GC156 Many Of My Family Members Have Cancers Cancer Genetics And Cytogenetics (notes)
Cancer genetics and cytogenetics is the study of hereditary gene mutations, chromosomal abnormalities, and familial cancer syndromes that predispose individuals and their relatives to an increased risk of developing various malignancies.
Cancer Genetics and Cytogenetics — "Many of My Family Members Have Cancers"
Lecture Map
Cancers are fundamentally genetic diseases. Most arise from acquired (somatic) mutations, but a clinically critical minority are driven by inherited (germline) mutations in tumour suppressor genes or DNA repair genes. Recognising these familial cancer syndromes transforms management — not just for the patient, but for their entire family — through genetic testing, intensified screening, prophylactic surgery, and genetic counselling. [1]
- Recognise that cancers develop from genetic or epigenetic aberrations — most acquired, some inherited
- Recognise that inherited defects in tumour suppressor genes lead to familial cancers
- Describe characteristics of familial cancers: same/specific cancer types in several members; relatively young age of onset
- Explain the need for family history of cancer in any patient with newly diagnosed cancer
- 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 cancer screening
- Recognise that genes in familial cancers are also mutated in sporadic cancers
This lecture sits at the intersection of genetics, surgical oncology, medical oncology, and preventive medicine. It links directly to GC lectures on breast mass, colorectal cancer, gynaecological cancer, paediatric cancers, and the molecular pathology seminar on gynaecological cancers. Exam-wise, expect MCQs on Knudson's hypothesis, Lynch syndrome diagnostic criteria, BRCA management, and FAP; SAQs on genetic counselling and screening; and minicases where you must recognise a familial pattern from a pedigree.
Core Concepts and Mechanisms
Cancers are the commonest genetic diseases. Most cancers are due to acquired genetic aberrations. [1]
Why does cancer arise? Every cell has built-in controls — tumour suppressors that put the brakes on proliferation, DNA repair enzymes that fix errors, and apoptotic pathways that kill damaged cells. Cancer emerges when enough of these safeguards are disabled by genetic or epigenetic changes.
Types of genetic aberration [1]:
| Level | Examples |
|---|---|
| Chromosomal | Deletions, duplications, translocations |
| Gene-level | Point mutations, gene deletions, gene duplications, gene fusions |
| Epigenetic | Promoter hypermethylation → silencing of tumour suppressor genes |
Epigenetic inactivation refers to epigenetic modification of the genes, mostly in the promoter regions, which results in suppression of expression of the genes concerned. [1]
Why epigenetics matters: A gene can be structurally intact but functionally silenced. This is reversible (unlike mutations), which has therapeutic implications (e.g., demethylating agents in MDS).
Key cellular processes disrupted [1]:
- Cell cycle regulation
- Apoptosis
- DNA repair
- Signal transduction
A tumour suppressor gene is involved. Normally, two copies (alleles) of a given tumour suppressor gene (paternal and maternal) are present. The expression of just one allele is enough to suppress tumour formation. Therefore, for cancers to form, both alleles of the tumour suppressor gene must be mutated in the same cell. [1]
Knudson's Hypothesis — The Core Concept
Sporadic cancer: Both hits are somatic → both alleles of a tumour suppressor gene must be independently mutated in the same cell → rare event → cancer appears later in life, usually unilateral/unifocal.
Familial (hereditary) cancer: One hit is inherited (germline) → every cell in the body already carries one mutant allele → only ONE more somatic hit is needed → cancer appears earlier, often bilateral/multifocal, and in multiple family members.
This is why familial cancers occur at younger ages, are often multifocal, and cluster in families — the probability of the "second hit" happening in at least one cell is very high when every cell already has the first hit.
Why is one functional allele enough? Tumour suppressor genes typically produce proteins that actively restrain the cell cycle (like a brake pedal). Even one working allele produces enough protein to brake effectively. This is why carriers are phenotypically normal — until the second allele is lost in a cell.
Loss of heterozygosity (LOH): The "second hit" can occur through various mechanisms: point mutation, chromosomal deletion, mitotic recombination, or epigenetic silencing. LOH is a hallmark finding in tumour tissue from familial cancer patients.
Retinoblastoma families are the prototype of one type of cancer family. [1]
| Feature | Sporadic RB | Hereditary RB |
|---|---|---|
| Germline mutation | No | Yes (RB1 gene) |
| Hits needed somatically | 2 | 1 |
| Age of onset | Later (usually >2 years) | Earlier (usually <2 years) |
| Laterality | Unilateral | Often bilateral |
| Family history | Negative | Positive |
| Other tumour risk | Low | Increased (osteosarcoma, soft tissue sarcomas) |
Why retinoblastoma is the prototype: It was the first cancer for which Knudson formulated his hypothesis (1971). He studied the age-incidence distribution and showed that familial cases fit a one-hit kinetic model while sporadic cases fit a two-hit model.
Familial Cancer Syndromes — Detailed Coverage
4. Lynch Syndrome (Hereditary NonPolyposis Colorectal Cancer, HNPCC)
Cancers of the colon and rectum is the second most common cancer in Hong Kong. Every year, there will be over 4000 new colorectal cancer cases diagnosed. About 4% of them are caused by Lynch Syndrome. [1]
Lynch Syndrome is caused by germline mutation in the DNA mismatch repair genes, including the MSH2, MLH1, MSH6 or PMS2 genes. The defective gene is inherited in autosomal dominant pattern. [1]
Why mismatch repair matters from first principles:
- During DNA replication, the polymerase occasionally inserts the wrong nucleotide or causes small insertions/deletions, especially at microsatellite regions (repetitive DNA sequences).
- The mismatch repair (MMR) system (MLH1, MSH2, MSH6, PMS2 working as heterodimers) detects and corrects these errors.
- When MMR is defective → errors accumulate → microsatellite instability (MSI) → frameshift mutations in tumour suppressor genes and growth regulatory genes → cancer.
Gene frequency breakdown [3]:
Individuals carrying the mutation have a very high lifetime risk of colorectal cancer (up to 80%), the risk for endometrial cancer in female is also very high (up to 60%). [1]
| Cancer | Lifetime Risk |
|---|---|
| Colorectal | Up to 80% |
| Endometrial | Up to 60% |
| Ovarian | Increased |
| Gastric (stomach) | Increased |
| Small bowel | Increased |
| Urinary tract (renal pelvis, bladder) | Increased |
| Brain (glioma/glioblastoma) | Increased |
| Biliary tract | Increased |
| Pancreatic | Increased |
| Sebaceous gland adenomas | Increased |
| Keratoacanthomas | Increased |
The complete list of HNPCC-related tumours [1]: Colorectal, endometrial, ovarian, gastric, biliary tract (gallbladder, bile duct, cholangiocarcinoma), pancreatic, small bowel, transitional cell carcinoma of renal pelvis/bladder, brain (glioma/glioblastoma), sebaceous gland adenomas, keratoacanthomas.
High Yield
Recognising the spectrum of tumour associated with Lynch syndrome is important in analysis of family history. [1] Don't just look for colon cancer in the family — endometrial, ovarian, gastric, urinary tract, and brain tumours all count. The family history that raises suspicion is familial clustering of Lynch-syndrome-related cancers, with at least one member having an early age of cancer onset ( < 50yrs). [1]
Individuals tend to develop the cancer at young age. Moreover, not infrequently, an individual may develop synchronous or metachronous tumours. [1]
- Young onset ( < 50 years)
- Right-sided predominance of colorectal cancers [2]
- Synchronous tumours (two cancers at the same time)
- Metachronous tumours (second cancer developing after the first)
- Multiple Lynch-related cancers across family members
- Poorly differentiated tumours with lymphocytic infiltration [2]
Don't Miss This
Doctor will miss a case of suspected Lynch Syndrome if they don't pay careful attention to the family history. [1] This is a direct lecture statement — always take a thorough family cancer history in any patient with a new cancer diagnosis.
The most definitive way to identify whether a patient is suffering from Lynch syndrome is through an initial genetic test known as microsatellite instability analysis that can be done on the paraffin blocks of the resected cancer tissue. [1]
Step-by-step diagnostic pathway:
- Suspect Lynch syndrome based on family history / young onset / tumour spectrum
- MSI testing on tumour tissue (paraffin-embedded) — and/or immunohistochemistry (IHC) for MMR proteins (MLH1, MSH2, MSH6, PMS2)
- If MSI-high or loss of MMR protein expression → suggests defective MMR system
- Germline mutation testing (blood) for MLH1, MSH2, MSH6, PMS2 (and EPCAM)
- Identifies the specific pathogenic variant
- Cascade (carrier) testing for family members once the mutation is known
It is now recommended internationally that any patient who developed colorectal cancer below age 50 should have the microsatellite instability test performed. [1]
Amsterdam II Criteria — '3-2-1 Rule'
From the surgical notes [2]:
- ≥3 relatives with Lynch-associated cancers (at least one pair of first-degree relatives)
- ≥2 successive generations affected
- ≥1 tumour diagnosed before age 50
- FAP excluded
- Tumours verified by pathology
Important nuance: Not all MSI-high tumours are Lynch syndrome. Approximately 15% of sporadic CRC shows MSI-H due to somatic hypermethylation of the MLH1 promoter (often associated with BRAF V600E mutation). This is NOT germline — it's an acquired epigenetic event. BRAF mutation testing can help distinguish: BRAF-positive MSI-H tumours are almost always sporadic, not Lynch. [3]
Regular colonoscopy examination in Lynch Syndrome gene carrier (once every one to two years, starting from age 20 to 25) can reduce the incidence of colon cancer by 60% and completely prevent colon cancer associated mortality. [1]
| Screening | Details |
|---|---|
| Colonoscopy | Every 1-2 years, starting age 20-25 |
| Endometrial screening | Regular ultrasound + endometrial aspirate |
| Mechanism | Detection and removal of adenomas before malignant transformation |
Screening and early detection of endometrial cancer is also possible through regular ultrasound examination and endometrial aspirate. [1]
Some people may choose not to know the information and not to undergo the genetic test because of the worry of being genetically labelled. Thus proper genetic counselling should be offered before genetic testing. [1]
This is a less common type of familial cancer syndrome, accounting for 1% of colon cancer. The genetic defect lies in the APC gene. Individuals carrying the germline APC gene mutation almost certainly will develop lots of adenomas in their colon starting from teenage, and eventually one or several of these adenomas will progress to become carcinoma, usually by age 50. Thus the penetrance of this disease is 100%. [1]
| Feature | Detail |
|---|---|
| Gene | APC (chromosome 5q21) — tumour suppressor gene |
| Inheritance | Autosomal dominant |
| Penetrance | ~100% for polyposis; ~100% for CRC if untreated |
| Number of polyps | Typically > 100 (usually 500-2500) by age 20 |
| CRC location | Predominantly left-sided [2] |
| Mean age of CRC | ~39 years (if untreated) |
| De novo mutations | Up to 25% (no family history!) [2] |
Extracolonic manifestations [2]:
| Benign | Malignant |
|---|---|
| Gastric fundic gland polyps | Duodenal/periampullary carcinoma |
| Osteoma (skull, mandible) | Papillary thyroid carcinoma |
| Epidermoid cysts | Hepatoblastoma (especially children) |
| Desmoid tumours (mesentery) | Medulloblastoma |
| CHRPE (congenital hypertrophy of retinal pigment epithelium) | Pancreatic cancer |
| Adrenal adenomas |
Variants [2]:
- Gardner syndrome = FAP + extracolonic manifestations (osteomas, desmoids, epidermoid cysts)
- Turcot syndrome = FAP + CNS tumours (medulloblastoma)
- Attenuated FAP (AFAP) = 10-99 polyps, later onset, right-sided predominance, APC mutation in only ~30%
Management:
Those carrying the mutation would need a prophylactic surgery to resect the whole colon. [1]
Surgical options [2]:
- Total colectomy + ileorectal anastomosis (IRA): avoids stoma, avoids risk of sexual dysfunction from proctectomy, lower morbidity
- Restorative proctocolectomy + ileal pouch-anal anastomosis (IPAA/RPC): eliminates rectal cancer risk
- Total proctocolectomy + end ileostomy: definitive but permanent stoma
Screening for FAP family members [3]:
- Flexible sigmoidoscopy/colonoscopy every 1-2 years from age 10-12 until 40, then every 5 years
- OGD every 3-5 years from onset of colonic polyposis or from age 25-30
- Annual thyroid ultrasound
6. BRCA1/BRCA2 Hereditary Breast/Ovarian Cancer Syndrome
There are two major breast and ovarian susceptibility genes, BRCA1 and BRCA2. About 30-70% of patients with hereditary breast/ovarian cancer and about 5-10% of all breast and/or ovarian cancer cases harbour a germline mutation in these genes. [1]
The defective gene is inherited in autosomal dominant pattern. [1]
Both BRCA1 and BRCA2 are tumour suppressor genes involved in homologous recombination DNA repair. When BRCA function is lost, cells cannot accurately repair double-strand DNA breaks → genomic instability → cancer.
- BRCA1: Chromosome 17q
- BRCA2: Chromosome 13q
Individuals carrying a mutation in the BRCA1 or BRCA2 genes have a 85% lifetime risk of breast cancer. [1]
| Cancer | BRCA1 | BRCA2 |
|---|---|---|
| Breast cancer lifetime risk | Up to 85% (72% by age 80) | Up to 85% (69% by age 80) |
| Ovarian/fallopian tube/peritoneal | 35-60% (44% by 80) | 10-27% (17% by 80) |
| Male breast cancer | Low increase | Definite increase |
| Prostate cancer | Possible | Definite increase |
| Pancreatic cancer | Possible | Definite increase |
There is also definite increased risk for prostate and pancreatic cancer as well as male breast cancer in BRCA2 mutation carriers. [1]
BRCA mutation carriers tend to develop breast cancer at a young age, may have bilateral breast cancer or have a personal history of both breast and ovarian cancer. [1]
Red flags from the lecture [1]:
- Two or more family members with breast cancer
- Both breast and ovarian cancer in the family
- Male breast cancer in the family
- Two primary cancers in one individual
- Young age of onset
- Bilateral breast cancer
Factors to estimate probability of heritable mutation [1]:
- Age of onset
- Number of affected relatives
- Biological relationships of affected relatives
- Ratio of affected to unaffected relatives
- Presence/absence of associated malignancies
- Ethnic background (e.g., Ashkenazi Jewish ancestry: much higher carrier rate)
About 80-90% breast cancers arising in BRCA1 mutation carriers are of a distinct subtype called basal-like cancer. [1]
| Feature | BRCA1-associated breast cancer |
|---|---|
| Subtype | Basal-like (80-90%) |
| Triple-negative | Yes (ER−, PR−, HER2−) |
| Age | Younger |
| Prognosis | Poorer outcome |
| Family history association | Stronger |
| Interval cancers | More frequent (arise between annual mammograms) |
| Mammographic features | Rapid progression |
BRCA1 related ovarian cancers tend to be advanced stage high-grade serous carcinomas. [1]
Basal-Like Breast Cancer
Basal-like cancer may also be found in about 15% breast cancers with no family history (sporadic breast cancer). [1] So triple-negative/basal-like cancer in a young woman should prompt you to ask about family history and consider BRCA testing, even if there's no obvious family history yet.
A blood sample is required for definitive genetic testing. [1]
Identification of a specific mutation in a family is a complex process and must usually begin by testing a blood sample from a family member who has had breast or ovarian cancer, called "index" testing. If a specific mutation is identified through index testing, then "carrier" testing is possible for family members. [1]
Important caveats:
- Several hundred different mutations exist across BRCA1/2 — these are very large genes
- Only a few mutations are recurrent in unrelated families
- A negative result in a family where no mutation has been identified cannot exclude other unknown genes [1]
Testing for mutations of inherited cancer susceptibility genes raises many issues for the individual and family, with medical, psychological, and social implications. Hence individuals are strongly recommended to receive genetic counselling prior to testing. Blood samples for genetic testing are accepted only after informed consent has been given. [1]
The interventions that can be offered to women with BRCA1 or BRCA2 mutation carriers include intensive screening, chemoprevention, prophylactic mastectomy and/or oophorectomy. [1]
| Intervention | Details | Evidence |
|---|---|---|
| Intensive screening | MRI + ultrasound + mammography combined (sensitivity ~95%) | Effect on morbidity/mortality unclear |
| Chemoprevention | Selective estrogen receptor modulators (tamoxifen) | Insufficient evidence for BRCA carriers |
| Prophylactic mastectomy | Bilateral; often skin-sparing ± nipple preservation | Fair evidence: significantly ↓ breast cancer incidence |
| Prophylactic oophorectomy | Bilateral salpingo-oophorectomy | ↓ ovarian cancer risk by 85-100%; ↓ breast cancer risk by 53-68% |
There is however fair evidence that prophylactic surgery for these women significantly decreases the incidence of breast and ovarian cancer. Oophorectomy reduced ovarian cancer risk by 85-100% and reduced breast cancer risk by 53-68%. [1]
Screening protocol for BRCA carriers [4]:
- MRI annually from age 25
- Mammography annually from age 30
- TVUS + CA-125 every 6 months from age 30 (or 5-10 years before earliest diagnosis in family)
Criteria for referral to genetic counselling (NCCN 2019) [4]:
- Breast cancer diagnosed ≤50 years
- Triple-negative breast cancer diagnosed ≤60 years
- ≥2 breast tumours or male breast cancer
- History of ovarian, pancreatic, or metastatic prostate cancer
- Ashkenazi Jewish heritage
- Close blood relatives with early-onset breast cancer (≤50y), ovarian, fallopian tube, primary peritoneal, male breast, pancreatic, or prostate cancer
Often, these cancers first become clinically manifest in young patients. There may be multiple family members affected by the same cancer. Alternatively, multiple family members may develop cancers of different histological types. In some circumstances, multiple tumours may develop in the same individual. A carefully taken family history often provides the first clue to an inheritable cancer. [1]
Table from lecture notes [1]:
| Syndrome | Tumour Types | Gene |
|---|---|---|
| Hereditary diffuse gastric cancer | Stomach | 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 |
Key points on inheritance and penetrance [1]:
- Lynch syndrome, BRCA: Incomplete penetrance — carriers have greatly increased risk but will not invariably develop cancer
- FAP: ~100% penetrance — virtually all carriers develop polyposis and cancer if untreated
- Ataxia-telangiectasia: Autosomal recessive — the exception to the AD pattern of most familial cancers
Autosomal Recessive Exception
Most familial cancer syndromes are autosomal dominant with variable penetrance. Ataxia-telangiectasia is inherited in autosomal recessive pattern. [1] This is a classic exam trap — if asked about inheritance patterns of familial cancers, remember ATM/A-T as the recessive outlier.
The management of a patient with familial cancer is not different from other patients with sporadic cancers. However, after successful treatment, subsequent follow up screening protocol to prevent metachronous cancer is needed. [1]
The significance of diagnosing familial cancers lies in the management of other family members. Once the genetic mutation leading to the cancer is known, asymptomatic family members can be offered genetic testing to define if the mutated gene has been inherited. [1]
For carriers: Regular screening initiated earlier than general population For non-carriers: Anxiety is prevented; they can follow population-level screening
In some circumstances, there may be familial clustering of cancers that may not be genetically related. One common example is hepatocellular carcinoma. Often, vertical transmission of hepatitis B virus infection leads to multiple members of the family being infected. [1]
Why this matters: Don't assume every family cluster is a genetic syndrome. Shared environmental exposures (HBV, smoking, diet) or infectious transmission can create the appearance of familial cancer without a single germline mutation.
Recently, genome-wide association studies have revealed some genetic loci that are associated with a slight to modest increased risk for various types of cancer (so-called low risk alleles). [1]
A complex interplay between genetic and environmental factors is also possible. [1]
These are common genetic variants (SNPs) that individually confer tiny risk increases. Their cumulative effect may explain some familial clustering where no high-penetrance gene is identified. They are NOT clinically actionable in the same way as BRCA or MMR mutations — currently used for research and polygenic risk scores, not routine clinical testing.
Cancer screening programmes can be divided into the following types [1]:
| Type | Examples |
|---|---|
| A. Physical examination | Breast examination, skin examination |
| B. Biochemical tests | Stool (FIT for CRC), blood (AFP for HCC, CA-125 for ovarian) |
| C. Endoscopic | Colonoscopy, OGD, flexible sigmoidoscopy |
| D. Radiological | Mammography, ultrasound, CT colonography, MRI breast |
| E. Genetic | Germline mutation testing (BRCA, MMR genes, APC) |
From supporting context [5][6]:
| Method | Principle | Clinical Use |
|---|---|---|
| Karyotyping | G-banding of chromosomes arrested at metaphase (requires actively dividing cells) | Detect large structural abnormalities: translocations, deletions, duplications. E.g., t(9;22) in CML |
| FISH | Fluorescent probes hybridise to specific DNA sequences | Higher sensitivity than karyotyping; can detect specific rearrangements even in non-dividing cells (interphase FISH) |
| PCR / RT-PCR | Amplify specific DNA/RNA sequences | Detect point mutations, fusion transcripts; quantitative monitoring (e.g., BCR-ABL in CML) |
| Next-generation sequencing | Massively parallel sequencing | Comprehensive mutation profiling; therapeutic target identification |
| MSI testing | PCR-based analysis of microsatellite markers | Lynch syndrome screening |
| IHC for MMR proteins | Antibodies detect MMR protein expression in tissue | Complement to MSI testing; loss of expression indicates defective gene |
Why metaphase is needed for karyotyping: Chromosomes are maximally condensed and visible only during metaphase. Colchicine (inhibits spindle formation) is added to arrest dividing cells at this stage. Indolent malignancies (e.g., CLL, myeloma) that don't divide quickly are harder to karyotype. [5][6]
Clinical Approach — Framework for Familial Cancer Assessment
- Cancer diagnosis details: Type, age at diagnosis, stage, treatment
- Family history (minimum 3 generations, both sides):
- Types of cancer
- Ages at diagnosis
- Outcomes
- Relationships between affected members
- Look for Lynch-spectrum and BRCA-spectrum tumours specifically
- Personal history: Multiple primary cancers, synchronous/metachronous tumours
- Ethnicity (Ashkenazi Jewish → higher BRCA carrier rate)
- Environmental exposures (to distinguish genetic vs environmental clustering)
- Complete examination relevant to the presenting cancer
- Look for stigmata of specific syndromes (e.g., CHRPE in FAP, mucosal neuromas in MEN2B)
- Tumour-based testing first:
- MSI analysis / IHC for MMR proteins (Lynch)
- Somatic mutation profiling
- Germline testing (blood):
- BRCA1/2
- MMR genes (MLH1, MSH2, MSH6, PMS2, EPCAM)
- APC, TP53, CDH1, etc., depending on clinical suspicion
- Index case tested first → then cascade to family
- Treat the patient's current cancer according to standard protocols
- Identify the germline mutation
- Offer genetic counselling to the family
- Carrier testing for at-risk family members
- Surveillance for carriers (colonoscopy, MRI, etc.)
- Prophylactic surgery where evidence supports it (mastectomy, oophorectomy, colectomy)
- Chemoprevention where applicable (limited evidence for BRCA; aspirin in Lynch under study)
- Psychosocial support — the impact of a "genetic label" is significant
From the 2021 SAQ [7] and AOS Pathology [8]:
Applications of molecular genetic testing in gynaecological cancers:
- BRCA1/2 germline testing → ovarian high-grade serous carcinoma; guides PARP inhibitor therapy and family screening
- MMR/MSI testing → endometrial cancer; identifies Lynch syndrome and guides immunotherapy
- Somatic DICER1 mutation → Sertoli-Leydig cell tumour (assists histopathological diagnosis)
- Somatic FOXL2 mutation → adult granulosa cell tumour (diagnostic)
- HPV testing → cervical cancer screening and management
Genetic counselling and patient consent is necessary for germline mutation tests (BRCA1/BRCA2) but NOT for somatic mutation tests (DICER1, FOXL2). [8] — Because germline results have implications for relatives; somatic results do not.
Exam Intelligence
| Trap | Correct Understanding |
|---|---|
| "Lynch syndrome = only colorectal cancer" | NO — it includes endometrial, ovarian, gastric, urinary tract, brain, small bowel, biliary, pancreatic, sebaceous tumours |
| "All MSI-high tumours = Lynch syndrome" | NO — ~15% of sporadic CRC are MSI-H due to MLH1 promoter methylation (check BRAF V600E; if positive → likely sporadic) |
| "FAP = many polyps, Lynch = no polyps" | Lynch has few polyps (HNPCC is a misnomer) but NOT zero; FAP has > 100 |
| "BRCA only affects women" | BRCA2 increases risk of male breast cancer, prostate cancer, pancreatic cancer |
| "Negative genetic test = no risk" | A negative test in a family with no identified mutation cannot exclude unknown genes |
| "All familial cancers are autosomal dominant" | Ataxia-telangiectasia is autosomal recessive |
| "Prophylactic mastectomy eliminates breast cancer risk" | It greatly reduces but does not completely eliminate risk (small amount of residual breast tissue) |
| "Family clustering always = genetic" | HCC clustering in HBV families is due to vertical viral transmission, not germline mutation |
| "Karyotyping can be done on any cell" | Requires metaphase → needs actively dividing cells → difficult in indolent malignancies |
| If the question says... | Think... |
|---|---|
| "DNA mismatch repair" | Lynch syndrome (MLH1, MSH2, MSH6, PMS2) |
| "APC gene" | FAP |
| "BRCA1/2" | Hereditary breast/ovarian cancer |
| "E-cadherin / CDH1" | Hereditary diffuse gastric cancer |
| "TP53 germline" | Li-Fraumeni syndrome |
| "VHL" | Von Hippel-Lindau (renal cell CA, haemangioblastoma, phaeochromocytoma) |
| "RET proto-oncogene" | MEN2 / medullary thyroid carcinoma |
| "MSI testing on tumour tissue" | Initial screening test for Lynch syndrome |
| "Prophylactic colectomy" | FAP (100% penetrance) |
| "Prophylactic oophorectomy" | BRCA (85-100% reduction in ovarian CA risk) |
| "Genetic counselling before testing" | GERMLINE tests (BRCA, MMR), NOT somatic tests |
Past Paper Questions
Stem: "Molecular genetic tests are increasingly applied in diagnosis and management of gynaecological malignancies. Which of the following conditions is MOST OFTEN associated with an increase in susceptibility to ovarian and endometrial carcinomas?"
Options: A. Ataxia telangiectasia B. DNA mismatch-repair / Lynch syndrome C. Familial adenomatous polyposis D. Peutz-Jeghers syndrome
Answer: B. DNA mismatch-repair / Lynch syndrome
Rationale: Lynch syndrome (MMR gene mutations) confers up to 60% lifetime risk of endometrial cancer and increased ovarian cancer risk. Ataxia-telangiectasia is associated with leukaemia/lymphoma. FAP is primarily colorectal. Peutz-Jeghers does increase some gynaecological cancer risk but Lynch is the most often associated with this combination.
Stem: "A 23-year-old lady was admitted for fever and dizziness. The complete blood count showed pancytopenia with circulating blasts and a diagnosis of acute leukaemia is suspected. Bone marrow examination was done and the sample was sent for cytogenetic testing. Which phase of the cell division cycle is needed for examination of karyotype for cytogenetic test?"
Options: A. Anaphase B. Metaphase C. Prophase D. Telophase
Answer: B. Metaphase
Rationale: Chromosomes are maximally condensed and individually distinguishable only at metaphase. Colchicine is used to arrest cells at this stage by inhibiting spindle formation.
Stem: "A 68-year-old male has melanoma. The BRAF gene mutation status can be used as a biomarker to predict the treatment response to vemurafenib. Which assay is MOST USEFUL to detect BRAF mutations in the tumour biopsy?"
Options: A. DNA Sequencing B. Fluorescence in-situ hybridisation C. Single nucleotide polymorphism microarray D. Southern blot
Answer: A. DNA Sequencing
Rationale: BRAF mutations are point mutations (e.g., V600E). DNA sequencing detects specific nucleotide changes. FISH detects translocations/amplifications, not point mutations. SNP microarray detects copy number changes. Southern blot detects large DNA alterations.
Stem: "A 56-year-old man was newly diagnosed to have chronic myeloid leukaemia (CML) and given imatinib upon discharge. What is the BEST method for monitoring the disease status of the patient?"
Options: A. Clinical examination B. Cytogenetics C. FISH D. Quantitative reverse transcription polymerase chain reaction
Answer: D. Quantitative RT-PCR
Rationale: RT-qPCR for BCR-ABL1 transcript levels is the gold standard for monitoring molecular response in CML. It has the highest sensitivity and can detect minimal residual disease.
Stem: "With advances of knowledge in carcinogenesis and development of molecular diagnostic tools, molecular genetic testing has been more frequently applied in the diagnosis and management of malignancies. (a) Please list applications in gynaecological cancers. (6 marks) (b) Please list specific tests used in the above applications. (4 marks)"
Markscheme answer: (a) Applications:
- BRCA1/2 germline testing for hereditary breast/ovarian cancer → guides risk-reducing surgery and PARP inhibitor therapy
- MMR protein IHC / MSI testing in endometrial cancer → identifies Lynch syndrome; may guide immunotherapy (checkpoint inhibitors)
- Somatic mutation profiling (e.g., DICER1 in Sertoli-Leydig cell tumour; FOXL2 in adult granulosa cell tumour) → assists histopathological diagnosis
- HPV genotyping → cervical cancer screening and triage
- HRD testing → predicts response to PARP inhibitors in ovarian cancer
(b) Specific tests: PCR-based HPV testing, IHC for MMR proteins, MSI analysis by PCR, DNA sequencing / NGS for BRCA1/2, DICER1, FOXL2 mutations, FISH
Stem: "A 63-year-old man with metastatic lung adenocarcinoma has been on targeted therapy against EGFR for 2 years. Chest X-ray shows suspected malignant pleural effusion but no malignant cells on cytology. Which test on the pleural tap sample is MOST APPROPRIATE?"
Options: A. Biochemical test for glucose and protein B. Genetic testing of cell-free component for EGFR mutation C. Genetic testing of cellular component for EGFR mutation D. Rapid tumour cell culture
Answer: B. Genetic testing of the cell-free component for EGFR mutation
Rationale: Cell-free DNA (cfDNA/liquid biopsy approach) can detect tumour-derived EGFR mutations even when no malignant cells are identified on cytology. This is essentially a liquid biopsy on the pleural fluid. Testing the cellular component would require malignant cells to be present (they aren't). Biochemical testing only classifies exudate vs transudate. Culture is impractical.
Stem: "Which of the following gene mutation tests is applied to assist histopathological diagnosis of ovarian Sertoli-Leydig cell tumour?"
Options: A. BRCA B. DICER C. EGFR D. KRAS
Answer: B. DICER
Rationale: DICER1 somatic mutations are characteristically found in Sertoli-Leydig cell tumours and assist in diagnosis. BRCA is for breast/ovarian carcinoma susceptibility. EGFR is for lung adenocarcinoma. KRAS is for CRC and lung adenocarcinoma.
High Yield Summary
-
Knudson's two-hit hypothesis: Familial cancers arise because one allele of a tumour suppressor gene is already mutated in the germline → only one somatic hit needed → earlier onset, bilateral, multifocal.
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Lynch syndrome: AD, germline MMR gene mutations (MLH1, MSH2, MSH6, PMS2, EPCAM), up to 80% CRC risk, 60% endometrial risk; wide tumour spectrum. Diagnose with MSI/IHC on tumour → germline blood testing. Screen with colonoscopy Q1-2y from age 20-25. Always take a family cancer history.
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FAP: AD, APC gene, > 100 polyps, 100% penetrance for CRC. Prophylactic colectomy. Up to 25% are de novo.
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BRCA1/2: AD, 85% lifetime breast cancer risk, 35-60% (BRCA1) or 10-27% (BRCA2) ovarian cancer risk. BRCA1 → basal-like/triple-negative breast cancer. Prophylactic oophorectomy ↓ ovarian CA 85-100%. Test index case first → cascade carrier testing.
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Genetic counselling is mandatory before germline testing — not before somatic testing.
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Not all family clusters are genetic — HBV-related HCC can cluster due to vertical viral transmission.
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Genes in familial cancers are also mutated somatically in sporadic cancers (e.g., APC in 60-70% of sporadic CRC, MLH1 hypermethylation in ~15% sporadic CRC).
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Karyotyping requires metaphase (actively dividing cells); FISH can work on interphase cells.
Active Recall - Cancer Genetics and Cytogenetics
[1] Lecture slides: GC 156. Many of my family members have cancers Cancer genetics and cytogenetics (Notes).pdf [2] Senior notes: Maksim Surgery Notes.pdf (Section 4.7 Colorectal carcinoma) [3] Senior notes: Ryan Ho GI.pdf (Lynch syndrome and FAP sections) [4] Senior notes: Ryan Ho Urogenital.pdf (BRCA section) [5] Senior notes: Ryan Ho Fundamentals.pdf (Cytogenetics section) [6] Senior notes: Ryan Ho Haemtology.pdf (Cytogenetics section) [7] Past papers: 2021 Fourth Summative SAQ.pdf (Q2) [8] AOS material: AOS - Pathology.pdf (Molecular genetic testing in gynaecological cancers) [9] Past papers: 2020 Fourth Summative Assessment MCQ paper.pdf (Q17, Q18, Q19) [10] Past papers: 2022 Fourth Summative MCQ.pdf (Q22, Q23) [11] Past papers: 2024 Fourth Summative MCQ.pdf (Q19)
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.
GC157 Paediatric Chemical Pathology
Paediatric chemical pathology is the subspecialty of clinical biochemistry focused on the diagnosis and monitoring of metabolic, endocrine, and biochemical disorders in neonates, infants, and children.