this pathway, but the repertoire is at least in part determined by the preferred selection of genes possessing short repetitive tracts within their coding sequences. In this regard TGFßRII (7) and bAX (8) might be viewed as substitutes for aPC and TP53. DNA MSI3 is an important biomarker for the mutator pathway, which applies to about 10% of sporadic colorectal cancers (9, 10, 11) as well as to cancers complicating the autosomal dominant condition HNPCC (12) .
The adenoma-carcinoma sequence is generally thought to apply in both the suppressor and mutator pathways. MSI-H in HNPCC adenomas is well documented (13, 14, 15, 16) but is rarely reported in sporadic adenomas. One study found no MSI in sporadic adenomas (16) , but the same authors subsequently reported MSI-L in 3 of 49 sporadic adenomas but no MSI-H (17) . Others described MSI-L in 7 of 70 sporadic adenomas, but none was MSI-H (18) . A single report documenting MSI in 20 of 73 proximal adenomas was not stringent either in excluding HNPCC or in distinguishing MSI-L and MSI-H (19) .
It has been suggested that a subset of colorectal cancers may develop through a different route of morphogenesis. In 1990, Longacre and Fenoglio-Preiser (20) characterized a variant of conventional adenoma distinguished by a serrated architecture similar to the HP. They also showed that 37% of serrated adenomas contained foci of high-grade dysplasia, and that carcinoma-in situ occurred in 10% of serrated adenomas. This pathway might, therefore, follow a relatively rapid course. In showing clonal relationships between the hyperplastic and dysplastic components of mixed polyps, the concept of a serrated pathway has been broadened to include HPs, mixed polyps, and serrated adenomas as a continuum (21) . The same study demonstrated a high frequency of MSI in dysplastic epithelium within either mixed polyps or serrated adenomas; 14 (48%) of 29 showed MSI-L and 5 (17%) of 29 were MSI-H (21) .
Mucins are a diverse family of high-molecular-weight glycoproteins that are widely expressed by epithelial tissues and characterized by the presence of tandem repeat sequences rich in serine and threonine residues that are highly O-glycosylated (22) . Mucins can be classified as either membrane-associated or secretory glycoproteins. MUC1 and MUC4 encode transmembrane mucins that are expressed within the intestinal tract. MUC1 is highly expressed in carcinomas and has been implicated in colonic tumor progression and metastasis (23 , 24) . MUC1 has been shown to modulate cell adhesion (25 , 26) and is involved in signal transduction (27) . MUC4 contains two extracellular epidermal growth factor-like domains that may interact with members of the c-erb family of growth factor receptors and, thereby, modulate growth control (28 , 29) . The genes encoding MUC2, MUC5AC, MUC5B, and MUC6, all of which are gel-forming secretory mucins, are clustered on 11p15 (30) . These mucins are produced and secreted by goblet cells and are the major constituents of mucus, which acts to lubricate and protect epithelial tissues (31) .
To date, the expression of mucins has not been studied in colorectal cancers stratified by microsatellite status. The relevance of such a study is 2-fold: (a) with regard to the possible histogenesis of MSI-H cancer through a pathway of serrated neoplasia, we have previously shown (32) that serrated epithelial polyps are characterized by increased expression of intestinal mucin MUC2, inappropriate expression of gastric mucin MUC5AC, and reduced expression of MUC4; and (b) MSI-H cancers are distinguished from MSS/MSI-L cancers by a number of clinicopathological features. These include reduced aggressiveness and overrepresentation of mucinous cancer (33, 34, 35, 36) . It is possible that some of these features are related to differences in mucin expression. In particular, the overrepresentation of mucinous cancers among MSI-H colorectal cancers may be explained by an origin from serrated polyps that show up-regulation of secretory mucins MUC2 and MUC5AC (32) .
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Monoclonal Antibodies.
Monoclonal antibodies used were BC2 (1.5
µg·ml-1) against MUC1 (39)
, 4F1
(4 µg·ml-1) against MUC2 (40)
,
M4.275 (5 µg·ml-1) against MUC4
(41)
, and M1 (2 µg·ml-1)
against MUC5AC (Neomarkers, Fremont, CA; Ref. 42
). BC2,
4F1, and M4.275 were generated using synthetic peptide sequences
derived from the respective apomucin amino acid tandem repeat regions,
and M1 was raised against human gastric mucin and subsequently was
shown to recognize a COOH-terminal sequence of the MUC5AC core protein
(43)
.
Immunohistochemistry.
The specimens were fixed for 4–16 h in 10% neutral buffered formalin
and then routinely were paraffin-embedded. Histologically normal mucosa
from the margins of the specimens served as control tissue.
Serial sections were stained immunohistochemically as described previously (32) . Paraffin sections (3–4 µm) were affixed to Superfrost Plus adhesive slides (Menzel-Gläser, Braunschweig, Germany) and were air-dried overnight at 37°C. Sections were dewaxed in xylol and rehydrated through descending graded alcohols to TBS [0.05 M Tris and 0.15 M NaCl (pH 7.2–7.4)]. Sections were incubated in 1% periodic acid in distilled H2O for 30 min (MUC1) or in 0.1% porcine trypsin (ICN Biomedicals Australasia, Sydney, Australia) with 0.1% CaCl2 in PBS for 30 min (MUC2), or transferred to 0.01 M citric acid buffer (pH 6) and boiled twice for 5 min each and then transferred to TBS (MUC4, MUC5AC; Ref. 44 ).
The sections were then incubated in 1.0% H2O2 and 0.1% NaN3 in TBS for 10 min to block endogenous peroxidase activity and then were washed in three changes of TBS for 5 min each. Nonspecific antibody-binding was inhibited by incubating the sections in 4% skim milk powder in TBS for 15 min, followed by a brief wash in TBS. The sections were then placed in a humidified chamber and incubated with 10% normal (nonimmune) goat serum (Zymed Corp., San Francisco, CA) for 20 min. Excess normal serum was decanted from the sections, and the primary antibody was applied overnight at room temperature except for BC2 (MUC1), which was applied for 60 min.
Sections were washed in three changes of TBS for 5 min each—the first buffer change contained 0.5% v/v Triton X-100—and then were incubated with biotinylated goat-antimouse immunoglobulins (Zymed) for 30 min. Sections were washed again in three changes of TBS for 5 min each (the first wash contained 0.1% v/v Triton X-100), were incubated with streptavidin-horseradish peroxidase conjugate (Zymed) for 15 min, and were washed in three changes of TBS for 5 min each. Color was developed in 3,3'-diaminobenzidine (Sigma Chemical Company, St. Louis, MO) with H2O2 as substrate for 5 min; then sections were washed in running tap water, lightly counterstained in Mayer‘s hematoxylin, dehydrated through ascending graded alcohols, cleared in xylol, and mounted using DePeX (BDH Gurr, Poole, United Kingdom).
As negative controls, serial sections were stained as above but
incubated either with TBS alone (i.e., with omission of the
primary antibody) or with a nonspecific monoclonal antibody, 401.21,
which is the same immunoglobulin isotype as BC2 and M4.275, and which
is directed against 
-gliadin from wheat gluten
(45)
.
Sections were scored by two independent observers (A-E. B-H., J.R.J.) with conflicts resolved using a conference microscope. The proportion of positive cancer cell staining was graded as follows: (a) 0 (= negative); (b) <10% (1+); (c) 11–25% (2+).; (d) 26–50% (3+); (e) 51–75% (4+); and (f) >75% (5+). The staining intensity of cancer cells was graded as weak (1+), moderate (2+), or strong (3+). The localization was classified as either cytoplasmic or cell membrane. Scoring results for intensity and proportion positive were combined by multiplication for each mucin core protein into a summary score. Summary scores were then classified as either high or low staining after consideration of the distribution within each summary score variable, to allow statistical comparison with other variables.
DNA Replication Error Assays.
The specimens were derived from a set of sporadic cancers characterized
previously for microsatellite status (35
, 46)
. Six
additional cancers that were obtained from the single subject with
hyperplastic poly-posis were also characterized. Briefly, DNA was
extracted from fresh cancer tissue samples for all of the cases except
for the tissue from the tumors from the subject with hyperplastic
polyposis, which were formalin-fixed and paraffin-embedded. DNA was
also extracted from matching germ-line control samples derived from
either normal colonic mucosa or peripheral blood lymphocytes. The DNA
samples were amplified using PCR at the following loci:
MYCL, aT3, d2S123, F13B
(47)
, bAT-26 and bAT-40
(48)
. The PCR reactions were performed in a final volume
of 20 µl, containing 100 ng of genomic DNA, 20 pmol of each
oligonucleotide primer, 1.25 µM dATP, 10
µM dCTP, dTTP, and dGTP, 6 µCi
[-35S]dATP, and 1 unit Taq polymerase
(Boehringer Mannheim, Mannheim, Germany). Reaction conditions consisted
of 3 min at 92°C, followed by 31 cycles (45 s at 94°C, 1.5 min at
55°C, 1.5 min at 72°C) followed by a final extension for 5 min at
72°C. The PCR products were electrophoresed on denaturing 5%
polyacrylamide (19:1) gels and visualized by autoradiography. Cancers
were classified as MSI-H if bandshifts occurred in at least 40% of
loci (11)
.
Data Analysis.
The 
2 test was used to test for significant
associations between variables.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The MUC2 precursor
detected by the monoclonal antibody 4F1 was expressed focally in
the perinuclear cytoplasm of normal goblet cells. In cancers, MUC2 was
present in the cytoplasm of cells assumed to be of goblet cell lineage
(Fig. 1B)
. In normal mucosa, MUC4 staining was seen in the
cytoplasm of both goblet and columnar cells. Similar but reduced
expression was observed within the cancers (Fig. 1C)
. In the
normal cells, focal expression of MUC5AC was seen in the
cytoplasm and mucous droplets of goblet cells in a minor proportion of
crypts. MUC5AC staining was similar to that of MUC2 in cancers,
although it was more often restricted to cells with an obvious
goblet-cell theca (Fig. 1D)
.
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). Similarly, there was no
significant association between MUC4 expression and these features with
the exception of tumor stage, in which there was high expression of
MUC4 in 11 (79%) of 14 stage I tumors compared with only 22 (28%) of
78 higher-stage lesions (P = 0.003).
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Combined MUC2+/MUC4-/MUC5AC+ Phenotype and Modified MUC2+/MUC5AC+
Phenotype.
The mucinous phenotype with high expression of MUC2 and MUC5AC and low
expression of MUC4 was seen in 5 (7%) of 74 adenocarcinomas and 8
(42%) of 19 mucinous cancers. There was no statistically significant
correlation between age, sex, stage, or site and expression of this
phenotype. There was a significant association between this mucinous
phenotype and poorly differentiated cancer (P = 0.02),
mucinous tumor type (P < 0.0001), and the MSI-H
phenotype (P = 0.0024). Because loss of MUC4 was not
associated with MSI-H status, associations with the modified mucinous
phenotype MUC2+/MUC5AC+ were determined. This occurred in 15 (68%) of
22 MSI-H cancers, 3 (13%) of 24 MSI-L, and 7 (15%) of 47 MSS cancers
(P < 0.0001). There were significant associations
between the modified mucinous phenotype MUC2+/MUC5AC+ and grade
(P = 0.02), type (P < 0.0001) and
MSI-H status (P < 0.0001). There was also a trend
(P = 0.053) between expression of the MUC2+/MUCSAC+
phenotype and tumor site. Of the MSI-H cancers with a mucinous
phenotype, 10 of 10 showed high MUC2 staining compared with 9 of 12
MSI-H nonmucinous cancers; 9 of 10 showed high MUC5AC reactivity as
opposed to 8 of 12 nonmucinous tumors; and 9 of 10 showed high MUC2 and
MUC5AC reactivity as opposed to only 6 of 12 nonmucinous tumors.
Hyperplastic Polyposis.
Among the six cancers from the subject with HPs, one was MSS, one was
MSI-L, and four were MSI-H. Three of the MSI-H cancers showed the
MUC2+/MUC5AC+ phenotype. The fourth was positive for MUC5AC but lost
MUC2 expression. Neither of the non-MSI-H cancers lost MUC4 or
expressed MUC5AC, but both retained MUC2.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. These
observations indicate a switch toward the mucous cell lineage within
MSI-H cancers.
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Although the mucinous phenotype MUC2+/MUC4-/MUC5AC+ was associated with
MSI-H cancers, the effect is explained by the changes in MUC2 and
MUC5AC rather than MUC4. The association of the modified phenotype
(MUC2+/MUC5AC+) with poor differentiation (Table 1)
fits with the known
tendency for MSI-H cancers to be poorly differentiated
(33, 34, 35, 36)
. Ten (45%) of 22 MSI-H cancers were poorly
differentiated in this study, and 8 (80%) of 10 showed the
MUC2+/MUC5AC+ phenotype. The modified phenotype MUC2+/MUC5AC+ was also
highly correlated with typing as mucinous carcinoma. Twelve (63%) of
19 mucinous cancers showed this phenotype, which was seen in only 13
(18%) of 74 adenocarcinomas (P < 0.0001). This fits
with the overrepresentation of mucinous cancer among the MSI-H subset
(33, 34, 35, 36)
. There was a tendency for MUC2+, MUC5AC+, and
MUC2+/MUC5AC+ cancers to be proximal, although this reached statistical
significance only for MUC2 (Table 1)
. Again, this fits with the
predilection by MSI-H cancers for the proximal colon. The mechanism for
up-regulation of the mucinous phenotype in MSI-H cancers is unknown.
One possibility could be abrogation of the TGF-ß signaling pathway
resulting in an uncontrolled autocrine effect. TGF-ß is known to
down-regulate colonocyte differentiation, whereas goblet cells are
resistant to the effects of TGF-ß (49)
. Hakomori
(50)
described significant perturbations in
O-glycosylation of tumor-associated mucins, predominantly in
the form of carbohydrate chain truncation and aberrant sialation or
fucosylation. The core protein epitopes that are recognized by many
antimucin antibodies, including those used in this study, are
potentially masked by glycosylation. It is conceivable that the
increased immunoreactivity in tumors is attributable, at least in part,
to the exposure of core protein that is available for antibody binding
without necessarily having increased protein synthesis. However,
there is no evidence to date that posttranslational modifications
differ in colorectal cancers according to microsatellite status. It is
more likely that the differences in the detection of core protein
relate to actual mucin expression changes associated with secretory
lineage differentiation (32)
.
In this study, the finding that the mucinous phenotype MUC2+/MUC5AC+ is seen in 15 (68%) of 22 MSI-H cancers but only 10 (14%) of 71 of the MSS/MSI-L cancers (P < 0.0001) is unexpected insofar as it associates the mucinous phenotype of serrated adenomas with MSI-H colorectal cancer (32) . Nevertheless, the data fit with our earlier observations in a series of sporadic serrated polyps in which 5 (17%) of 29 dysplastic samples from mixed hyperplastic/adenomatous polyps or serrated adenomas were MSI-H (21) .
It could be argued that sporadic MSI-H cancers do arise from conventional adenomas as is the case in HNPCC adenomas (13, 14, 15 , 51) . This would be feasible if MSI-H were acquired at the point of transition from adenoma to carcinoma (analogous to TP53 in MSS cancers). However, this is not supported by molecular data. The tumor suppressor gene aPC plays a critical role in the initiation of colorectal adenoma. MSI-H cancers would, therefore, be expected to show aPC alterations if the adenoma-carcinoma sequence applied. Yet, an extremely low rate of aPC mutation has been reported in MSI-H cancers (52 , 53) , even after full-length sequencing of APC derived from MSI-H colorectal cell lines (54) . Two studies failed to show a single example of 5q loss of heterozygosity in a total of 29 MSI-H colorectal cancers (46 , 52) . Furthermore, aberrant (nuclear) immunolocalization of ß-catenin is rarely observed in MSI-H cancers, which suggests that the entire WNT signaling pathway is intact (46) . A higher frequency of aPC mutation in MSI cancers (although still significantly lower then in MSS cancers) has been reported (55) . However, 19 of the 52 cancers with DNA replication errors were from subjects with HNPCC and 6 of 9 DNA markers used in this study were for dinucleotide repeats, which may show instability in MSI-L cancers.
We suggested previously that MSI-L colorectal cancer might arise through neoplastic transformation of a HP (21) . It now seems likely that some, if not all, MSI-H cancers arise through a similar morphogenetic pathway. This would explain the infrequency of both sporadic MSI-H adenomas and aPC alterations in MSI-H cancers. The mechanism could be through transformation of a HP or a serrated adenoma arising de novo. We do not believe that all of the colorectal cancers arising through the serrated pathway would be MSI-H. Although we have observed MSI-H cancers arising in association with hyperplastic polyposis (56) , MSS and MSI-L cancers occur in the same condition (57) . Similar findings were seen in the subject with multiple colorectal cancers and hyperplastic polyposis described in this study. However, it seems probable that many, if not all, MSI-H cancers do arise through the alternative serrated pathway. Given the numerous clinical, pathological, and molecular differences between MSI-positive and MSI-negative cancers that have now been demonstrated, it would perhaps be surprising if differences in early morphogenesis did not exist also.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by a grant from the Queensland
Cancer Fund and NIH Grant 1-UO1 CA74778 (Collaborative Family Registry
for Colorectal Cancer Studies). 
2 To whom requests for reprints should be
addressed, at Department of Pathology, Mayne Medical School, Herston,
QLD 4006, Australia. Phone: 61-7-3365-5340; Fax: 61-7-3365-5511;
E-mail: j.jass{at}mailbox.uq.edu.au
3 The abbreviations used are: MSI, microsatellite
instability; HNPCC, hereditary nonpolyposis colorectal cancer; MSI-H,
high-level MSI; MSI-L, low-level MSI; MSS, stable MSI; HP, hyperplastic
polyp; TBS, Tris-buffered saline; TGF, transforming growth factor.
Received 12/14/99; revised 2/10/00; accepted 2/16/00.
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