Episode 223: Oncogenic Viruses

Episode 223: Oncogenic Viruses Introduction Mehr: Hi everyone, welcome back to the Rio Bravo qweek podcast. Back by popular demand is Me, Mehr Boparai a third-year medical student at COMP-NW. Here with me is Jeremy Pan from COMP who is also a third-year medical student. How are you doing Jeremy? Jeremy: I’m doing great Mehr.Thanks for the kind intro; we had a fun time this morning doing street medicine and had some practice giving Toradol injections and wound dressings. So excited to be back for another podcast episode this afternoon! Mehr: This week, we are moving away from bacteria and antibiotics and diving deeper into cancer-causing viruses. Jeremy: Yes, and if you are interested at all in public health, this is one of those areas where medicine overlaps with public health in a really tangible way. I think one of the most underappreciated aspects of this topic is that we have vaccines that can prevent many of these cancers. If you told someone 50 years ago we’d be vaccinating against cancer, they probably wouldn’t believe you! It’s amazing to see how far medicine has come. How viruses cause cancer: Jeremy: Before jumping into specific viruses, I always think having a mechanism-based framework makes everything stick better. Mehr: Right, because they don’t all cause cancer the same way. Medicine can never be easy huh? Jeremy: Yea…this career really is just a lifetime of discovery. So just to start, in broad terms, we can think of three main buckets of how viruses can cause cancer: Direct oncogenesis where viral proteins interfere with tumor suppressors like P53 and Rb. We will go over their specific mechanisms a little later in the discussion. Mehr:  Chronic inflammation where viruses cause repeated injury through production of reactive oxygen species. They also increase the chance of mutation through repeated DNA replication, leading to cancer.  Jeremy: Immune evasion or suppression leads to decreased tumor surveillance. What this means essentially is that our immune system is constantly removing abnormal cells before they become cancerous. This is completed by CD8 T cells and natural killer, or NK, cells. CD8 T cells recognize abnormal peptides presented on Major Histocompatibility Complex, or MHC, class I molecules and induce apoptosis in those cells. Mehr: And NK cells step in when cells decide to stop expressing MHC I, which abnormal cells like to hide to avoid being caught. So just to reiterate, there are two layers to dissect here: if a cell looks suspicious with an abnormal MHC, CD8 T-cells kill them. If the abnormal cell decides to hide its MHC, then the NK cell will kill it instead. Jeremy: So, for the final big picture, we can think of oncogenic viruses as either disabling tumor suppression, causing chronic damage over time through inflammation, and weakening the immune system’s ability to catch cancer in time before it develops. HPV Mehr: Let’s start with one of the most common viruses afflicting our population – Human Papilloma Virus otherwise known as HPV.  Jeremy: Right, this notorious virus is probably the most clinically impactful oncogenic virus. The key players HPV utilizes are proteins E6 and E7. Mehr: Right! E6 binds to and inhibits p53, which normally acts to induce cell cycle arrest, and E7 inhibits Rb, which normally acts as a tumor suppressor gene that inhibits the G1 to S phase transition in a normal cell cycle. Jeremy: So essentially, we are losing both apoptosis and losing cell cycle control at the same time. What is interesting about HPV is that persistent infection, not just exposure to the virus, is what drives cancer risk.  Mehr: Exactly, most HPV infections clear on their own, but the ones that persist are the problem. Clinically, many end up being asymptomatic. However, for high-risk infections, we can see genital warts that can itch, feel tender, or cause abnormal vaginal bleeding and discharge. Patients are sometimes not able to have a vaginal delivery because of the warts that are present along their genital tract. We can also see warts on the hands and fingers or plantar surface of our feet. Jeremy: Another interesting point is that we are also seeing a shift where there are more cases of oropharyngeal cancers in younger, non-smoking patients. This is why if we see an abnormal neck lymph node or persistent sore throat after swallowing in a young patient, HPV should definitely be on the differential.  Mehr: Screening is very important as well! We typically discover high-risk HPV infections through routine Pap smears and other HPV specific tests through DNA PCR and RNA tests. We also encourage vaccination for effective prevention of both genital warts and high-risk HPV-related cancers. There was also a study in Scotland where there were zero cases of HPV in adults who received the vaccine between 12-13 years of age! Which is crazy!  EBV HBV & HCV Mehr: Now let’s shift to viruses that affect the liver, Hepatitis B virus and Hepatitis C virus. Jeremy: Both are strongly associated with hepatocellular carcinoma, but they actually get there in slightlydifferent ways. Mehr: Right. Hepatitis B is a DNA virus that can integrate directly into the host genome, which can disrupttumor suppressor genes and promote oncogenesis. Jeremy: Whereas Hepatitis C is an RNA virus, so it doesn’t integrate into the host genome. Instead, it causes chronic inflammation Over time, that leads to repeated cycles of hepatocyte injury and regeneration, along withoxidative stress from reactive oxygen species, which increases the risk of DNA mutations. Mehr: One really important clinical pearl is that Hep B can actually cause hepatocellular carcinoma evenwithout cirrhosis. Whereas with Hep C, the pathway is usually chronic inflammation → fibrosis → cirrhosis → dysplasia→ cancer.  Jeremy: So, screening becomes really important for both of these viruses. For high-risk patients—like those with chronic hepatitis or cirrhosis—we typically dosurveillance with liver ultrasound every 6 months, sometimes with alpha-fetoprotein levels to see if it is elevated. Mehr: From a prevention standpoint, the Hep B vaccine is a huge win. It significantly reduces the risk ofhepatocellular carcinoma. For Hep C, we don’t have a vaccine, but direct-acting antivirals can actually cure the infection andreduce long-term cancer risk, which is why we screen between ages 18-79  nowadays. Global Hep B and C account for 65% of all HCC cases! So, it makes sense that primary care itself is increasing the treatment of Hep C cases as well since it is easier to prescribe and that you want to be treated ASAP.  Jeremy: Yea, the ability to treat Hep C is so beneficial to population health. Now let’s say you have a patient who develops hepatocellular carcinoma, options can include surgicalresection, liver transplantation, local therapies, or systemic treatments depending on stage.  Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at [email protected], or visit our website riobravofmrp.org/qweek. See you next week!  __________________________________ References: Barry H. C. (2024). Scottish Screening: No Cases of Invasive Cervical Cancer in Women Who Received at Least One Dose of Bivalent HPV Vaccine at 12 or 13 Years of Age. American family physician, 110(2), 201–202. https://pubmed.ncbi.nlm.nih.gov/39172683/ Theme song, Works All The Time by Dominik Schwarzer, YouTube ID: CUBDNERZU8HXUHBS, purchased from https://www.premiumbeat.com/. Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at [email protected], or visit our website riobravofmrp.org/qweek. See you next week!