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Single-Nucleotide Polymorphisms and Cancer Risk, Tumor Recurrence, or Survival of Head and Neck Cancer Patients
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hospital, Sweden.
University of Uppsala Hospital, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hospital, Sweden.
Ryhov Hospital, Sweden.
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2017 (English)In: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, Vol. 92, no 3, p. 161-169Article in journal (Refereed) Published
Abstract [en]

Objective: This paper aims at studying the influence of single-nucleotide polymorphisms (SNPs) on cancer risk, tumor recurrence, and survival in head and neck (Hamp;N) cancer patients. Methods: A total of 45 SNPs in 41 genes were investigated. A total of 174 Caucasian Hamp;N cancer patients and 245 healthy blood donors were enrolled in the study. Results: Ten SNPs were associated with Hamp;N cancer risk, but the identified SNPs differed among males and females. Some of the SNPs were related to immune response genes. The immune response gene SNPs were also related to survival. In particular, we noted that the tumor necrosis factor alpha (TNF alpha) rs1800629 could have an influence on cancer risk; tumor recurrence as well as survival. Conclusion: Genetic variation of the TNFa rs1800629 might be useful as a biomarker in clinical decision-making since it was found to be related to cancer risk, tumor recurrence, and survival of Hamp;N cancer patients. (C) 2016 S. Karger AG, Basel

Place, publisher, year, edition, pages
KARGER , 2017. Vol. 92, no 3, p. 161-169
Keywords [en]
Head and neck cancer; Tumor recurrence; Survival time; Single-nucleotide polymorphisms
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-136217DOI: 10.1159/000452278ISI: 000395366800005PubMedID: 27997918OAI: oai:DiVA.org:liu-136217DiVA, id: diva2:1086261
Note

Funding Agencies|Jonkoping Clinical Cancer Research Foundation; Futurum; FORSS; Swedish Laryngeal Foundation

Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2019-11-19
In thesis
1. Circulating Biomarkers in Patients with Head and Neck Cancer and the Influence of Cigarette Smoking
Open this publication in new window or tab >>Circulating Biomarkers in Patients with Head and Neck Cancer and the Influence of Cigarette Smoking
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck cancer (HNC) is a collective name for heterogeneous tumors located in the head and neck regions for which smoking, alcohol and human papillomavirus (HPV) are documented risk factors. The survival of HNC patients has only improved marginally during the last decade. The most important prognostic factors are tumor size, local spread and distant metastases, tumor node metastasis (TNM) staging. Prognostic biomarkers are needed as a complement to TNM staging.

The aim for this thesis was to investigate rapid and low cost blood based biomarkers which could indicate the risk of HNC, recurrence of the disease or the survival of HNC patients. Furthermore, the aim was to examine how cigarette smoking influences the levels of biomarkers.

In paper I, a possible role of plasma cytokines or proteins associated with immune response or inflammation, as biomarkers for the survival of HNC patients was investigated. Higher levels of C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) were detected in plasma of the patients compared with the levels in the controls. The elevated levels of these two biomarkers detected in patients were associated with decreased survival.

In paper II, the influence of 45 single nucleotide polymorphisms (SNPs) located in 41 genes associated with cell cycle progression, cell death, DNA repair or immune response on cancer risk, tumor recurrence and survival in HNC patients were investigated. SNPs in immune response genes were associated with risk for HNC, an elevated risk for recurrence and a decreased survival in HNC patients.

In paper III, the influence of cigarette smoking on levels of inflammatory cells, proteins or cytokines/chemokines, microRNAs (miRNAs) and SNPs was analysed in healthy smokers and non-smokers. Higher levels of total white blood cells (WBCs), neutrophils, monocytes, lymphocytes, neutrophil to lymphocyte ratio (NLR), CRP, monocyte chemoattractant protein- 1 (MCP-1) and interferon gamma (IFN-γ) were detected in smokers compared to non-smokers and indicate an inflammatory response. Also, a lower level of oncomiRNA miR-21was detected in smokers. This alteration, in combination with the elevated levels of IFN-γ in smokers could be a protective response to cigarette smoke. The higher levels of IFN-γ in smokers compared to non-smokers were however only detected in individuals with SNP rs2069705 genotype AG/GG. This indicates a genetic association of the levels of IFN-γ.

In paper IV, the separate effects of cigarette smoking and HNC on inflammatory or immune biomarkers and the impact of high risk human papillomavirus, age and gender were investigated. Comparisons of circulating levels of WBCs and its subpopulations, plasma proteins or cytokines/chemokines between smoking and non-smoking patients, smoking and non-smoking controls and between the patient and control groups were analysed. Smoking had highest impact on elevated levels of WBCs, IFN-γ and MCP-1, and HNC had highest impact on elevated levels of neutrophils, monocytes, NLR, CRP, macrophage inflammatory protein 1 beta and TNF-α.

In conclusion, host immune response associated parameters could be suitable as biomarkers for the risk of HNC, risk of recurrence or in predicting survival of HNC patients. This thesis show that HNC are associated with systemic inflammatory response and upregulated CRP and TNF-α is related to shorter survival in HNC patients. Additionally, SNPs in immune response genes such as rs1800629 in the TNF-α gene indicates a risk for HNC or an elevated risk for recurrence and a decreased survival in HNC patients. These rapid and low cost blood based biomarkers could be used in combination or as a supplement to established biomarkers in the clinic for a more personalized treatment modality.

Abstract [sv]

Huvud- och halscancer (HH-cancer) innefattar tumörer belägna i huvud och halsområdet. Tobaksrökning ökar risken dramatiskt för olika sjukdomar. Knappt hälften av rökande patienter dör i de av rökning orsakade sjukdomarna. Cancer är orsaken till en tredjedel av de rökrelaterade dödsfallen av vilka HH-cancer är en. En andel av patienterna med HH-cancer dör på grund av att tumören varit för stor redan vid diagnos eller att tumören har spridit sig till övriga delar av kroppen. Men för många patienter är det mycket oklart vad som bestämmer behandlingsresultatet. Tumörerna är till synes lika och behandlingen standardiserad.

Målet med denna doktorsavhandling var att undersöka billiga och lättillgängliga biologiska markörer som kan indikera risk för att drabbas av HH-cancer eller om dessa markörer kan förutspå behandlingsresultat och överlevnad hos de drabbade patienterna. Dessutom undersöktes hur cigarettrökning påverkade nivåerna av markörerna.

I studie I, undersöktes om molekyler i blodet (biomarkörer), förknippade med immunförsvaret, kunde förutsäga överlevnaden hos HH-cancerpatienter. I jämförelse med friska individer sågs högre nivåer av molekylerna TNF-α och CRP hos patienterna och dessa förhöjningar var relaterade till förkortad överlevnad hos patienterna.

I studie II, var målet att undersöka om variationer i gener, förknippade med immunförsvaret, celldelning, celldöd eller enzymer som reparerar skadat DNA, kunde påverka risk och prognos för HH-cancer. Resultatet visade framför allt att små ärftliga variationer i gener som reglerar immunförsvaret kunde påverkade risk för HH-cancer, risk för återfall i sjukdomen samt överlevnaden hos patienterna.

I studie III, jämfördes inflammatoriska och immunförknippade biomarkörer som kunde påverkas av cigarettrökning mellan friska rökare och friska icke-rökare. Rökarna hade en högre inflammatorisk aktivitet med högre nivåer av totalt antal vita blodkroppar och tre av dess olika undergrupper (neutrofiler, monocyter och lymfocyter) samt av biomarköerna CRP, MCP-1 och IFN-γ. De funna lägre nivåerna av den cancerförknippade biomarkören miR-21 och högre nivåer av den förmodat skyddande biomarkören IFN-γ hos rökarna, kan vara ett uttryck för kroppens försvar mot den cancerframkallade cigarettröken. Ärftliga faktorer tycks kunna påverka de högre nivåerna av IFN-γ hos rökarna, eftersom ökningen endast fanns i en grupp individer med viss typ av genetisk uppsättning.

Eftersom både rökning och HH-cancer ger upphov till inflammation, undersöktes i studie IV hur dessa var för sig påverkade nivåerna av inflammatoriska biomarkörer. Detta för en bättre förståelse hur immunförsvaret reagerar på rökning och HH-cancer. Jämförelser av inflammatoriska markörer från rökande och icke-rökande patienter, och rökande och ickerökande friska individer genomfördes. Rökning hade störst påverkan på de högre nivåerna av totalt antal vita blodkroppar och signalmolekylerna MCP-1 och IFN-γ. HH-cancer hade störst påverkan på högre nivåerna av neutrofiler, monocyter, kvoten mellan neutrofiler och lymfocyter, CRP, MIP-1b och TNF-α.

Uppkomsten av HH-cancer, behandlingsresultat och överlevnad bland patienterna kan antas inte bara bero på tumörens egenskaper, utan även på värdfaktorer hos patienten. Dessa kan vara ärftliga, eller bero på reglering av gener eller tumörens omgivning av t.ex. immunceller och inflammatoriska molekyler och hur dessa samverkar med miljöfaktorer som tobaksrökning. I denna avhandling presenteras biomarkörer som kan bidra med information om risk och prognos för HH-cancer samt hur tobaksrökning påverkar dessa markörer.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. p. 59
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1719
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-162097 (URN)10.3384/diss.diva-162097 (DOI)9789179299538 (ISBN)
Public defence
2019-12-13, Originalet, Qulturum, Länssjukhuset Ryhov, Jönköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2019-11-19 Created: 2019-11-19 Last updated: 2024-02-21Bibliographically approved

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