L3 Cancer Molecular Epidemiology

Question 1

What is the definition of epidemiology?

Answer 1

“The study of the distribution and determinants of health-related conditions or events in specified populations and the application of this study to the control of health problems”

Question 2

What are the aims of epidemiology?

Answer 2

Distribution - identify problems, inequities
Causes - primary prevention
Screening and early detection - secondary prevention
Natural history - prognosis (survival and progression)
Treatment effectiveness and harms - tertiary prevention

Question 3

What is the lifetime risk of cancer in the UK, and how many new cases are there per year?

Answer 3

50% lifetime risk
375k new cases/ year
Deprivation - 50% more cases in least vs most deprived areas.

Question 4

What are the main causes of cancer in the UK?

Answer 4

Main - smoking and obesity
Other - UVR, infection, alcohol, lack of fibre, air pollution, inactivity, processed meat

Question 5

What does PAF mean?

Answer 5

Population attributable fraction - cases of cancer prevented if we removed the exposure.

Question 6

What percentage of cancers in the UK are preventable?

Answer 6

37.7%

Question 7

What percentage are smokers likely to have cancer compared to non smokers?

Answer 7

50.1% compared to 26.6%. Twice as likely to have a preventable cancer.

Question 8

Cancer is often treatable if detected early. For lung, bowel and breast, what are the survival statistics by stage at diagnosis?

Answer 8

Lung - early = 3 in 10, late = <1 in 10.
Bowel - early = 9 in 10, late = <1 in 10.
Breast - early ~10 in 10, late = 2 in 10.

Question 9

What are the five key roles of molecular biomarkers in cancer molecular epidemiology?

Answer 9

Screen: Identify individuals at high risk for cancer
Detect: Discover cancer early
Diagnose: Determine the type of cancer
Treat: Select the most appropriate treatment
Monitor: Detect cancer recurrence

Question 10

What is Prostate-Specific Antigen (PSA), and what does a high PSA level indicate?

Answer 10

PSA is a glycoprotein enzyme encoded by the KLK3 gene that liquefies semen to allow sperm to swim freely.

High PSA levels suggest an abnormality in the prostate, which could be prostatitis, benign prostatic hyperplasia (BPH), or prostate cancer — but high levels do not necessarily mean cancer.

Question 11

How effective is PSA at detecting prostate cancer early?

Answer 11

Trial
Intervention arm and comparison arm.
No statistical significance between deaths.
PSA test as 0.49 > 0.05

Question 12

What is the PLCOm2012 Model for Lung Cancer Screening?

Answer 12

PLCOm2012 was developed from data collected from 36,286 individuals enrolled in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.

It is a risk prediction model designed to better select individuals for lung cancer screening compared to simple criteria like age and smoking history alone.

Goal: to estimate the 6-year risk of developing lung cancer for an individual.

Question 13

Name three risk factors included in the PLCOm2012 model.

Answer 13

Age
Smoking history (intensity and duration)
Family history

Question 14

How does the sensitivity of the PLCOm2012 model compare to traditional screening criteria?

Answer 14

PLCOm2012 has a higher sensitivity, meaning it identifies more true lung cancer cases.

Question 15

Does the PLCOm2012 model have higher or lower specificity compared to traditional criteria?

Answer 15

Lower - slightly more false positives

Question 16

Overall, how does the accuracy of the PLCOm2012 model compare to older methods?

Answer 16

It has better overall accuracy, leading to more efficient lung cancer screening.

Question 17

What is the “5-protein score” used for in lung cancer screening?

Answer 17

It is a blood-based biomarker panel designed to predict lung cancer risk more accurately than clinical models like PLCOm2012.

Question 18

How does the 5-protein score compare to the PLCOm2012 model?

Answer 18

The 5-protein score outperforms PLCOm2012 by achieving higher sensitivity, specificity, and overall predictive accuracy.

Question 19

What advantage does a biomarker based approach offer over demographic based models like PLCOm2012?

Answer 19

Biomarkers can directly reflect biological changes linked to cancer, improving early detection and risk prediction.

Question 20

What does higher sensitivity mean when comparing the 5-protein score to PCLOm2012?

Answer 20

It means that the 5-protein score is better at correctly identifying people who truly have lung cancer.

Question 21

What is ctDNA?

Answer 21

Small fragments of DNA shed by cancer cells into the bloodstream. They carry genetic mutations, methylation patterns, and other alterations specific to the tumour.

Question 22

How can screening ctDNA be used for predicting lung cancer stage?

Answer 22

Higher ctDNA = more advanced disease
Early stages = low (or undetectable) ctDNA
stage III-IV - detectable and higher levels of ctDNA
Mutational burden - tends to increase with disease progression.

Question 23

What can measuring ctDNA help with?

Answer 23

Estimating tumour burden (how much cancer is present).
Support staging decisions, especially when imaging is unclear.

Question 24

With reference to treatment, what do ctDNA levels indicate?

Answer 24

ctDNA remains high or increases = resistance to treatment, early relapse.
ctDNA decrease - treatment is working and tumour burden is reducing.

Question 25

How can ctDNA aid in personalised therapies?

Answer 25

Sequencing ctDNA can reveal targetable mutations (e.g. EGFR) and guide selection of therapies. ctDNA can also reveal new resistance mutations, allowing treatment adjustment.

Question 26

What is CancerSEEK?

Answer 26

An experimental blood based test designed to detect multiple types of cancer early from a single blood sample.

Question 27

What does CancerSEEK combine detection of?

Answer 27

- ctDNA mutations - cancer-associated protein biomarkers Thus, it is a multi-analyte liquid biopsy test integrating genomic and proteomic data.

Question 28

What ctDNA analysis is done in CancerSEEK?

Answer 28

sequencing of specific mutations in tumour-associated genes (e.g. TP53, KRAS)

Question 29

What protein biomarker measurements are done in CancerSEEK?

Answer 29

measures levels of 8 specific proteins known to be elevated in various cancers (e.g. CEA, CA-125).

Question 30

What is the combined analysis of CancerSEEK?

Answer 30

An algorithm integrates mutation data and protein levels to: - predict presence of cancer - estimate the likely organ of origin

Question 31

What is epigenetics?

Answer 31

changes in gene function without changes to the DNA sequence. DNA methylation is a key epigenetic mechanism where methyl groups are added to DNA, often silencing genes.

Question 32

When DNA methylation patterns in cancer are abnormal, what are the consequences?

Answer 32

Tumour suppressor genes may be silenced. Oncogenes may be activated indirectly. Abnormal methylation is a hallmark of cancer and can be used as a biomarker.

Question 33

What is GRAIL?

Answer 33

A multi-cancer early detection blood test that analyses DNA methylation patterns in cell free DNA (cfDNA) circulating in the blood.

Question 34

Why is GRAIL useful?

Answer 34

Different cancers have distinct methylation fingerprints and so detecting these patterns helps identify cancer presence and pinpoint the tissue of origin.

Question 35

How does GRAIL work for diagnostics?

Answer 35

1. Blood draw (liquid biopsy). 2. cfDNA extraction. 3. DNA methylation analysis using machine learning models trained on cancer and healthy methylation profiles. 4. Detection: - Whether cancer is present. - Likely tissue of origin (e.g., lung, breast, colon).

Question 36

How can GRAIL inform treatment?

Answer 36

Early detection = treatment starts sooner, often with curative intent. Tissue origin prediction = directs appropriate diagnostics and treatment without exhaustive imaging. Personalised medicine = methylation profiling may suggest which therapies are more or less likely to work (still in development stages).