The Office of Cancer Genomics (OCG), along with the Office of HIV and AIDS Malignancies (OHAM), initiated the HIV+ Tumor Molecular Characterization Project (HTMCP) to gain insight into the genetic events driving HIV- associated cancers and to determine why certain cancers, but not others, have higher incidences in HIV-positive patients. The molecular characterization data from patients identified through HTMCP will be available to the research community worldwide in a publicly available, yet patient privacy-protected database.
Acquired immunodeficiency syndrome (AIDS) is a complex and devastating disease caused by infection with human immunodeficiency virus (HIV). The advent of highly active anti-retroviral therapy (HAART) has considerably slowed disease progression from HIV to full-blown AIDS, thereby increasing the number of people living with HIV. Despite this success in survivorship, certain types of cancers are becoming more prevalent in the expanding pool of HIV-infected individuals. This poses a challenge to global health, since at the end of 2017 approximately 36.9 million people were living with HIV worldwide (25.7 million in Sub-Saharan Africa and over 1.1 million in the US, according to the UNAIDS, World Health Organization, and HIV.gov). While co-infecting viruses and, possibly, immunodeficiency may play a role in the pathogenesis of HIV-associated cancers, our understanding of its etiology is inadequate. Understanding the molecular causes of these tumors may translate into improved therapies for a growing population of patients doubly afflicted with HIV and cancer.
HTMCP is an ongoing project; diffuse large B-cell lymphoma (DLBCL) and lung cancer projects are currently in Phase II of the timeline. Cervical cancer project is in Phase IV of the timeline.
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HTMCP studies the following cancers based on their high rates of incidence and mortality among HIV-positive patients:
Cervical Cancer: Human papillomavirus (HPV) infection is required but not sufficient for cancer development. Cervical cancer is classified as an AIDS-defining malignancy, like Kaposi’s sarcoma, because of its prevalence in AIDS patients. According to UNAIDS, women infected with HIV are 5 times more likely to develop cervical cancer than women not infected with HIV.
Diffuse Large B-Cell Lymphoma (DLBCL): Diffuse Large B-cell Lymphoma is the most common form of non-Hodgkin lymphoma (NHL), a cancer of the white blood cells. DLBCL is an AIDS-defining malignancy that is common in AIDS and HIV-positive patients. People infected with HIV are over 20 times more likely to be diagnosed with NHL, largely in the form of DLBCL, than those without HIV infection.
Lung Cancer: Lung cancer has high mortality in both men and women. It has been established that cigarette smoking is the leading cause of squamous cell carcinoma of the lung; however, lung adenocarcinoma develops in people who have never smoked. HIV-infected individuals have a 3-fold increased risk of lung cancer, see source, mostly in the form of adenocarcinoma, as compared to the general population. This rate is expected to rise over time. Notably, the subtypes and aggressiveness of lung cancers in HIV-positive patients are different from that seen in HIV-negative cases, suggesting differences in underlying biological mechanisms.
HTMCP is presently accruing diffuse large B-cell lymphoma, and lung cancer tissues (and case-matched controls) from HIV-positive patients. Tissue accrual for the cervical cancer from HIV-positive patients in Uganda has been completed. The Genome Sciences Centre, British Columbia Cancer Agency in Vancouver, Canada is generating whole genome and transcriptome (mRNA and miRNA) sequencing data on each case. The analysis will uncover somatic mutations, genomic rearrangements, copy number alterations, gene expression differences, chimera transcripts, and single-nucleotide polymorphisms (SNPs) for loss of heterozygosity.
The ultimate goal for HTMCP is to produce comprehensive molecular profiles of the three tumor types primarily from HIV-positive patients and some HIV-negative patients, to match the ethnic genetic backgrounds, using state-of-the-art genomic methods. Comparing molecular profiles between the two sets of patients with the same tumor type will enable identification of potentially causative mutations and pathways occurring in HIV- associated cancers, which may respond to novel therapies.
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