Screening for cancer: are biomarkers of value?

– February/March 2011 12 Tumour markers
spectrometry approach, we observed that
associated antigen responses were diagnostic
for both CRC and polyp patients
[25,26]. The presence of serum IgG against
ribosomal protein (Rp) L7/L12 was monitored
in two independent sample collections
using an ELISA-based approach.
This demonstrated that anti-RpL7/
L12 response was most pronounced in
patients with early stage CRC and significantly
different from that of healthy control
subjects [27]. A drawback of the use
of this antigen is its conservation in bacteria.
Consequently, the cross reactivity of
this assay results in a large overlap in anti-
RpL7/L12 titres between CRC cases and
controls. The specificity for CRC was only
57% at a sensitivity of 75%. Accordingly,
current activities include the identification
of alternative S. gallolyticus antigens that
are more specific for this bacterial species.
We anticipate that a broader approach will
yield more accurate assays that may be
applied on the individual level. This view
is corroborated by a recent study showing
that an ELISA-based assay using a mixture
of surface proteins from S. gallolyticus as
potential antigens yielded a similar sensitivity
of 73%, but an improved specificity
of 83% [28]. The identification of diagnostic
antigens from other intestinal bacteria
is also in progress. These include antigens
from species such as S. gallolyticus, which
take advantage of a pre-malignant lesion
to invade the human body and thereby
cause an antigen response, but antigens
will also be sought from pathogenic bacteria
that have been implicated in CRC
initiation as discussed previously [Figure 1].
FIigure 2. Hybrid antigen panels for the early
diagnosis of CRC.
Hybrid multimarker assays
for CRC
From a genetic perspective, CRC is a highly
heterogeneous disease [29,30], which
makes accurate diagnosis based on a single
biomarker unlikely at the population level.
On the contrary, multimarker assays are
likely to provide diagnostic platforms that
can be used to screen populations for CRC
and select high-risk individuals or individuals
with early stage disease for follow up.
As illustrated in Figure 1, certain mucosaassociated
bacteria may be involved in
CRC initiation. Invasiveness of these pathogens
or exposure to their antigens may
elicit an IgG response that is valuable for
CRC risk assessment in individuals. These
individuals may not need a bowel examination
immediately, but can be enrolled in a
more strict monitoring programme. When
an IgG response is detected against bacterial
antigens that use polyps or tumours as
a portal of infection, this may be an important
sign of early stage disease, especially
when IgGs against tumour antigens are also
detected in the same subject [Figure 2]. It
may be envisaged that immune responses
against bacterial antigens decrease upon
disease progression [27], whereas assays
based purely on tumour antigens may
leave early disease stages undetected.
Thus a hybrid approach combines indirect
bacterial markers that are associated
with CRC risk and early stage disease with
tumour markers that are diagnostic for the
disease itself.
Conclusions
Hybrid antigen panels provide a promising
new concept for CRC screening. However,
much still needs to be learned about bacterial
interference in CRC. It goes without
saying that, when established, hybrid antigen
panels would need a thorough clinical
validation phase before decision algorithms
based on these antigen panels can
be developed.
Acknowledgements
The author would like to thank Annemarie Boleij,
Rian Roelofs, Bas Dutilh, Wilbert Peters, Julian
Marchesi and Ikuko Kato for inspiring discussions.
The financial support from the Dutch Cancer Society
(project KUN-2006-3591) and the Dutch Digestive
Diseases Foundation (project WO10-53) for
our work on innovative CRC diagnostics is warmly
acknowledged.
References
1. Jass JR, Morson BC. J Clin Pathol 1987; 40:
1016-1023.
2. Booth RA. Cancer Letters 2007; 249: 87-96.
3. Simon J. N Engl J Med 1998; 338: 1151-1152.
4. Tjalsma H. Exp Rev Proteomics 2010; 7: 879-895.
5. Reuschenbach M, Kloor M, Morak M et al.
Familial Cancer 2010; 9: 173-179.
6. Tjalsma H, Schaeps RMJ, Swinkels DW. Proteomics
Clin Appl 2008; 2: 167-180.
7. Vignali DA. J Immunol Methods 2000; 243:
243-255.
8. He YJ, Mou ZR, Li WL et al. Int J of Colorecta Dis
2009; 24: 1271-1279.
9. Ran YL, Hu H, Zhou Z et al. Clin Cancer Res 2008;
14: 2696-2700.
10. Babel I, Barderas R, Diaz-Uriarte R et al. Mol Cell
Proteomics 2009; 8: 2382-2395.
11. Silk AW, Schoen RE, Potter DM et al. Mol Immunol
2009; 47: 52-56.
12. Dethlefsen L, Eckburg PB, Bik EM et al. Trends
Ecol Evol 2006; 21: 517-523.
13. Qin JJ, Li RQ, Raes J et al. Nature 2010; 464:
59-U70.
14. Green GL, Brostoff J, Hudspith B et al. J Appl
Microbiol 2006; 100: 460-469.
15. Costello EK, Lauber CL, Hamady M et al. Science
2009; 326: 1694-1697.
16. Toprak NU, Yagci A, Gulluoglu BM et al. Clin
Microbiol Infect 2006; 12: 782-786.
17. Wang XM, Allen TD, May RJ et al. Cancer Res
2008; 68: 9909-9917.
18. Wu SG, Rhee KJ, Albesiano E et al. Nature Medicine
2009; 15: 1016-U1064.
19. Cuevas-Ramos G, Petit CR, Marcq I et al. Proc
Natl Acad Sci USA 2010; 107: 11537-11542.
20. Lee SH, Hu LL, Gonzalez-Navajas J et al. Nature
Medicine 2010; 16: 665-U665.
21. Hausen HZ. Int J Cancer 2006; 119: XI-XII.
22. Boleij A, Schaeps RMJ, Tjalsma H. J Clin Microbiol
2009; 47: 516-516.
23. Boleij A, Muytjens C, Bukhari S et al. J Infect Dis
2011; in press.
24. Wentling GK, Metzger PP, Dozois EJ et al. Dis
Colon Rectum 2006; 49: 1223-1227.
25. Tjalsma H, Scholler-Guinard M, Lasonder E et al.
Int J Cancer 2006; 119: 2127-2135.
26. Tjalsma H, Lasonder E, Scholler-Guinard M et al.
Proteomics Clin Appl 2007; 1: 429-434.
27. Boleij A, Roelofs R, Schaeps RM et al. Cancer
2010;116: 4014-4022.
28. Abdulamir AS, Hafidh RR, Mahdi LK et al. BMC
Cancer 2009;
29. Kaiser J. Science 2006; 313: 1370-1370.
30. Sjoblom T, Jones S, Wood LD et al. Science 2006;
314: 268-274.
The author
Dr Harold Tjalsma
Department of Laboratory Medicine (830),
Nijmegen Institute for Infection, Inflammation
and Immunity (N4i) & Radboud University
Centre for Oncology (RUCO) of the Radboud
University Nijmegen Medical Centre.
P.O. Box 9101, 6500 HB Nijmegen
The Netherlands
Tel. +31-24-3618947
e-mail: h.tjalsma@labgk.umcn.nl