GC156 Many Of My Family Members Have Cancers Cancer Genetics And Cytogenetics (file 1)
Cancer genetics and cytogenetics is the study of hereditary gene mutations and chromosomal abnormalities that predispose individuals and their families to the development of various malignancies.
Cancer Genetics and Cytogenetics — "Many of My Family Members Have Cancers"
Big Idea: Cancer is fundamentally a genetic disease. While most cancers arise from acquired (somatic) changes, a clinically important subset reflects an inherited (germline) predisposition. Recognising syndromes such as Lynch syndrome (historically called HNPCC) and familial adenomatous polyposis (FAP) can prevent cancer in relatives through cascade testing, tailored surveillance and, in selected settings, risk-reducing surgery. The lecture's central message is therefore family-wide: treat the index patient, but also recognise who else may be at risk.
Learning Objectives (from lecture notes) [1][2]:
- Recognise that cancers develop from genetic or epigenetic aberrations — most acquired, some inherited
- Recognise that inherited defects in tumour suppressor genes are the most common cause of familial cancers
- Describe characteristics of familial cancers: same/specific cancer types clustering in families, early age of onset
- Explain the need for taking a family history of cancer in every newly diagnosed cancer patient
- Recognise that a strong family history is an indication to search for known cancer genes
- Identify confirmed cancer families who should be offered more frequent and specific screening
- Recognise that genes involved in familial cancers are also mutated in sporadic cancers
Core Concepts and Mechanisms
Cancer arises from two fundamental classes of genetic change: (1) overactivity of oncogenes and (2) inactivation of tumour suppressor genes (TSGs). These changes can be acquired (somatic) or inherited (germline). Inherited mutations in tumour suppressor genes are the most common causes of familial cancer. [1]
Why this matters from first principles:
- Every cell's growth is balanced between accelerators (oncogenes) and brakes (TSGs).
- Cancer occurs when the balance tips — either the accelerator gets stuck "on" or the brakes fail.
- Oncogenes are activated by: gene amplification, point mutation, chromosomal translocation, viral promoter insertion [1]
- TSGs are inactivated by: deletion, mutation, epigenetic inactivation (e.g. promoter methylation) [1]
How to read the opening balance diagrams:
| Visual element | Meaning |
|---|---|
| Red blocks labelled A–E | Multiple routes by which a proto-oncogene can become overactive; the diagram shows increasing pro-growth drive |
| Paired pale blocks on homologous chromosomes | The two alleles of a tumour-suppressor locus |
| Level balance beam | Pro-growth and growth-suppressing forces are initially balanced |
| Beam tipping towards “stimulate” | Extra oncogenic drive and/or loss of suppressor function shifts the cell towards net growth |
The picture is conceptual rather than quantitative: cancer usually reflects the accumulation and selection of several cooperating driver alterations, not a literal count of red blocks.
Key Distinction: Oncogenes vs TSGs in Familial Cancer
Many classic hereditary cancer syndromes involve a germline loss-of-function variant in a tumour-suppressor or DNA-repair gene. At the organism level, susceptibility is inherited dominantly; at the cell level, tumour formation often requires inactivation of the remaining functional allele. Do not turn this into an absolute rule: inherited activating variants do exist (for example, RET in MEN2), and not every tumour-suppressor gene follows a simple two-hit mechanism.
Tumour suppressor genes protect cells from neoplastic transformation. Two copies are present in each cell (paternal and maternal alleles). Expression of one allele is enough to suppress tumour formation. For cancers to form, both alleles need to be inactivated (2-hit) in the same cell. [1]
The logic:
- You have two copies of every TSG (one from each parent).
- One functioning copy is sufficient — the TSG product is still made and the cell remains protected.
- Cancer requires loss of both copies in a single cell.
| Scenario | First Hit | Second Hit | Clinical Consequence |
|---|---|---|---|
| Sporadic cancer | Somatic mutation in one allele of one cell | Somatic mutation/LOH in the same cell's remaining allele | Both hits must occur somatically → rare event → late onset, usually single tumour |
| Familial cancer | Germline mutation inherited at birth → present in ALL cells | Somatic loss of remaining allele in ANY cell | Only one somatic hit needed → much higher probability → early onset, often multiple tumours |
In familial cancer, one copy is already defective in all cells at birth. Normal development is still possible because there remains a functioning copy in all cells. When the remaining copy is inactivated in any cell, cancer can develop. Thus the observed cancer risk is substantially higher and cancers occur at an early age. Furthermore an individual may develop multiple cancers. [1]
What the animated cell mosaic adds:
- Top row (sporadic): all cells begin
+/+. One clone becomes+/−, then a descendant acquires the second hit and becomes−/−; two rare events must occur in the same lineage. - Bottom row (Lynch carrier): every cell begins
+/−because the first hit is germline. A single somatic second hit creates an MMR-deficient−/−clone, which can expand. - The repeated “30 years” labels emphasise time and probability, not a fixed latency. A carrier has many more at-risk cells and may develop earlier or multiple primaries, but cancer is not inevitable at a particular age.
Exam Trap: Why Normal Development in Carriers?
Students often ask: "If every cell has a defective allele, why doesn't the patient have cancer from birth?" In the classical two-hit model, the remaining allele supplies enough function until a susceptible cell acquires a second hit. The carrier is heterozygous; do not call this haploinsufficiency, which specifically means that one functional copy is not sufficient. Also remember that haploinsufficiency, dominant-negative effects and epigenetic silencing are genuine exceptions to the simple model.
The lecture shows a CRC patient with germline c.1452-1455delAATG in MSH2 and loss of the wild-type allele in the tumour [1]. In the blood chromatogram, the heterozygous deletion causes overlapping peaks after the variant because both alleles are being read. Comparison with tumour DNA demonstrates preferential loss of the wild-type contribution: a molecular illustration of the second hit.
LOH means loss of one parental allele at a locus; it can result from deletion, mitotic recombination, gene conversion or chromosome loss with reduplication. It does not always mean that a visibly large chromosome segment was deleted, and a second hit can also occur without LOH (for example, a second sequence variant or promoter methylation).
Lynch Syndrome (historically HNPCC)
The lecture estimates HNPCC at ~4% of CRC and emphasises early onset, autosomal-dominant inheritance with incomplete penetrance, extracolonic cancers, and the absence of an obvious premonitory phenotype. [1]
Current terminology prefers Lynch syndrome; “non-polyposis” is misleading because carriers can develop adenomas and cancers outside the colon. Contemporary estimates place Lynch syndrome at about 3% of newly diagnosed CRC [13]. Family history remains essential, but an unremarkable pedigree does not exclude it: small families, adoption, incomplete penetrance, later-onset MSH6/PMS2 disease and de novo or unrecognised variants can conceal the pattern.
Lynch-associated cancers commonly show mismatch-repair deficiency (dMMR) and microsatellite instability (MSI). Lynch syndrome results from a germline pathogenic variant in MLH1, MSH2, MSH6 or PMS2, or an EPCAM deletion that epigenetically silences adjacent MSH2. [1][13]
From first principles — what is DNA mismatch repair?
- During DNA replication, DNA polymerase occasionally makes errors (e.g. inserting the wrong base, or slipping on repetitive sequences).
- The MMR system is a quality-control team that:
- Recognises the mismatch
- Excises the erroneous segment
- Re-synthesises the correct sequence
- Key MMR proteins: MLH1, MSH2, MSH6, PMS2 [1][3]
What the protein-complex diagram shows:
- MutSα (MSH2–MSH6) recognises base–base mismatches and small insertion/deletion loops.
- MutSβ (MSH2–MSH3) preferentially recognises larger insertion/deletion loops.
- MutLα (MLH1–PMS2) is recruited downstream to coordinate excision and resynthesis.
- The slide also displays meiotic MSH4–MSH5 complexes; these are not the four proteins routinely stained when screening a colorectal tumour for Lynch syndrome.
What happens when MMR is deficient?
- Replication errors accumulate, especially at microsatellites — short tandem repeat sequences (e.g. CA repeats) scattered throughout the genome.
- DNA polymerase slippage at these repeats causes insertions (backward slippage) or deletions (forward slippage) [1].
- Normally, MMR corrects these. Without MMR → the repeats expand or contract → microsatellite instability (MSI).
The repeat diagram starts with six CA units. A loop in the newly synthesised strand adds a repeat (seven units); a loop in the template strand loses one (five units). The important endpoint is the length difference between tumour and normal microsatellite alleles—not the arrow names in isolation.
Microsatellite instability (MSI) is a form of genetic instability characterised by the expansion and contraction of small repeat sequences during DNA replication. This is related to defect in the DNA mismatch repair (MMR) system. [1]
Why MSI leads to cancer:
- Some microsatellites are located within coding regions of important growth-regulatory genes (e.g. TGFBR2, BAX, IGFR2).
- Insertions/deletions cause frameshift mutations → loss of function of these genes → uncontrolled growth.
Colorectal cancer with microsatellite instability is distinguished into two groups according to age of onset:
- Early onset group — germline mutation in the DNA mismatch repair genes (HNPCC)
- Late onset group — Promoter methylation of the MLH1 gene which is somatically acquired [1]
The early/late split is a useful historical teaching model, but age does not determine aetiology. Older patients can have Lynch syndrome, and younger patients can have sporadic dMMR tumours.
| Feature | Lynch-associated dMMR/MSI-H | Common sporadic MLH1-methylated dMMR/MSI-H CRC |
|---|---|---|
| Initiating predisposition | Germline pathogenic variant in an MMR gene, or EPCAM deletion | Acquired MLH1 promoter hypermethylation in tumour precursor cells |
| Typical context | Often younger/multiple primaries or suggestive family history, but none is required | More common at older age and usually no Lynch pedigree |
| IHC pattern | Depends on the affected gene and its binding partner | Usually paired MLH1/PMS2 loss |
| Helpful CRC reflex test | Germline assessment after appropriate tumour triage | MLH1 promoter methylation; BRAF V600E supports a sporadic colorectal origin |
High Yield: BRAF V600E as Discriminator
In a colorectal tumour with MLH1/PMS2 loss, MLH1 promoter methylation testing and/or BRAF V600E can help triage likely sporadic cases. A BRAF V600E result strongly supports sporadic MLH1 methylation, but BRAF-negative does not diagnose Lynch; proceed through genetics assessment and germline testing as appropriate. Do not transplant this BRAF rule uncritically to endometrial cancer. Rare constitutional MLH1 methylation and biallelic somatic MMR alterations also complicate the binary model [13].
The slide's historical local series of 132 MSI-H CRCs reported loss of at least one of the three MMR proteins then assessed in 95% of cases. [1]
IHC for MLH1, MSH2, MSH6, PMS2 on tumour tissue is a practical first-line test:
- Normal: nuclear staining in tumour cells (internal positive control: stromal/inflammatory cells should stain)
- Abnormal: loss of nuclear staining in tumour cells with retained stromal staining → indicates which MMR protein is deficient → guides which gene to sequence
In the four micrographs, retained MSH2/MLH1 appears as brown tumour-cell nuclear staining. In the loss examples the malignant glands are pale, while non-neoplastic stromal/lymphoid nuclei remain brown and prove that the stain worked. Cytoplasmic colour alone is not retained MMR expression.
| IHC Loss Pattern | Gene Most Likely Mutated |
|---|---|
| MLH1 + PMS2 loss | MLH1 (or sporadic methylation) |
| MSH2 + MSH6 loss | MSH2 (or EPCAM) |
| MSH6 loss alone | MSH6 |
| PMS2 loss alone | PMS2 |
Why the paired loss? MLH1 stabilises PMS2, while MSH2 stabilises MSH6. Thus loss of MLH1 commonly causes secondary PMS2 loss, and loss of MSH2 commonly causes secondary MSH6 loss. The reverse is not obligatory, which is why isolated PMS2 or isolated MSH6 loss occurs.
The younger the age of colon cancer onset, the risk of HNPCC is higher:
- Age ≤35: 60% due to HNPCC
- Age 36-45: 20% due to HNPCC
- The risk increases further if there is a positive family history of colon cancer [1]
Treat these percentages as a historical, selected local study quoted by the lecture, not current population prevalence. The durable lesson is that very early CRC and a positive family history should heighten suspicion. Current practice goes further: all newly diagnosed CRCs should undergo tumour screening for dMMR/MSI rather than limiting screening to young patients [13].
Diagnostic Criteria
Amsterdam criteria — at least three relatives with histologically verified CRC; one is a 1st degree relative of the other 2; at least 2 successive generations affected; one of the CRC diagnosed before age 50. [1]
Subsequently it was found that > 90% of HNPCC families satisfying Amsterdam Criteria are due to germline DNA MMR gene mutation (MSH2 and MLH1). [1]
| Rule | Criterion |
|---|---|
| 3 relatives | With histologically verified CRC (one 1st-degree relative of other two) |
| 2 generations | At least 2 successive generations affected |
| 1 before 50 | At least one CRC diagnosed before age 50 |
| Exclude FAP | Must rule out FAP |
| Pathology verified | Tumours verified by pathological examination |
The slide states the original CRC-focused Amsterdam I formulation. Amsterdam II broadened the qualifying tumour spectrum to CRC, endometrial, small-bowel, ureteric and renal-pelvis cancers. These criteria identify striking pedigrees but are not sufficiently sensitive to rule Lynch syndrome in or out.
Revised Bethesda criteria (2004):
- CRC diagnosed in a patient < 50 years
- Synchronous and metachronous CRC or other HNPCC-associated tumours regardless of age
- CRC diagnosed in two or more 1st or 2nd degree relatives with HNPCC-related tumours, regardless of age [1]
The slide displays an abridged three-item version. For exams that ask for the complete 2004 Revised Bethesda guidelines, tumour MSI testing was indicated if any one applied [13]:
- CRC diagnosed before age 50.
- Synchronous or metachronous CRC or another Lynch-associated tumour, regardless of age.
- CRC with MSI-H-associated histology diagnosed before age 60 (tumour-infiltrating lymphocytes, Crohn-like reaction, mucinous/signet-ring or medullary pattern).
- CRC plus at least one first-degree relative with a Lynch-associated tumour, with one tumour diagnosed before age 50.
- CRC plus two or more first- or second-degree relatives with Lynch-associated tumours, regardless of age.
Key difference: Amsterdam describes high-risk families; Bethesda was a broader trigger for tumour testing. Neither is a modern gatekeeper: universal dMMR/MSI screening of all newly diagnosed CRC (and commonly all endometrial cancers) is more sensitive [13].
Histological spectrum of HNPCC-related extra-colonic cancers: [1]
- Endometrial carcinoma
- Ovarian carcinoma
- Gastric adenocarcinoma
- Hepatobiliary/cholangiocarcinoma
- Pancreas adenocarcinoma
- Small bowel adenocarcinoma
- Urothelial carcinoma of the renal pelvis, ureter or bladder
- Brain (glioma/glioblastoma)
- Sebaceous gland adenomas
- Keratoacanthomas
Memory Aid: Lynch Extra-Colonic Cancers
Think "CLOSE-UP": Colon, Liver/bile duct, Ovary, Stomach, Endometrium, Ureter/renal pelvis, Pancreas/brain/skin. Endometrial cancer is the major extracolonic association, but penetrance and the tumour spectrum are gene-specific. Sebaceous neoplasms point towards the Muir–Torre phenotype. A syndrome association does not automatically mean that population-style screening for every listed organ has proven benefit.
Pedigree lesson from the image-heavy slides: the diagnosis is not restricted to a family with three obvious CRCs. The examples include an adopted patient with no accessible family history, an endometrial-cancer family, and a young person whose relatives have different Lynch-associated tumours. Read each pedigree in three passes: (1) tumour type and age, (2) lineage across generations, and (3) which person is the index case/inquirer. Blank symbols mean unaffected or unknown—not genetically negative.
The later cascade-testing sequence adds coloured result markers to the same pedigrees. Those colours and smiley faces are lecture-specific annotations, not standard pedigree symbols: use the accompanying text to decide who carries the familial variant and who is a tested non-carrier. The surveillance outcomes are the clinical payoff—a 28-year-old relative had a 5 cm serrated lesion with severe dysplasia removed, while another newly identified carrier had a caecal tumour and synchronous adenomas found at colonoscopy. The visual message is that predictive testing does not merely label risk; it selects relatives in whom surveillance can remove an advanced precursor or find an otherwise occult cancer.
Slide-era aggregate risk table (risk by age 70): [1]
| Cancer | General-population risk shown | HNPCC risk shown | Mean age shown |
|---|---|---|---|
| Colorectal | 4–5% | 52–80% | 44 years |
| Endometrial | 1.5–2.7% | 20–60% | 46 years |
| Gastric | < 1% | 11–19% | 56 years |
| Ovarian | 1.6% | 9–12% | 42.5 years |
| Hepatobiliary | < 1% | 2–7% | Not reported |
| Urinary tract | < 1% | 4–5% | ~55 years |
| Small bowel | < 1% | 1–4% | 49 years |
| Brain | < 1% | 1–3% | ~50 years |
These older, pooled figures explain the lecture's emphasis on earlier multisystem cancer, but they should not be used as a present-day personalised risk calculator. Modern estimates vary markedly by gene, sex, age and ascertainment [13].
Genetic Diagnosis for HNPCC: [1]
- Analysis of MSI in tumour tissue (can be performed in paraffin blocks, paired tumour/normal tissue)
- Immunohistochemical staining for MMR protein
- Genetic diagnosis of MMR genes in blood samples — combination of direct DNA sequencing & MLPA analysis (or next generation sequencing)
- Once the germline mutation is defined for an index patient, simpler molecular diagnostic test can be devised for the specific family
Practical flow:
- Screen the tumour universally: perform four-protein MMR IHC and/or MSI testing in every newly diagnosed CRC; universal testing is also widely used for endometrial cancer [13].
- Interpret the pattern: MLH1/PMS2 loss in CRC prompts MLH1 promoter methylation and/or BRAF V600E triage; other loss patterns direct genetics evaluation.
- Test the germline with consent and counselling: a blood or saliva multigene panel assesses MLH1, MSH2, MSH6, PMS2 and EPCAM, including copy-number changes. A variant of uncertain significance is not a positive predictive result.
- Resolve unexplained dMMR when needed: paired tumour–normal testing may reveal biallelic somatic MMR hits rather than inherited Lynch syndrome.
- Cascade test relatives only after a familial pathogenic/likely pathogenic germline variant is established; targeted testing is then simpler and more informative.
The sequencing images make the specimen distinction concrete: blood leucocyte DNA demonstrates the constitutional heterozygous variant, while tumour DNA can demonstrate the acquired second hit. Tumour-only findings must not automatically be labelled germline.
Family members are at risk of inheriting the disease/defective genes (50% chance). Enough evidence to support that screening and surveillance of these high risk individuals can: detect premalignant lesions, detect cancer at early stages, prevent cancer development and overall decrease CRC morbidity and mortality. [1]
| Site | What the lecture-era table shows | Current interpretation |
|---|---|---|
| Colon | Colonoscopy from 20–25 every 2 years, then annually after 40 | High-quality colonoscopy every 1–2 years is the core intervention. Starting age is gene- and family-history-specific: generally earlier for MLH1/MSH2/EPCAM and later for MSH6/PMS2 [13] |
| Endometrium | Examination, aspirate and ultrasound from 30–35 every 1–2 years | Teach prompt recognition (especially abnormal bleeding). Endometrial biopsy every 1–2 years from 30–35 may be considered, but survival benefit is unproven; TVUS is not a reliable premenopausal screening test [13] |
| Ovary | Ultrasound and CA-125 from 30–35 every 1–2 years | Routine ovarian screening with CA-125/ultrasound is not recommended; discuss gene-specific risk and risk-reducing surgery after childbearing [13] |
| Stomach/other organs | EGD, urinary ultrasound and cytology in selected families | Individualise by pathogenic gene, ancestry and family history; EGD is commonly considered from 30–40, whereas evidence for routine urinary screening is limited [13] |
The serial-colonoscopy slide follows one young male carrier from age 41 to 44: a rectal tubulovillous adenoma is removed, another sigmoid polyp appears the next year, a further tubulovillous adenoma appears a year later, and two more adenomas are removed at 44. This visual is the practical rationale for repeated surveillance—polypectomy prevents progression, but a clear examination does not end future risk.
Regular colonoscopy screening (every 2-3 yrs) in HNPCC gene carriers reduces colon cancer incidence by 60% and mortality by 100%. [1]
High Yield Screening Fact
The slide's “60% reduction in incidence and 100% reduction in mortality” comes from a particular controlled family study: 8/133 screened relatives developed CRC versus 19/119 controls, and there were zero versus nine CRC deaths during that study's follow-up [13]. Report it as a study result, not a guarantee that surveillance makes an individual's lifetime CRC mortality zero. Interval cancers still occur, which is why the short colonoscopy interval matters.
Advantages: [1]
- Identify defective gene carriers from non-carriers within families
- Vigilant clinical screening, early intervention, possibly chemopreventive measures targeted to high-risk members
- Prophylactic surgery to prevent gynaecological cancers after completion of family in female gene carriers
- Low-risk members are spared from repeated colonoscopy
Proper genetic counseling before decision to undertake genetic testing. Genetic counseling given again as guided by results. Low-risk individuals are relieved from unnecessary psychological burden. For high-risk individuals, detail explanations concerning the nature of the disease and discussions on possible options and alternatives on prevention. [1]
Why pre-test counselling is essential:
- The result has implications not just for the patient but the entire family
- Genetic stigma, privacy/insurance concerns and psychological burden [1]
- Patient must understand what a positive result means (not certainty of cancer, but increased risk) and what options exist
- Possible outcomes include pathogenic/likely pathogenic variant, true negative for a known familial variant, uninformative negative, or variant of uncertain significance
Barriers to genetic testing in HK: reasons for declining include not wanting to know, genetic stigma, psychological burden, worry about insurance. [1]
Genetic Counselling is Required for Germline Tests
The AOS teaching distinction is that formal pre-test genetic counselling is central to germline testing (e.g. BRCA1/2 or Lynch genes) because results affect relatives and future surveillance [5]. Somatic tumour tests may be ordered for diagnosis or treatment without the same hereditary-cancer pathway, but they still require ordinary informed clinical discussion and can occasionally reveal a possible germline finding that needs confirmation. “Somatic test = no consent or no family relevance” is therefore too absolute.
Classic FAP is caused by a germline APC pathogenic variant. Colorectal adenomas usually begin in adolescence and become numerous; untreated classic disease carries a near-100% lifetime CRC risk. Planned colorectal surgery is therefore a central preventive intervention. [1][13]
| Feature | FAP | Lynch Syndrome |
|---|---|---|
| Gene | APC (chromosome 5q21) | MLH1, MSH2, MSH6, PMS2; EPCAM deletion can silence MSH2 |
| Inheritance | AD; classic polyposis has very high penetrance | AD; penetrance and organ-specific risks vary substantially by gene |
| Polyp number | Hundreds to thousands ( > 100) | Few (HNPCC is a misnomer!) |
| CRC risk | Near 100% in untreated classic FAP | Roughly 10–56% by age 75 depending on the gene [13] |
| Distribution | Profuse colorectal polyposis | CRC often proximal/right-sided, but can occur anywhere |
| Extra-colonic | Duodenal adenomas, desmoids, osteomas, CHRPE, thyroid (papillary), hepatoblastoma | Endometrial, ovarian, gastric, urinary tract, brain, sebaceous |
| Cancer pathway | Chromosomal instability (CIN) | Microsatellite instability (MSI) |
| Management | Endoscopic surveillance plus appropriately timed colectomy/proctocolectomy; continue surveillance of retained rectum/pouch and upper GI tract | Frequent colonoscopy; gene- and sex-specific risk reduction, including discussion of hysterectomy ± salpingo-oophorectomy |
Key points from lecture:
- FAP: the visual pedigree uses triangles to show affected members in an autosomal-dominant vertical pattern; a normal symbol does not prove a relative is a non-carrier unless predictive testing was done.
- FAP: surgery is anticipated for classic disease, but timing and operation depend on polyp burden, dysplasia/cancer, APC phenotype, continence/fertility considerations and ability to survey remaining mucosa.
- Lynch: polyposis is not the defining phenotype; prevention relies chiefly on close colonoscopic surveillance plus tailored risk-reducing options.
- FAP causes under 1% of CRC; the lecture's ~4% Lynch estimate is close to the contemporary estimate of approximately 3% [1][13].
FAP variants (from senior notes for context) [3][4]:
- Gardner syndrome = FAP + extracolonic manifestations (osteomas, desmoids, epidermoid cysts)
- Turcot syndrome = FAP + CNS tumours (medulloblastoma)
- Attenuated FAP = fewer adenomas (often 10–99), later onset and relatively proximal distribution; if APC testing is unrevealing, consider phenocopies such as MUTYH-associated polyposis rather than assuming the phenotype is non-genetic
Table from lecture slides: [1]
| Familial Cancer Syndrome | Tumour Types | Gene |
|---|---|---|
| Hereditary diffuse gastric cancer | Stomach (diffuse/signet ring) | E-cadherin (CDH1) |
| Li-Fraumeni Syndrome | Sarcoma, breast cancer, leukaemia, brain tumours, adrenocortical carcinoma | TP53 |
| Von Hippel-Lindau syndrome | Renal cell carcinoma, haemangioblastoma (CNS/retina), phaeochromocytoma | VHL |
| Familial Malignant Melanoma | Melanoma | CDKN2A |
| Ataxia-telangiectasia | Leukaemia and lymphoma | ATM |
Additional from lecture notes:
- Depending on mode of inheritance and penetrance, family members who inherited the mutated allele will not invariably develop cancer (e.g. Lynch, BRCA). In other instances, penetrance is 100% (e.g. FAP). Some cancers are inherited in autosomal recessive pattern (e.g. ATM). [2]
- More precisely, ataxia-telangiectasia requires biallelic pathogenic variants in ATM and is autosomal recessive. A heterozygous ATM pathogenic variant is a different clinical state associated with moderate cancer susceptibility; do not call every ATM carrier an ataxia-telangiectasia patient [14].
Hereditary Breast/Ovarian Cancer (BRCA1/2) — covered in File 2 of this lecture but briefly:
- BRCA1 (chr 17q), BRCA2 (chr 13q) — TSGs involved in DNA double-strand break repair
- AD inheritance, ~5% of all breast cancers
- BRCA1: 72% lifetime breast cancer risk, 44% ovarian cancer risk
- BRCA2: 69% lifetime breast cancer risk, 17% ovarian cancer risk [6]
- Options: enhanced screening (MRI/MMG), chemoprevention (tamoxifen), prophylactic bilateral mastectomy, bilateral salpingo-oophorectomy
Hepatitis B virus infection — vertical transmission from mother to children with multiple chronic carriers in the family, leading to substantially increased risk for hepatocellular carcinoma. Common exposure to environmental carcinogens. Yet unknown genes for cancer susceptibility (intermediate or low risk alleles). Complex interplay between genetic and environmental factors. [1]
This is a critical exam discriminator: not every family cluster is a monogenic cancer syndrome. Perinatally transmitted HBV can cluster in a Hong Kong family and raise HCC risk without a cancer-predisposition allele; shared carcinogen exposure and polygenic susceptibility can also aggregate disease. A cluster still deserves a careful pedigree and exposure history rather than an automatic “genetic” or “non-genetic” label.
This File 1 deck itself is about hereditary cancer genetics and does not teach karyotype/FISH technique. The following short cross-reference comes from the cited supporting notes and past papers because the session title includes “cytogenetics”; keep it conceptually separate from the slide-derived Lynch/FAP material.
- Cells must be in metaphase (chromosomes maximally condensed and visible)
- Add colchicine to inhibit spindle formation → arrest in metaphase
- Giemsa staining (G-banding) to identify chromosomal abnormalities
- Limitation: requires dividing cells → difficult for indolent malignancies (e.g. CLL, myeloma)
FISH (Fluorescence In Situ Hybridisation) [7]:
- Fluorescent probes bind specific DNA sequences
- Higher sensitivity than karyotyping (can detect smaller abnormalities)
- Can be done on non-dividing cells
- Used for: diagnosis (e.g. t(9;22) in CML), prognostication, treatment selection
Molecular genetics [7]:
- PCR-based and next-generation sequencing
- Detect point mutations, small insertions/deletions
- Used for germline testing (Lynch, BRCA) and somatic testing (EGFR, KRAS, BRAF)
Familial cancer is not uncommon — family history is important. Characteristics: familial clustering of same or specific types of cancer (e.g. colon and endometrium; breast and ovary) plus early age of onset. Genetic diagnosis available for many familial cancers. Increased alertness and diligent referral can help patient and family to prevent cancer through prophylactic screening or treatment. A doctor does not just treat a patient, but also the family. A doctor does not just treat a cancer after it develops, but can prevent cancer if proper attention is paid to family history. [1]
Exam Intelligence
| Trap | Correct Understanding |
|---|---|
| "HNPCC = no polyps" | Lynch carriers still form adenomas; “non-polyposis” means they do not have the profuse polyposis of FAP |
| Confusing Amsterdam and Bethesda | Amsterdam identifies striking families; Bethesda was a broader historical trigger for MSI testing. Neither replaces universal tumour screening |
| Thinking all MSI-H CRC = Lynch | dMMR/MSI-H can be sporadic, especially through MLH1 methylation; biallelic somatic MMR hits are another cause |
| Thinking BRAF wild type = Lynch | BRAF V600E supports sporadic MLH1-methylated CRC; its absence only means further assessment is needed |
| Forgetting extra-colonic cancers in Lynch | Endometrial cancer is the major extracolonic association, but screening and risk reduction must be gene- and evidence-specific |
| FAP vs Lynch: surgery | Classic FAP generally requires planned colorectal surgery; Lynch usually uses intensive colonoscopy, with surgery tailored to cancer and individual risk |
| Germline vs somatic testing | A tumour result is not automatically constitutional; confirm suspected germline findings in normal tissue with counselling |
| Karyotyping phase | Metaphase — not prophase or anaphase |
| Sporadic vs familial: age | Early onset raises suspicion but age alone cannot classify a tumour; the lecture's 60% figure came from a historical selected HK cohort |
- CRC with MLH1/PMS2 loss: Check MLH1 methylation ± BRAF V600E; an unmethylated/BRAF-wild-type tumour needs genetics work-up, not an automatic Lynch label
- FAP vs attenuated FAP: Classic FAP > 100 polyps, AFAP = 10-99 polyps, later onset
- BRCA1 vs BRCA2: BRCA1 = higher ovarian risk (44% vs 17%); BRCA2 = also male breast cancer, pancreatic
- Chromosomal instability (CIN) vs MSI pathway: CIN = APC → KRAS → p53 (adenoma-carcinoma sequence); MSI = MMR deficiency
High Yield Summary
-
Cancer is a genetic disease
- driven by oncogene activation and TSG inactivation — most acquired, some inherited.
-
Knudson's two-hit hypothesis
- In the classical model, a hereditary carrier begins
+/−in every cell and needs one somatic second hit, whereas a sporadic clone begins+/+and needs two. This explains earlier/multiple tumours but has biological exceptions.
- In the classical model, a hereditary carrier begins
-
Lynch syndrome
- Approximately 3% of newly diagnosed CRC; AD predisposition from MLH1, MSH2, MSH6, PMS2 or EPCAM, with gene-specific incomplete penetrance.
- Universally screen CRC tumours with MMR IHC and/or MSI. Use the loss pattern and MLH1 methylation/BRAF triage to select germline assessment; Amsterdam/Bethesda are historical clinical tools.
- Extra-colonic cancers: endometrial, ovarian, gastric, urinary tract, brain, sebaceous.
- Colonoscopy every 1–2 years is central; starting age and extracolonic management are gene- and family-specific. The slide's “100% mortality reduction” was an observed trial result, not a lifetime guarantee.
-
FAP
- APC gene, usually hundreds of adenomas and near-100% untreated CRC risk in classic disease; surveillance and appropriately timed colorectal surgery are required.
-
Sporadic MSI-H CRC
- Commonly results from somatic MLH1 promoter methylation. In MLH1/PMS2-deficient CRC, methylation and/or BRAF V600E help triage—but no single negative test proves Lynch syndrome.
-
Always take a family history of cancer.
- The doctor treats not just the patient but the whole family.
Active Recall - Lecture Notes
[1] Lecture slides: GC 156. Many of my family members have cancers Cancer genetics and cytogenetics (File 1).pdf [2] Lecture slides: GC 156. Many of my family members have cancers Cancer genetics and cytogenetics (Notes).pdf [3] Senior notes: Maksim Surgery Notes.pdf (section 4.7 Colorectal carcinoma) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (section III Hereditary CRC syndromes) [5] AOS material: AOS - Pathology.pdf (Molecular genetic testing in Gynaecological cancers) [6] Senior notes: Ryan Ho Urogenital.pdf (BRCA1/2 mutation section) [7] Senior notes: Ryan Ho Fundamentals.pdf (Cytogenetics section) [8] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (CML cytogenetics case study) [13] National Cancer Institute. Genetics of Colorectal Cancer (PDQ®), Health Professional Version (contemporary guidance on Lynch syndrome testing, tumour-screen interpretation and surveillance) [14] GeneReviews: Ataxia-Telangiectasia
GC155 Is Blood Transfusion Absolutely Required In Patient Management Nowadays
Blood transfusion remains essential in specific clinical scenarios such as massive hemorrhage, severe anemia, and critical coagulopathies, though modern alternatives like cell salvage, erythropoietin, and restrictive transfusion strategies have significantly reduced its absolute necessity.
GC156 Many Of My Family Members Have Cancers Cancer Genetics And Cytogenetics (file 2)
Cancer genetics and cytogenetics involve the study of hereditary gene mutations and chromosomal abnormalities that predispose individuals and their family members to developing multiple cancers across generations.