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Why Do Cancer Risks Differ Between People With The Same Lynch Syndrome Gene Variant? 🧬

The INDICATE study explores whether HLA type, a key factor in immune recognition, may influence cancer risk and age of onset in Lynch syndrome

ABSTRACT

Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR-deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR-deficient cancers leads to a counter-selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier’s HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors.

Full paper – https://onlinelibrary.wiley.com/doi/full/10.1002%2Fijc.34312

UKCGG One-page Gene-Specific Management Guidelines – (inc) Lynch Syndrome

These guidelines from the UK Cancer Genetics Group were developed using data from individuals ascertained as carriers of cancer susceptibility genes through diagnostic, family history or other clinical pathways where evidence supports standard actionability of the identified variant.

These recommendations are based on evidence around the likely benefits of proposed interventions weighed against any possible harms for standard penetrance in clinically ascertained cohorts.

The risks and benefits of these interventions for individuals identified as carriers of cancer susceptibility genes through other routes, such as incidental findings or population screening have not been clearly established. Clinical judgement needs to be exercised when counselling and implementing on-going surveillance, early detection and prevention interventions where penetrance may be lower than expected and personalised more conservative management may be considered (e.g. surveillance versus irreversible risk-reducing surgery).

https://www.ukcgg.org/information-education/ukcgg-leaflets-and-guidelines

AI assistance does not improve adenoma detection in Lynch syndrome, trial finds

What was studied: Researchers tested whether adding artificial intelligence (AI) to colonoscopy helps doctors find more precancerous growths (adenomas) in people with Lynch syndrome — an inherited condition that greatly raises the risk of colorectal cancer and requires regular colonoscopy screening.

How it was done: About 750 adults with Lynch syndrome at nine specialist centres in Belgium, Germany, the Netherlands and Spain were randomly assigned to have either a standard high-definition colonoscopy or the same procedure with an AI system (CAD EYE) that flags suspicious areas on the screen in real time. The AI was also tested on its ability to tell, on the spot, whether a growth was precancerous or harmless.

What was found:

  • Adenomas were found in 34% of patients with AI vs 31% without — a difference too small to be meaningful.
  • No advantage for AI in any other measure, including flat growths, advanced adenomas, or cancers detected.
  • Procedure times (about 26 minutes) and patient comfort were the same in both groups.
  • For identifying growth types on sight, the AI performed slightly worse than the expert doctors, and both struggled with a tricky lesion type called sessile serrated lesions.
  • Safety was similar; three minor complications occurred in the AI group, none clearly caused by the AI.

What it means: In expert centres where doctors are already highly skilled and take their time, adding this AI tool didn’t improve results. Careful technique, good bowel preparation and adequate inspection time still matter most.

Important caveats: The study wasn’t designed to prove the two approaches are equivalent — only that AI wasn’t better in this setting. AI could still help in less specialised clinics where detection rates vary more, and future AI trained specifically on the subtle, flat lesions typical of Lynch syndrome might perform better.

Bottom line for patients: A high-quality standard colonoscopy at an experienced centre remains appropriate care — you’re not missing out if your clinic doesn’t use AI.

Published in The Lancet Gastroenterology & Hepatology (CADLY2 trial; first author Dr Robert Hüneburg, University Hospital Bonn).

https://news.gastro.org/issues/2026/august-2026/ai-assistance-does-not-improve-adenoma-detection-in-lynch-syndrome-trial-finds/?utm_medium=Social&utm_campaign=AGA-posts&utm_source=linkedin

Can Lifestyle Alter Genetic Risk? What the science says.

Lynch syndrome confers an inherited genetic predisposition — but environmental and lifestyle factors also influence how that risk is expressed. 

Current evidence indicates that chronic inflammation may contribute to tumour development in mismatch repair-deficient cells. Modifiable factors — including regular physical activity, avoiding tobacco, and a diet high in fibre and low in processed meat — may therefore support risk reduction.

These measures complement, but do not replace, established clinical surveillance.

Endometrial Cancer Risk in Lynch Syndrome:Early Signs Matter.

In Lynch syndrome, colorectal cancer receives the most attention — but gynaecological risk requires equal clinical vigilance. 

For women with Lynch syndrome, the lifetime risk of endometrial cancer is substantially elevated and varies according to the gene affected, reaching up to 40–60% in carriers of pathogenic MLH1 and MSH2 variants. Endometrial cancer is frequently the first, or ‘sentinel’, cancer diagnosed.

Awareness of early symptoms — including abnormal or postmenopausal bleeding — together with adherence to established surveillance guidelines, supports earlier diagnosis. PREDI-LYNCH incorporates gynaecological clinical data so that predictive models reflect risk in women accurately.

New Research | The Lasting Physical Impact of Cancer Survivorship

As more people survive cancer and live longer, understanding the long-term effects of cancer and its treatment becomes increasingly important.

Using data from The Irish Longitudinal Study on Ageing (TILDA), researchers from the Trinity St James’s Cancer Institute, School of Medicine, Trinity College Dublin and TILDA examined physical function among community-dwelling adults aged over 50 with and without a history of cancer.

🔵 Recent cancer survivors were almost twice as likely to report a physical performance limitation.

🔵 Long-term cancer survivors had more than twice the risk of osteoporosis, highlighting an increased risk of falls, fractures, and loss of independence.

🔵 Cancer survivorship has a lasting burden on functional independence that persists past diagnosis and treatment.

https://www.sciencedirect.com/science/article/pii/S1879406826001918

Fully immersive scientific training residency for people with lived experience of cancer

It’s about bringing the patient voice, lived experience and perspective into cancer research and science.

Places still available for the first ever programme in Ireland. The programme is free to attend, with all accommodation, meals and training costs covered to ensure an inclusive and accessible learning environment.

WHY ATTEND?

People living with and beyond cancer hold vital knowledge and experience, yet many face barriers that limit their involvement in research and decision making. These can include unfamiliar scientific language, lack of confidence or structural imbalances within healthcare and research systems.

https://www.aicri.org/voice-ireland

ESGO Consensus Statement on endometrial cancer prevention, risk reduction strategies, and management of women with Lynch syndrome

Highlights
  • Gene-specific cancer risks in Lynch syndrome (LS) warrant individualised counselling.
  • Personalised risk-reducing strategies should be offered to LS carriers.
  • Hormone therapy may be considered for LS carriers with a personalised risk–benefit.
  • Reproductive and assisted reproduction issues should be discussed with LS carriers.
  • These Statements guide LS management, including addressing areas of uncertainty.

In the general female population, Endometrial Cancer and Ovarian Cancer lifetime risk is estimated to be 2.7% and 1.6%, respectively, while for LS women, the risk is significantly higher, up to 45.7% for EC and 13.4% for OC.

Additionally, LS women typically experience an earlier onset, often before 50 years. However, the estimated cumulative risks of EC and OC by age 40 remain low (1.1–2% for EC and 1.1–1.6% for OC). By age 75, the risk of developing EC in MLH1, MSH2 and MSH6 PVs/LPVs carriers increases to 45.7%, and the risk of OC reaches 13.4%. In contrast, carriers of PMS2 pathogenic variants have substantially lower risks (21.2% and 2.5% for EC and OC, respectively).

https://www.sciencedirect.com/science/article/pii/S0959804926005204

I’m an oncologist: Cancer can develop in anyone — even a healthy person doing all the right things

Why genetics is changing cancer care:

A big part of my work is around genetic risk. About 12% of cancers have a known underlying DNA alteration which, over a lifetime, will increase cancer risk.

They’re the population I really want to identify in my clinic because they’re women and men who may develop cancer under the age of the national screening programmes.

They won’t be picked up through screening in the majority of cases.

I developed mainstream testing pathways in Vincent’s. It’s the first hospital in Ireland bringing genetic testing for high-risk patients to an earlier point of care across breast, ovarian, pancreatic, prostate and GI cancers.

A healthy person who’s doing all [the right things] can still develop cancer. One in two people in Ireland, during their lifetime, will have a cancer diagnosis.

Lynch syndrome for example, [an inherited genetic condition] which is pretty common in Ireland, increases uterine cancer(as well as other risks) risk for a woman by up to 50%, depending on the variant. It’s an area where there’s a lot of clinical research, which is a real positive because, for many years, there hadn’t been as much by way of clinical trials or new treatment opportunities for women. We’re seeing a big change now and a lot of new drug options coming online.

Being an oncologist has made me more aware of what is within my control and what’s outside my control.

People are living longer with cancer. If it’s not curable, it can still be treated.



https://www.irishexaminer.com/lifestyle/healthandwellbeing/arid-41895703.html

Early onset gastrointestinal cancers – a needs analysis

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2026.1870123/full

Conclusion: 

This needs analysis highlights the importance of specialised clinical pathways, for early onset GI cancer patients focusing on these unique and complex needs.

Financial supports, conversations regarding sexual health/function, fertility preservation and psychosocial support are critical areas requiring structured intervention.