L06 Cancer Cancer genetics

Overview

This lecture covers two linked topics in cancer genetics: inherited cancer syndromes affecting breast, colorectal and gastric cancer (their genetics, penetrance and clinical management), and the application of cancer genetics to sporadic (non-inherited) cancer, where genetic testing increasingly guides personalised prognosis, drug selection and monitoring for relapse.

Heritability of Cancer

• Penetrance: the likelihood that a carrier of a mutation will develop cancer.
• Cancer splits into three groups by heritability: sporadic (~80% of cases), inherited low-penetrance (~15%), and inherited highly penetrant/cancer syndromes (~5%).

High-Penetrance Inherited Cancer Syndromes

A wide range of tumour suppressor/repair gene syndromes are highly penetrant and confined largely to specific tissues:

Syndrome	Gene(s)	Major tissue
Ataxia telangiectasia	ATM	haemopoietic
Bloom syndrome	BLM	haemopoietic
Cowden syndrome	PTEN	breast, thyroid, endometrial
Familial adenomatous polyposis	APC, MUTYH	colorectal
Familial malignant melanoma	CDKN2A, CMM1, CDK4	skin
Fanconi anemia	FANC A-L	haemopoietic, liver
Hereditary breast-ovarian cancer (BRCA1/2)	BRCA1, BRCA2	breast, ovary
Hereditary diffuse gastric cancer (HDGC)	CDH1, CTNNA1	stomach, breast
Lynch syndrome	MLH1, MSH2, MSH6, PMS2	colorectal
Hereditary papillary renal cell carcinoma	MET	kidney
Juvenile polyposis	SMAD4, BMPR1A, ENG	gastrointestinal tract
Li-Fraumeni syndrome	TP53	sarcomas, breast, brain
Multiple endocrine neoplasia type 1	MEN1	parathyroid, pituitary
Multiple endocrine neoplasia type 2	RET	thyroid
Neurofibromatosis type 1	NF1	neural, optic
Neurofibromatosis type 1 [as printed on slide; likely a typo for type 2]	NF2	brain, spinal cord
Nevoid basal cell carcinoma	PTC	skin
Nijmegen breakage syndrome	NBS1	B cells
Peutz-Jeghers syndrome	STK11	colorectal
Retinoblastoma	RB1	retina
Testicular cancer	TCG1	testes
Tuberous sclerosis	TSC1, TSC2	broad; angiofibromas
Von Hippel-Lindau syndrome	VHL	kidney
Xeroderma pigmentosum	XPA, XPC, XPE; ERCC3-5	kidney

The slide's row "neurofibromatosis type 1 / NF2 / brain, spinal cord" appears to be a slide typo for neurofibromatosis type 2, but is transcribed exactly as shown.

Four of these syndromes (familial adenomatous polyposis, hereditary breast-ovarian cancer, HDGC, Lynch syndrome) are covered in detail below.

Familial Breast-Ovarian Cancer: BRCA1/2

• BRCA1 and BRCA2 are dsDNA repair genes; inactivation increases mutation rate 8-fold.
• Incidence: 1 in 500-1000 for each gene; up to 1 in 100 in Ashkenazi Jews, due to two founder BRCA1 mutations.
• Lifetime risk: breast cancer 40-90%, ovarian cancer 30-60%.
• Clinical management:
  • Surveillance: clinical breast exam every 6-12 months from 25 years; annual MRI/mammography from ~30 years.
  • Prophylactic/risk-reducing surgery: mastectomy gives ~90% risk reduction (residual tissue remains); oophorectomy gives ~90% risk reduction if performed before age 45.
  • Chemoprevention: tamoxifen and aromatase inhibitors reduce breast cancer risk by ~40%, but tamoxifen increases endometrial cancer risk.

Other Familial Breast Cancer Risk Genes

• TP53 (Li-Fraumeni syndrome) and CDH1 (hereditary diffuse gastric cancer) also raise familial breast cancer risk.
• ATM, CHEK2, BRIP1, PALB2 are dsDNA damage repair genes that roughly double breast cancer risk.
• Tens of additional low-penetrance genes contribute smaller risk increments.

Lynch Syndrome

• Accounts for 3% of all colorectal cancer (CRC); incidence 1 in 300.
• Caused by germline mutation of mismatch repair genes: MLH1, MSH2, MSH6, PMS2.
• 80% lifetime risk of CRC; also raised risk of other GI, endometrial, ovarian, urothelial and CNS cancers.
• Surveillance: annual colonoscopy from 20-25 years.

Familial Adenomatous Polyposis (FAP)

• Caused by APC mutations; incidence 1 in 10,000; 100% penetrance.
• Produces 100s-1000s of adenomatous polyps in the colon, also in stomach and duodenum.
• Classic and attenuated forms show genotype-phenotype correlation: the attenuated form has fewer polyps and a later age of onset.
• Clinical management:
  • Surveillance: sigmoidoscopy or colonoscopy every 1-2 years from ~12 years old.
  • Prophylactic surgery: most classic FAP patients undergo colectomy at 15-25 years; duodenal cancer becomes the biggest threat after colectomy.

Hereditary Diffuse Gastric Cancer (HDGC)

• Dominantly inherited; incidence 5-10 per 100,000, with a 5x higher rate in Māori.
• Caused by germline CDH1 mutations (CDH1 encodes E-cadherin, a cell-to-cell adhesion protein) or, rarely, CTNNA1 mutations.
• E-cadherin molecules span adjacent cell membranes and bind each other extracellularly; intracellularly they link via β-catenin and CTNNA1 (α-catenin), maintaining tissue integrity, cell polarity and differentiation.
• Penetrance: up to 70% for advanced diffuse gastric cancer (DGC); ~40% risk of lobular breast cancer.
• Family A case study: a multigenerational pedigree with gastric, breast and colorectal cancer illustrates dominant inheritance and high, early-onset penetrance.

  The pedigree in Family A was too dense/small to transcribe individual by individual; the overall pattern (multigenerational, dominant, mixed gastric/breast/colorectal cancer) is clear.

• Age-of-death data show Family A gastric cancer deaths clustering at young ages (peak ~8 cases at 31-40 years), compared with the general NZ population, whose gastric cancer deaths peak much later (71-80 years, ~130 cases/year) — illustrating the markedly earlier onset in inherited HDGC.
• The causal mutation in Family A is a single G→T germline change in CDH1: one altered letter among 3 billion base pairs of DNA.
• HDGC produces multifocal disease: in one 28-year-old case, numerous signet ring cell carcinoma foci were scattered across the fundic/body, junctional and antral mucosa.
• Clinical management: CDH1 genetic testing from age >16; annual surveillance endoscopy or prophylactic gastrectomy (from age >20); annual breast MRI surveillance; consider risk-reducing mastectomy. The exact management path (surveillance vs surgery, for stomach and breast) depends on family history and the severity/certainty of the mutation, following a structured testing and decision pathway (2020 Wanaka International Gastric Cancer Linkage Consortium HDGC testing criteria).

  The management flowchart's decision/management box text was too small to transcribe in full; the overall branch logic (genetic testing → pathogenic/uncertain/negative result → family history checks → risk category → tailored surveillance/surgery recommendations) is captured, not the exact wording of each box.

Hallmarks and Summary of Inherited Cancer

• Hallmarks suggesting an inherited cancer: high incidence within family groups, predominance of particular cancer types, early age of onset, increased risk of multifocal or bilateral disease.
• Highly penetrant cancer syndromes are caused by germline mutations in tumour suppressor genes and are usually dominantly inherited.
• They are relatively rare but have very high impact.
• Management strategies: surveillance (“watchful waiting”), prophylactic surgery, chemoprevention, and pre-implantation genetic screening/IVF.
• Correct management leads to a very low mortality rate.

Personalised Medicine in Sporadic Cancer: Prognosis and Recurrence Risk

• Two treatment paradigms: population-based protocols give the treatment best for the average patient (good only if the patient is average); the emerging personalised approach gives the treatment best for that patient’s particular cancer.
• Genetic methods supporting personalised treatment fall into three categories: (a) prognosis/risk of recurrence via gene expression analysis, (b) drug target identification, (c) markers of treatment response and relapse.
• Mammaprint: a 70-gene expression signature predicting metastasis in node-negative breast cancer; expression patterns visibly differ between patients who do and do not develop metastasis within 5 years.
• Oncotype Dx Breast Cancer Recurrence Score: PCR-based quantification of 21 tumour mRNA genes, grouped into proliferation (Ki-67, STK15, Survivin, Cyclin B1, MYBL2), invasion (Stromelysin 3, Cathepsin L2), HER2 (GRB7, HER2), estrogen (ER, PR, Bcl2, SCUBE2), reference genes (beta-actin, GAPDH, RPLPO, GUS, TFRC), and other (GSTM1, CD68, BAG1).
  • Recurrence Score = +0.47 x HER2 group score, -0.34 x ER group score, +1.04 x Proliferation group score, +0.10 x Invasion group score, +0.05 x CD68, -0.08 x GSTM1, -0.07 x BAG1.
  • Risk categories: <18 low, 18-25 intermediate, >25 high recurrence risk.
  • Outcome data (Dowsett et al. 2010): at 9 years, node-negative breast cancer recurrence-free survival was 96% (low), 88% (intermediate), 75% (high) (high vs low HR 5.2); node-positive breast cancer was 83%, 72%, 51% respectively (high vs low HR 2.7). Higher recurrence score groups have progressively worse distant-recurrence-free survival in both node-negative and node-positive disease.

Drug Target Identification

• Example categories: growth factor receptor amplification, receptor mutations, mutations conferring drug resistance or response, and other signalling-pathway mutations.
• HER2 amplification: found in ~25% of breast cancers, causing over-active (or in some receptors, blocked) signalling. Trastuzumab (Herceptin) prevents growth factor binding and activates an immune response. Newer antibody-drug conjugates such as trastuzumab-deruxtecan link a HER2 antibody, via a cysteine residue and chemical linker, to a toxic payload that is delivered specifically to HER2-expressing cells.
• EGFR mutations in non-small cell lung carcinoma (NSCLC): ~25% of patients carry activating somatic EGFR mutations, enhancing cell survival/proliferation. Osimertinib blocks this signalling and increases median survival in stage 2-3 mutation-positive patients from 18 months to ~5 years.
• Anti-EGFR resistance in colorectal cancer: cetuximab (or other anti-EGFR antibodies) is useful but ineffective in ~45% of patients. This is explained by downstream activating mutations that keep the pathway signalling despite receptor blockade: EGF receptor → GRB2 → KRAS (mutated in 35% of CRC) → BRAF (mutated in 13% of CRC) → MEK1/2 → ERK1/2 → nucleus, driving cell survival, proliferation, angiogenesis and migration. Mutations in KRAS or BRAF render anti-EGFR antibodies ineffective because they act downstream of the blocked receptor.
• Mismatch repair status and immunotherapy: in colorectal cancer, mismatch-repair-deficient tumours (which carry a higher mutation burden and so present more neoantigens) respond better to PD-1/PD-L1 immunotherapy than mismatch-repair-proficient tumours — overall survival at 12-15 months was ~70% vs ~35% (P=0.03).
• High-throughput panel sequencing: FoundationOne sequences 315 cancer genes per tumour.

  The full gene panel grid was too dense/small to transcribe every gene name with confidence; representative genes and the highlighted subset (including BRAF, BRCA1/2, MLH1, MSH2, EGFR, CDH1, KRAS, TP53, TERT, MYC) are recorded.

  • Example CRC report: 7 genomic findings including BRAF V600E, MET amplification, FBXW7 R505L, RNF43 S475fs*2, TP53 R175H; microsatellite-stable, tumour mutational burden intermediate (7 mutations/Mb); no alterations found in KRAS or NRAS. This yielded 9 therapies with potential clinical benefit and 25 matching clinical trials — e.g. BRAF V600E is FDA-approved for regorafenib in CRC, and matched to other BRAF/MEK inhibitors (binimetinib, cobimetinib, dabrafenib, encorafenib, trametinib, vemurafenib) approved in other tumour types.
  • Real-world impact: about 30% of patients who undergo DNA sequencing workup receive a matched drug (US/Europe); those who receive a matched drug have longer progression-free and overall survival than those who do not (hazard ratio ≈0.5, Gibbs et al. 2023 meta-analysis).

Acquired Drug Resistance

• Mechanism: natural selection favours tumour subclones carrying mutations that bypass the drug blockade (analogous to Darwinian selection, e.g. Darwin’s finches).
• BRAF V600E (Val600Glu) mutation is present in >50% of melanomas and is targeted by vemurafenib, acting on the same EGFR → GRB2 → KRAS → BRAF → MEK1/2 → ERK1/2 → nucleus pathway.
• Clinical example: a patient with numerous subcutaneous melanoma metastases showed dramatic regression after 15 weeks of vemurafenib.

  The slide heading also referenced a 23-week timepoint, but only "before" and "15-week" photographs were shown.

• Two resistance mechanisms follow initial response: (1) selection for new BRAF mutations that prevent vemurafenib from binding; (2) activation of alternative signalling pathways, or selection for new activating mutations, that bypass BRAF inhibition entirely.
• Proactive use of drug combinations delays resistance: BRAF/MEK inhibitor combinations give a median progression-free survival of 15 months.

Markers of Treatment Response and Relapse

• Methods include radiographic imaging (CT scan), serum antigens (e.g. CEA), and circulating tumour DNA (ctDNA) — mutated tumour-derived DNA shed into plasma.
• ctDNA allows rapid assessment of treatment efficacy, stopping futile treatment sooner, earlier identification of relapse, and quick assessment of novel treatments.
• Case example (M019, TP53 c.818 G>A, colorectal cancer metastatic to liver and lymph nodes): ctDNA fell from ~500 to a nadir of ~35 copies/mL plasma during initial CAPEOX chemotherapy, then rose progressively above 10,000 despite a lower dose and a switch to FOLFIRI, before falling again later. Radiographic assessments (partial response/progressive disease) lagged behind the ctDNA trend, showing ctDNA can detect treatment response and relapse ahead of imaging.

Cancer as a Chronic Disease

Personalised cancer management is framed as a cyclical process: initial diagnosis (genomics, pathology and imaging) leads to personalised drug selection (drug combinations and immunotherapies targeting driver mutations), which is tracked by surveillance (ctDNA following response); on relapse, the tumour is resequenced to identify how it has evolved (“redesign”), and this feeds back into a new round of personalised drug selection, closing the loop.

Self-test

1. Define penetrance, and give the approximate proportion of all cancers falling into each of the three heritability categories.
2. List the four inherited cancer syndromes covered in detail in this lecture, with their associated gene(s).
3. Describe how BRCA1/2 inactivation affects mutation rate, and give the lifetime risks of breast and ovarian cancer for carriers.
4. Outline the three components of BRCA1/2 clinical management, with one example of each.
5. Distinguish Lynch syndrome from familial adenomatous polyposis in terms of causative genes, incidence, and lifetime colorectal cancer risk.
6. Describe the genotype-phenotype correlation between classic and attenuated FAP.
7. Explain the normal function of the protein encoded by CDH1, and describe how its loss contributes to hereditary diffuse gastric cancer.
8. What single genetic event caused hereditary diffuse gastric cancer in Family A, and what does this illustrate about the scale of the human genome?
9. List the four hallmarks suggesting a cancer is inherited rather than sporadic.
10. Distinguish the “now” (population-based) and “emerging” (personalised) treatment paradigms for sporadic cancer, and name the three categories of genetic methods supporting personalised treatment.
11. Describe how the Oncotype Dx Recurrence Score is calculated and used, including its three risk categories.
12. Explain why anti-EGFR antibodies (e.g. cetuximab) fail in a substantial proportion of colorectal cancer patients.
13. Describe how mismatch repair status predicts response to PD-1/PD-L1 immunotherapy in colorectal cancer, and explain why.
14. Describe two distinct mechanisms by which melanomas become resistant to vemurafenib, and one strategy used to delay resistance.
15. Explain why circulating tumour DNA (ctDNA) can be more useful than radiographic imaging for monitoring treatment response and relapse, using the M019 case as an example.
16. Describe the four-stage cyclical model of cancer as a chronic disease.

Answers

Reveal answers

1. Penetrance is the likelihood that a carrier of a mutation will develop cancer. Roughly 80% of cancers are sporadic, 15% are inherited with low penetrance, and 5% are inherited highly-penetrant cancer syndromes.
2. Hereditary breast-ovarian cancer (BRCA1, BRCA2), Lynch syndrome (MLH1, MSH2, MSH6, PMS2), familial adenomatous polyposis (APC, MUTYH), and hereditary diffuse gastric cancer (CDH1, CTNNA1).
3. Inactivation of BRCA1/2 (dsDNA repair genes) increases mutation rate 8-fold. Lifetime risk is 40-90% for breast cancer and 30-60% for ovarian cancer.
4. Surveillance (clinical breast exam every 6-12 months from 25y, annual MRI/mammography from ~30y); prophylactic surgery (mastectomy or oophorectomy, each ~90% risk reduction); chemoprevention (tamoxifen/aromatase inhibitors, ~40% breast cancer risk reduction, though tamoxifen raises endometrial cancer risk).
5. Lynch syndrome is caused by germline mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2), has an incidence of 1 in 300, and carries an 80% lifetime CRC risk. FAP is caused by APC mutations, has an incidence of 1 in 10,000, and has 100% penetrance for polyposis/CRC.
6. Classic FAP produces 100-1000s of colonic polyps and typically requires colectomy at 15-25 years; attenuated FAP has fewer polyps and a later age of onset, reflecting a milder underlying APC genotype.
7. CDH1 encodes E-cadherin, a cell-to-cell adhesion protein that (with β-catenin and CTNNA1/α-catenin) maintains tissue integrity, cell polarity and differentiation. Loss of E-cadherin function disrupts cell adhesion control, permitting the multifocal, infiltrative diffuse gastric cancer (and lobular breast cancer) characteristic of HDGC.
8. A single germline G→T point mutation in CDH1, one changed letter among 3 billion base pairs of DNA. This illustrates how a single nucleotide change can underlie a whole family’s inherited cancer risk.
9. High incidence in family groups, predominance of particular cancer types, early age of onset, and increased risk of multifocal/bilateral disease.
10. “Now” gives population-based treatment that suits the average patient; “emerging” gives personalised treatment matched to the individual’s cancer. The three method categories are: prognosis/risk of recurrence (gene expression analysis), drug target identification, and markers of treatment response and relapse.
11. It is a PCR-based recurrence score from 21 tumour mRNA genes (proliferation, invasion, HER2, estrogen, reference and other genes), combined in a weighted formula dominated by the proliferation and HER2 group scores. Scores <18 are low risk, 18-25 intermediate risk, and >25 high risk of recurrence.
12. In ~45% of patients the pathway remains active downstream of the blocked receptor: activating mutations in KRAS (35% of CRC) or BRAF (13% of CRC) keep GRB2→KRAS→BRAF→MEK1/2→ERK1/2 signalling on regardless of EGFR blockade.
13. Mismatch-repair-deficient tumours carry a higher mutation burden, producing more neoantigens that the immune system can recognise, so they respond better to PD-1/PD-L1 inhibitors than mismatch-repair-proficient tumours (overall survival ~70% vs ~35% at 12-15 months, P=0.03).
14. (1) Selection for new BRAF mutations that prevent vemurafenib from binding; (2) activation of alternative signalling pathways or new activating mutations that bypass BRAF inhibition. Proactive combination therapy (e.g. BRAF/MEK inhibitors) delays resistance, giving a 15-month median progression-free survival.
15. ctDNA directly measures tumour-derived mutant DNA in plasma, so its levels change in near-real time with tumour burden; in the M019 case, ctDNA rose sharply while imaging still showed only a lagging partial response, meaning ctDNA can flag treatment failure and relapse earlier than radiographic imaging.
16. Initial diagnosis (genomics, pathology, imaging) → personalised drug selection (targeted drugs/immunotherapies) → surveillance (ctDNA tracking response) → on relapse, redesign (resequencing to track tumour evolution) → feeding back into a new round of personalised drug selection.