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Leucine-rich repeats and immunoglobulin-like domain (LRIG) proteins: possible prognostic markers in vulvar squamous cell carcinoma, endometrial carcinoma, and oropharymgeal squamous cell carcinoma
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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 [en]
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: urn:nbn:se:umu:diva-214944ISBN: 978-91-8070-153-2 (electronic)ISBN: 978-91-8070-152-5 (print)OAI: oai:DiVA.org:umu-214944DiVA, id: diva2:1802505
Public defence
2023-11-03, Byggnad 1D, Hörsal B T9, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2023-10-13 Created: 2023-10-04 Last updated: 2023-10-10Bibliographically approved
List of papers
1. LRIG1‑2 and LMO7 immunoreactivity in vulvar squamous cell carcinoma: association with prognosis in relation to HPV‑DNA and p16INK4a status
Open this publication in new window or tab >>LRIG1‑2 and LMO7 immunoreactivity in vulvar squamous cell carcinoma: association with prognosis in relation to HPV‑DNA and p16INK4a status
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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
Keywords
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:nbn:se:umu:diva-159681 (URN)10.3892/or.2019.7138 (DOI)000474808700012 ()31059071 (PubMedID)2-s2.0-85066789212 (Scopus ID)
Available from: 2019-06-03 Created: 2019-06-03 Last updated: 2024-07-02Bibliographically approved
2. The prognostic role of lrig proteins in endometrial cancer
Open this publication in new window or tab >>The prognostic role of lrig proteins in endometrial cancer
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2021 (English)In: Cancers, ISSN 2072-6694, Vol. 13, no 6, p. 1-12, article id 1361Article in journal (Refereed) Published
Abstract [en]

Endometrial cancer (EC) is the most common gynecologic malignancy in Sweden and it has various prognostic factors. The LRIG family is a group of three integral surface proteins with a similar domain organization. The study aimed to explore LRIG family as prognostic factor proteins in EC. The initial study cohort included 100 women with EC who were treated at the Department of Women’s and Children’s Health, Karolinska University Hospital Solna, between 2007 and 2012. We assessed the associations between LRIG protein expression and type, grade, and stage of EC, as well as progression‐free and overall survival. Immunohistochemistry results revealed that most women in the analytical sample had >50% LRIG1‐, LRIG2‐ and LRIG3‐positive cells. A statistically significant association was observed between having a high number of LRIG3‐positive cells and superior overall survival (incidence rate ratio = 0.977; 95% confidence interval: 0.958–0.996, p = 0.019). Moreover, positive LRIG3 staining of the cell membrane was associated with reducing in the risk of death (hazard ratio = 0.23; 95% confidence interval: 0.09–0.57). Our results show that LRIG3 expression might be a prognostic factor in EC. The role of LRIG1 and LRIG2 expression remains to be further investigated.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
Endometrial cancer, LRIG1, LRIG2, LRIG3, Prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-181783 (URN)10.3390/cancers13061361 (DOI)000634344300001 ()2-s2.0-85102558250 (Scopus ID)
Funder
Cancerforskningsfonden i Norrland
Available from: 2021-04-01 Created: 2021-04-01 Last updated: 2023-10-04Bibliographically approved
3. CD8, CD44, Ki-67, and p53 immunoreactivity in vulvar squamous cell carcinoma: correlation with prognosis in relation to HPV-DNA and p16ink4a status
Open this publication in new window or tab >>CD8, CD44, Ki-67, and p53 immunoreactivity in vulvar squamous cell carcinoma: correlation with prognosis in relation to HPV-DNA and p16ink4a status
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-214806 (URN)
Available from: 2023-09-30 Created: 2023-09-30 Last updated: 2023-10-04
4. High LMO-7 expression is a positive prognostic factor in oropharyngeal squamous cell carcinoma
Open this publication in new window or tab >>High LMO-7 expression is a positive prognostic factor in oropharyngeal squamous cell carcinoma
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-214807 (URN)
Available from: 2023-09-30 Created: 2023-09-30 Last updated: 2023-10-04

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