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LRIG1‑2 and LMO7 immunoreactivity in vulvar squamous cell carcinoma: association with prognosis in relation to HPV‑DNA and p16INK4a status
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2019 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 42, no 1, p. 142-150Article in journal (Refereed) Published
Abstract [en]

The present study was conducted to investigate the possible prognostic value of molecular markers LRIG1‑2 and LIM domain 7 protein (LMO7) in vulvar squamous cell carcinoma (VSCC) and their possible correlation to human papilloma virus (HPV)‑ and p16INK4a‑status of the tumors. Patients diagnosed with VSCC at the University Hospital of Umeå, Sweden, during the years 1990‑2013 were selected. Tumor blocks were retrieved from tissue archives and clinical data were collected from the records of patients. HPV‑PCR analysis, HPV genotyping and immunohistochemistry were performed. In total, 112 patients were included. Forty percent of the tumors were HPV‑positive, 27% were p16INK4a‑positive and 23% were positive for both HPV and p16INK4a (considered HPV‑driven). HPV‑positivity and p16INK4a‑positivity were associated with prolonged disease‑free survival (DFS) in Kaplan‑Meier survival analysis. Leucine‑rich repeats and immunoglobulin‑like domains 1 (LRIG1) immunoreactivity was not significantly associated with survival. High leucine‑rich repeats and immunoglobulin‑like domains 2 (LRIG2) immunoreactivity was associated with a prolonged overall survival (OS) (P=0.001). By analyzing HPV‑negative cases only, it was determined that high LRIG2 immunoreactivity was associated with both favorable OS (P=0.008) and DFS (P=0.031). LRIG2 immunoreactivity was also an independent prognostic factor in multivariate analysis of OS (P=0.002, HR=0.41; 95% CI, 0.24‑0.71). High immunoreactivity with LMO7‑1250 antibody was associated with survival benefits in the whole cohort (OS; P=0.011) although DFS was only prolonged in HPV‑negative and not HPV‑driven tumors (P=0.038 and 0.042, respectively). The present study indicated that LRIG2 and LMO7 may be useful prognostic markers in VSCC, particularly for patients without HPV‑driven tumors or with advanced tumors at diagnosis. In contrast to earlier observations regarding other types of squamous cell carcinoma, LRIG1 was not a significant prognostic factor in VSCC.

Place, publisher, year, edition, pages
Spandidos Publications , 2019. Vol. 42, no 1, p. 142-150
Keywords [en]
vulvar squamous cell carcinoma, leucine‑rich repeats and immunoglobulin‑like domains, human papillomavirus, p16INK4a, survival
National Category
Cancer and Oncology
Research subject
health services research
Identifiers
URN: urn:nbn:se:umu:diva-159681DOI: 10.3892/or.2019.7138ISI: 000474808700012PubMedID: 31059071Scopus ID: 2-s2.0-85066789212OAI: oai:DiVA.org:umu-159681DiVA, id: diva2:1319901
Available from: 2019-06-03 Created: 2019-06-03 Last updated: 2023-10-04Bibliographically approved
In thesis
1. Leucine-rich repeats and immunoglobulin-like domain (LRIG) proteins: possible prognostic markers in vulvar squamous cell carcinoma, endometrial carcinoma, and oropharymgeal squamous cell carcinoma
Open this publication in new window or tab >>Leucine-rich repeats and immunoglobulin-like domain (LRIG) proteins: possible prognostic markers in vulvar squamous cell carcinoma, endometrial carcinoma, and oropharymgeal squamous cell carcinoma
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human leucine-rich repeats and immunoglobulin-like domain (LRIG) gene family comprises three genes, LRIG1, LRIG2 and LRIG3, which encode the LRIG1, LRIG2 and LRIG3 proteins, respectively. Previous stidies have revealed the different prognostic roles of these proteins in different cancers, and it has been shown that LRIG1 functions as a tumour suppressor in certain cancers via its negative regulation of several receptor tyrosine kinases. Much less is known about the functionof LRIG2 and LRIG3. The expression of all three LRIG genes has been studied with human papillomavirus (HPV). In particular, expression of LRIG1 has been associated with improved survival in cervical, vaginal, and oropharyngeal cancers. Since LRIG1 has been shown to predict sensitivity to paltinum-based chemotherapy when studied in different cell lines, the possible role of LRIG protein expression in HPV-associated and other cancers may be interesting to investigate furthur.

The overall aim of this thesis was to evaluate the immunoreactivity of LRIGs in vulvar squamous cell carcinoma (VSCC), endometrial carcinoma (EC) and oropharyngeal squamous cell carcinoma (OPSCC) and to investigate the potential prognostic value of LRIG proteins in association with HPV and p16 status in VSCC and OPSCC and to investigate the possible prognostic value of LMO7 and other prognostic markers of interest. Expression of the LRIG proteins and other markers was evaluated with immunohistochemistry, and HPV status was determined by PCR.

In VSCC, high immunoreactivity of LRIG2 and LMO7 was associated with good survival. LRIG1 was not a significant prognostic factor in VSCC. We also conducted a pilot study to evaluate the immunoreactivity of LRIG proteins in 75 women with EC. Most of the patients in this cohort had very high positivity for LRIG proteins. High expression of LRIG3 was associated with better survival. LRIG1 and LRIG2 expression in tumours had no impact on prognosis in this study, but this should be interpreted with great caution due to the limited size of the cohort. Finally, high expression of LMO7 was associated with improved survival in OPSCC. In this cohort of 143 patients, LRIG1 expression was associated with worse survival in HPV-driven tumours. This is in contrast to previous published work where high LRIG1 expression has been associated with good survival. Notably, in both the VSCC and OPSCC cohort, a new polyclonal LRIG1 antibody was used in contrast to that in a previous study of OPSCC.

In conclusion, we report additional data on the prognosticvalue of LRIG proteins in smaller cohort of VSCC, EC and OPSCC and suggest that these molecular markers need to be investigated furthur to elucidate possible clinical implications. In addition, a new monoclonal antibody against LRIG1 needs to be developed to ensure the reproducibility of the data.  

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 77
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2256
Keywords
Vulvar squamous cell carcinoma, endometrial carcinoma, oropharyngeal squamous cell carcinoma, LRIG1-3, HPV, LMO7, HPV-driven, non-HPV-driven, prognosis, overall survival, disease-free survival, p53, Ki-67, CD8+ TILs, CD44.
National Category
Cancer and Oncology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-214944 (URN)978-91-8070-153-2 (ISBN)978-91-8070-152-5 (ISBN)
Public defence
2023-11-03, Byggnad 1D, Hörsal B T9, Norrlands universitetssjukhus, Umeå, 09:00 (English)
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Available from: 2023-10-13 Created: 2023-10-04 Last updated: 2023-10-10Bibliographically approved

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Stefansson, KristinaOda, HusamÖfverman, CharlotteLundin, EvaHedman, HåkanLindquist, David

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