Projects


Human Papillomavirus antibodies and risk of subsequent head and neck cancer

Dr. Tim Waterboer

© dkfz.de

Human papillomavirus type 16 (HPV16) infection is causally associated with a subset of oropharyngeal cancers (OPC), mainly tonsillar cancer. Similar to cervical cancer, antibodies to the E6 oncoprotein are strongly associated with HPV-driven OPC in patients after diagnosis. We currently investigate whether HPV antibodies are associated with OPC risk when measured prior to tumor diagnosis. Pre-diagnostic plasma samples from patients and controls enrolled in the EPIC (European Prospective Investigation into Cancer and Nutrition) cohort were analyzed for antibodies against multiple proteins of HPV16 and other HPV types, and Odds Ratios (ORs) and 95% Confidence Intervals (CI) were calculated, adjusting for potential confounders.
HPV16 E6 seropositivity was present in pre-diagnostic samples for 34.8% of patients with OPC and 0.6% of controls (OR 274, 95% CI 110 to 681). The increased risk of OPC among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis of OPC [1]. We are currently replicating these findings in other international cohort studies and investigate the potential of E6 antibody assays to serve as screening tools.

1. Kreimer AR, Johansson M, Waterboer T, Kaaks R, Chang-Claude J, Drogen D, Tjønneland A, Overvad K, Quirós JR, González CA, Sánchez MJ, Larrañaga N, Navarro C, Barricarte A, Travis RC, Khaw KT, Wareham N, Trichopoulou A, Lagiou P, Trichopoulos D, Peeters PH, Panico S, Masala G, Grioni S, Tumino R, Vineis P, Bueno-de-Mesquita HB, Laurell G, Hallmans G, Manjer J, Ekström J, Skeie G, Lund E, Weiderpass E, Ferrari P, Byrnes G, Romieu I, Riboli E, Hildesheim A, Boeing H, Pawlita M, Brennan P. Evaluation of human papillomavirus antibodies and risk of subsequent head and neck cancer. J Clin Oncol. 2013 Jul 20;31(21):2708-15.


Epidemiological evidence for associations of Helicobacter infections with gastrointestinal cancers

Dr. Angelika Michel

© dkfz.de

Introduction
Persistent Helicobacter pylori infection is causally associated with severe gastric disease including gastric cancer. Some reports suggest an association of entero-hepatic Helicobacter spp. infections with other gastrointestinal cancers, i.e. cancer of the bile system or the pancreas. Helicobacter infections lead to strong antibody responses to a large variety of bacterial proteins that can be exploited as diagnostic markers for infection and potentially also of Helicobacter-associated disease.
Objective and Methods
A high-throughput antibody profiling platform based on Luminex technology, H. pylori multiplex serology, has been developed and validated for antibodies to a large series of H. pylori proteins (UreA, GroEL, Catalase, NapA, CagA, CagM, Cagδ, HP0231, VacA, HpaA, Cad, HyuA, Omp, HcpC and HP0305) [1]. H. pylori multiplex serology has been applied in several case-control studies of gastrointestinal cancers and precursors and identified antibodies to several H. pylori proteins as prognostic markers.
Results
Using H. pylori multiplex serology, we have identified antibodies to HcpC and GroEL as new independent virulence factors that, in combination with the established markers anti-CagA and anti-VacA, were highly predictive of chronic atrophic gastritis risk [2]. We also found anti-CagA and anti-GroEL to be independent predictors of gastric cancer in a German case-control study [3]. Antibodies to all fifteen H. pylori proteins were associated with gastric cancer in a Swedish population-based cancer case-control study [4] and seropositivity to six proteins (Omp, HP305, HyuA, HpaA, CagA and VacA) may be a risk marker for distal gastric cancer in the high-incidence population of China [5]. Furthermore, individuals with high levels of antibodies to five specific H. pylori proteins, VacA, HP231, HP305, NapA, HcpC may be at higher risk of colon cancer [6].
Ongoing research interest is the evaluation of the diagnostic value of CagA and VacA serotypes, the disease associations of Helicobacter ssp. and the role of Epstein Barr Virus (EBV) infection as co-factor in gastric carcinogenesis.


1. Michel A, Waterboer T, Kist M, Pawlita M (2009) Helicobacter pylori multiplex serology. Helicobacter 14: 525-535.
2. Gao L, Weck MN, Michel A, Pawlita M, Brenner H (2009) Association between chronic atrophic gastritis and serum antibodies to 15 Helicobacter pylori proteins measured by multiplex serology. Cancer Res 69: 2973-2980.
3. Gao L, Michel A, Weck MN, Arndt V, Pawlita M, Brenner H (2009) Helicobacter pylori infection and gastric cancer risk: evaluation of 15 H. pylori proteins determined by novel multiplex serology. Cancer Res 69: 6164-6170.
4. Song H, Michel A, Nyren O, Ekstrom AM, Pawlita M, Ye W (2013) A CagA-independent cluster of antigens related to the risk of noncardia gastric cancer: Associations between Helicobacter pylori antibodies and gastric adenocarcinoma explored by multiplex serology. Int J Cancer Nov 20 [Epub ahead of print].
5. Epplein M, Zheng W, Xiang YB, Peek RM, Jr., Li H, Correa P, Gao J, Michel A, Pawlita M, Cai Q, Shu XO (2012) Prospective study of Helicobacter pylori biomarkers for gastric cancer risk among Chinese men. Cancer Epidemiol Biomarkers Prev 21: 2185-2192.
6. Epplein M, Pawlita M, Michel A, Peek RM Jr, Cai Q, Blot WJ (2013) Helicobacter pylori protein-specific antibodies and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 22:1964-74.


HPV detection in oesophageal cancer – Finding the “needle in the haystack” by a combination of serological screening and molecular diagnostics

Dr. Tim Waterboer

© dkfz.de

It is highly controversial whether high-risk HPV types (mostly HPV type 16) cause esophageal squamous cell carcinoma (ESCC). In epidemiological studies, mostly weak (or no) associations between HPV antibodies and ESCC are found, probably because HPV-associated tumorigenesis is a rare event in the esophagus. This is why evidence for a causal role of HPV can only be provided by molecular diagnostics, demonstrating presence and active replication of HPV by detection of viral DNA, RNA, and typical immunohistochemistry patterns (p16 up-regulation, pRb down-regulation) in cancer tissue. However, these analyses are time-consuming and expensive, and cannot be economically applied to hundreds or thousands of tissue samples. Therefore, we test patients’ sera for antibodies to early HPV proteins as “screening tool”. Serologically interesting antibody patterns are used to identify promising cases, allowing us to analyze a much smaller number of tumor tissue samples in order to find the “needle in the haystack” [1].

1. Sitas F, Egger S, Urban MI, Taylor PR, Abnet CC, Boffetta P, O'Connell DL, Whiteman DC, Brennan P, Malekzadeh R, Pawlita M, Dawsey SM, Waterboer T; InterSCOPE Collaboration. InterSCOPE study: Associations between esophageal squamous cell carcinoma and human papillomavirus serological markers. J Natl Cancer Inst. 2012 Jan 18;104(2):147-58.

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