Prostate cancer (PCa) is the main cause of death in the male population. Incidence rates seem to vary by ethnicity, geography, and race, yet additionally by aging, obesity, diet and family history. Both genitourinary infections and chronic inflammation can contribute to the development of prostate cancer and tumor progression. PCa is a heterogeneous disease and one of the challenges is that current diagnostic tests such as protease-specific antigen (PSA) screening and histopathological examinations can not discriminate between indolent and invasive tumors. Nearly 8% of the human genome consists of sequences derived from endogenous retroviruses (ERVs). Human endogenous retroviruses (HERVs) are not infective and the pathogenicity has been weakened by the accumulation of genetic and epigenetic modifications responsible for the diminished HERV expression. Evidence indicates a possible involvement of HERV envelope proteins in several types of cancer, particularly the association between PCa and HERV-K. Furthermore, the application of next-generation sequencing (NGS) techniques to cancer research paved the way to new routes of investigation concerning the genetic background of individuals affected by PCa as well the potential impact of gene variants on cancer progression, metastases, and the response to cancer therapy. MHC class I and II play a critical role in mediating the immune responses against cancer cells. In PCa, loss of HLA class I expression has been observed in the primary tumor and lymph node metastases. The first part of this project focuses on the evaluation of the antibody response against highly immunogenic peptides obtained by the envelope protein of HERV-H, HERV-K, and HERV-W in plasma of patients with PCa, BPH, a borderline group of individuals with atypical small acinar proliferation (ASAP) and prostatic intraepithelial neoplasia (PIN), and a population of healthy controls (HCs). The second part focuses on the application of a NGS-based approach to characterize the variability within the Major Histocompatibility Complex (MHC) class I and II, one of the most variable region of human genome, and to analyze a panel of genes in a cohort of PCa patients and HCs. The multigene panel analyzed was composed of 35 genes involved in innate and adaptative immune response, cancer, autophagy, and previously associated-PCa genes. Data presented in this thesis provides further evidence for the association between PCa and HERV-K, and new proof for HERV-H possible involvement in PCa pathogenesis emphasizing its potential to be used as a disease biomarker. Additionally, genotyping analysis of the MHC class I and II provides new data about the association of HLA-A and HLA-B and PCa risk. The analysis of the multigene panel detected novel genetic modifications in a cohort of individuals with PCa and one of healthy individuals. These findings shed light on novel SNPs and their potential impact on PCa risk, prognosis, survival and the patient response to cancer therapy.

Prostate cancer (PCa) is the main cause of death in the male population. Incidence rates seem to vary by ethnicity, geography, and race, yet additionally by aging, obesity, diet and family history. Both genitourinary infections and chronic inflammation can contribute to the development of prostate cancer and tumor progression. PCa is a heterogeneous disease and one of the challenges is that current diagnostic tests such as protease-specific antigen (PSA) screening and histopathological examinations can not discriminate between indolent and invasive tumors. Nearly 8% of the human genome consists of sequences derived from endogenous retroviruses (ERVs). Human endogenous retroviruses (HERVs) are not infective and the pathogenicity has been weakened by the accumulation of genetic and epigenetic modifications responsible for the diminished HERV expression. Evidence indicates a possible involvement of HERV envelope proteins in several types of cancer, particularly the association between PCa and HERV-K. Furthermore, the application of next-generation sequencing (NGS) techniques to cancer research paved the way to new routes of investigation concerning the genetic background of individuals affected by PCa as well the potential impact of gene variants on cancer progression, metastases, and the response to cancer therapy. MHC class I and II play a critical role in mediating the immune responses against cancer cells. In PCa, loss of HLA class I expression has been observed in the primary tumor and lymph node metastases. The first part of this project focuses on the evaluation of the antibody response against highly immunogenic peptides obtained by the envelope protein of HERV-H, HERV-K, and HERV-W in plasma of patients with PCa, BPH, a borderline group of individuals with atypical small acinar proliferation (ASAP) and prostatic intraepithelial neoplasia (PIN), and a population of healthy controls (HCs). The second part focuses on the application of a NGS-based approach to characterize the variability within the Major Histocompatibility Complex (MHC) class I and II, one of the most variable region of human genome, and to analyze a panel of genes in a cohort of PCa patients and HCs. The multigene panel analyzed was composed of 35 genes involved in innate and adaptative immune response, cancer, autophagy, and previously associated-PCa genes. Data presented in this thesis provides further evidence for the association between PCa and HERV-K, and new proof for HERVH possible involvement in PCa pathogenesis emphasizing its potential to be used as a disease biomarker. Additionally, genotyping analysis of the MHC class I and II provides new data about the association of HLA-A and HLA-B and PCa risk. The analysis of the multigene panel detected novel genetic modifications in a cohort of individuals with PCa and one of healthy individuals. These findings shed light on novel SNPs and their potential impact on PCa risk, prognosis, survival and the patient response to cancer therapy.

HUMORAL RESPONSE AGAINST HERV-K AND HERV-H EPITOPES, AND GENETIC VARIABILITY WITHIN THE MAJOR HISTOCOMPATIBILITY COMPLEX AND A MULTIGENE PANEL THROUGH NGS IN PROSTATE CANCER PATIENTS / Manca, Maria Antonietta. - (2022 Jul 25).

HUMORAL RESPONSE AGAINST HERV-K AND HERV-H EPITOPES, AND GENETIC VARIABILITY WITHIN THE MAJOR HISTOCOMPATIBILITY COMPLEX AND A MULTIGENE PANEL THROUGH NGS IN PROSTATE CANCER PATIENTS

MANCA, Maria Antonietta
2022-07-25T00:00:00+02:00

Abstract

Prostate cancer (PCa) is the main cause of death in the male population. Incidence rates seem to vary by ethnicity, geography, and race, yet additionally by aging, obesity, diet and family history. Both genitourinary infections and chronic inflammation can contribute to the development of prostate cancer and tumor progression. PCa is a heterogeneous disease and one of the challenges is that current diagnostic tests such as protease-specific antigen (PSA) screening and histopathological examinations can not discriminate between indolent and invasive tumors. Nearly 8% of the human genome consists of sequences derived from endogenous retroviruses (ERVs). Human endogenous retroviruses (HERVs) are not infective and the pathogenicity has been weakened by the accumulation of genetic and epigenetic modifications responsible for the diminished HERV expression. Evidence indicates a possible involvement of HERV envelope proteins in several types of cancer, particularly the association between PCa and HERV-K. Furthermore, the application of next-generation sequencing (NGS) techniques to cancer research paved the way to new routes of investigation concerning the genetic background of individuals affected by PCa as well the potential impact of gene variants on cancer progression, metastases, and the response to cancer therapy. MHC class I and II play a critical role in mediating the immune responses against cancer cells. In PCa, loss of HLA class I expression has been observed in the primary tumor and lymph node metastases. The first part of this project focuses on the evaluation of the antibody response against highly immunogenic peptides obtained by the envelope protein of HERV-H, HERV-K, and HERV-W in plasma of patients with PCa, BPH, a borderline group of individuals with atypical small acinar proliferation (ASAP) and prostatic intraepithelial neoplasia (PIN), and a population of healthy controls (HCs). The second part focuses on the application of a NGS-based approach to characterize the variability within the Major Histocompatibility Complex (MHC) class I and II, one of the most variable region of human genome, and to analyze a panel of genes in a cohort of PCa patients and HCs. The multigene panel analyzed was composed of 35 genes involved in innate and adaptative immune response, cancer, autophagy, and previously associated-PCa genes. Data presented in this thesis provides further evidence for the association between PCa and HERV-K, and new proof for HERVH possible involvement in PCa pathogenesis emphasizing its potential to be used as a disease biomarker. Additionally, genotyping analysis of the MHC class I and II provides new data about the association of HLA-A and HLA-B and PCa risk. The analysis of the multigene panel detected novel genetic modifications in a cohort of individuals with PCa and one of healthy individuals. These findings shed light on novel SNPs and their potential impact on PCa risk, prognosis, survival and the patient response to cancer therapy.
Prostate cancer (PCa) is the main cause of death in the male population. Incidence rates seem to vary by ethnicity, geography, and race, yet additionally by aging, obesity, diet and family history. Both genitourinary infections and chronic inflammation can contribute to the development of prostate cancer and tumor progression. PCa is a heterogeneous disease and one of the challenges is that current diagnostic tests such as protease-specific antigen (PSA) screening and histopathological examinations can not discriminate between indolent and invasive tumors. Nearly 8% of the human genome consists of sequences derived from endogenous retroviruses (ERVs). Human endogenous retroviruses (HERVs) are not infective and the pathogenicity has been weakened by the accumulation of genetic and epigenetic modifications responsible for the diminished HERV expression. Evidence indicates a possible involvement of HERV envelope proteins in several types of cancer, particularly the association between PCa and HERV-K. Furthermore, the application of next-generation sequencing (NGS) techniques to cancer research paved the way to new routes of investigation concerning the genetic background of individuals affected by PCa as well the potential impact of gene variants on cancer progression, metastases, and the response to cancer therapy. MHC class I and II play a critical role in mediating the immune responses against cancer cells. In PCa, loss of HLA class I expression has been observed in the primary tumor and lymph node metastases. The first part of this project focuses on the evaluation of the antibody response against highly immunogenic peptides obtained by the envelope protein of HERV-H, HERV-K, and HERV-W in plasma of patients with PCa, BPH, a borderline group of individuals with atypical small acinar proliferation (ASAP) and prostatic intraepithelial neoplasia (PIN), and a population of healthy controls (HCs). The second part focuses on the application of a NGS-based approach to characterize the variability within the Major Histocompatibility Complex (MHC) class I and II, one of the most variable region of human genome, and to analyze a panel of genes in a cohort of PCa patients and HCs. The multigene panel analyzed was composed of 35 genes involved in innate and adaptative immune response, cancer, autophagy, and previously associated-PCa genes. Data presented in this thesis provides further evidence for the association between PCa and HERV-K, and new proof for HERV-H possible involvement in PCa pathogenesis emphasizing its potential to be used as a disease biomarker. Additionally, genotyping analysis of the MHC class I and II provides new data about the association of HLA-A and HLA-B and PCa risk. The analysis of the multigene panel detected novel genetic modifications in a cohort of individuals with PCa and one of healthy individuals. These findings shed light on novel SNPs and their potential impact on PCa risk, prognosis, survival and the patient response to cancer therapy.
Prostate Cancer; Multigene panel; HLA-alleles; HERVs; NGS
NGS
HUMORAL RESPONSE AGAINST HERV-K AND HERV-H EPITOPES, AND GENETIC VARIABILITY WITHIN THE MAJOR HISTOCOMPATIBILITY COMPLEX AND A MULTIGENE PANEL THROUGH NGS IN PROSTATE CANCER PATIENTS / Manca, Maria Antonietta. - (2022 Jul 25).
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11388/294804
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