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
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 “up to 80%/60%” maxima are lecture-era pooled estimates. Contemporary counselling uses gene-, sex- and age-specific risks: MLH1/MSH2 generally confer higher colorectal risk, while MSH6/PMS2 can have later and lower penetrance. The durable visual lesson is the tumour spectrum, not a single risk percentage for every carrier [12].
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]
This is lecture-era wording: MSI is a tumour-screening phenotype, not a definitive germline diagnosis. Four-protein MMR immunohistochemistry and/or MSI can identify dMMR/MSI-H tumours, but Lynch syndrome is established by appropriate germline evaluation; sporadic MLH1 methylation and biallelic somatic MMR changes are important alternatives [12].
Step-by-step diagnostic pathway:
- Screen every newly diagnosed colorectal cancer with MMR IHC and/or MSI rather than using age or pedigree as a gatekeeper [12].
- Interpret the tumour pattern: loss of MSH2/MSH6, isolated MSH6 or isolated PMS2 prompts genetics assessment; MLH1/PMS2 loss requires triage for sporadic MLH1 promoter methylation (and, in CRC, BRAF V600E may help).
- Perform germline testing for MLH1, MSH2, MSH6, PMS2 and EPCAM as clinically appropriate; a positive result establishes the heritable diagnosis.
- Offer targeted cascade testing to adult relatives after identifying a pathogenic/likely pathogenic familial variant.
It is now recommended internationally that any patient who developed colorectal cancer below age 50 should have the microsatellite instability test performed. [1]
The slide's age-under-50 threshold is historical and too narrow. Young onset remains a red flag, but current practice supports universal tumour screening of newly diagnosed CRC [12]. Amsterdam/Bethesda rules remain useful exam history, not a modern exclusion test.
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. Sporadic CRC commonly acquires MLH1 promoter methylation, and biallelic somatic MMR alterations are another cause. In an MLH1/PMS2-deficient colorectal tumour, MLH1 methylation and/or BRAF V600E help triage likely sporadic disease, but a BRAF-negative result does not diagnose Lynch. Do not transfer the CRC BRAF rule to endometrial cancer [12].
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]
| Prevention | Current interpretation |
|---|---|
| Colonoscopy | High-quality examination every 1–2 years; starting age is gene- and family-specific (usually earlier for MLH1/MSH2/EPCAM and later for MSH6/PMS2) [12] |
| Endometrium | Teach prompt assessment of abnormal bleeding. Endometrial biopsy may be considered, but survival benefit is unproven; transvaginal ultrasound is not a reliable premenopausal screening test [12] |
| Ovary | Routine CA-125/ultrasound screening is not supported; discuss gene-specific risk and risk-reducing surgery after childbearing [12] |
| Mechanism | Colonoscopy detects and removes precursor lesions, but interval cancers can still occur |
Screening and early detection of endometrial cancer is also possible through regular ultrasound examination and endometrial aspirate. [1]
The reported “complete prevention” of CRC mortality was zero versus nine deaths during one controlled study's follow-up, not a guarantee of zero lifetime mortality [12]. Likewise, the ultrasound/aspirate sentence should not be memorised as an evidence-proven screening programme.
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 | Classic FAP has very high penetrance and near-100% CRC risk if untreated; attenuated APC phenotypes are less uniform [12] |
| 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]
This overcompresses modern management. Colorectal surgery is central to classic FAP, but timing and operation are individualised to polyp burden, dysplasia/cancer, APC phenotype, continence/fertility priorities and the feasibility of surveilling retained rectum or pouch. “Whole colon” does not describe every operation below.
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 |
|---|---|---|
| Female breast, lifetime | > 60% | > 60% |
| Ovarian/fallopian tube/peritoneal, lifetime | 39–58% | 13–29% |
| Male breast by age 70 | 0.2–1.2% | 1.8–7.1% |
| Prostate by age 80 | 7–26% | 19–61% |
| Pancreatic, lifetime | up to 5% | 5–10% |
The slide's 85%, 35–60% and 10–27% values are preserved above as historical lecture estimates, not universal individual predictions. Contemporary NCI ranges are shown in the table; penetrance varies with age, variant, family history and modifiers. Prostate, pancreatic and male-breast associations are stronger for BRCA2. Reported associations with melanoma, stomach and uterine serous carcinoma remain uncertain [13].
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]
Germline testing can use blood or saliva. A BRCA1/2 variant found on tumour testing may be somatic or inherited, so a possible hereditary finding must be confirmed in a germline sample with counselling [13].
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]
- Prefer testing an affected relative first when investigating a family. If none is available, an unaffected person may still be tested after counselling; a negative result is then commonly uninformative.
- Modern reports use pathogenic/likely pathogenic, VUS, and benign/likely benign categories. A VUS must not direct risk-reducing surgery or routine predictive testing [13][15].
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 |
|---|---|---|
| Breast surveillance | MRI plus mammography, started earlier under a high-risk protocol | MRI adds sensitivity; false positives occur [13] |
| Ovarian screening | TVUS/CA-125 does not detect cancer early enough to improve long-term survival | Not a substitute for risk-reducing surgery [13] |
| Chemoprevention | Tamoxifen/raloxifene | Primary-prevention evidence in BRCA carriers remains uncertain; possible contralateral and ER-positive BRCA2 benefit [13] |
| Risk-reducing bilateral mastectomy | Optional, irreversible, preference-sensitive | At least 95% breast-risk reduction in BRCA1/2 carriers, but not zero [14] |
| Risk-reducing salpingo-oophorectomy (RRSO) | Remove both ovaries and entire tubes after childbearing | Substantially lowers tubo-ovarian risk; residual primary-peritoneal risk remains [13] |
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]
Treat the quoted percentages as lecture-era study estimates. Current evidence on breast-risk reduction after RRSO is conflicting, so do not promise that oophorectomy halves breast risk [14]. The distal-tube/STIC images explain why the correct operation is salpingo-oophorectomy, with complete tubal removal and specialised pathology—not oophorectomy alone.
Current practical frame: breast surveillance commonly uses annual MRI from young adulthood with mammography added according to age and local protocol. No effective ovarian screening is known [13]. Discuss RRSO after childbearing using gene-specific timing; NICE advises no earlier than age 35 for BRCA1 and 40 for BRCA2, then individualise to family age of onset and multidisciplinary advice [17].
Current testing frame: family red flags still matter, but old age/TNBC thresholds should not be used as the sole gatekeeper. ASCO–SSO recommends BRCA1/2 testing for all newly diagnosed breast-cancer patients aged 65 or younger, and selected patients older than 65 based on personal/family history, ancestry and treatment eligibility [15]. ASCO recommends germline BRCA1/2 and other ovarian-susceptibility testing for all epithelial ovarian cancers, not only high-grade serous cases [16].
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
- Classic FAP: very high penetrance with near-100% untreated CRC risk; attenuated APC phenotypes are less uniform
- Ataxia-telangiectasia: autosomal recessive, caused by biallelic ATM pathogenic variants [18]
Autosomal Recessive Exception
Most familial cancer syndromes in this lecture are autosomal dominant with variable penetrance. Ataxia-telangiectasia is inherited in autosomal recessive pattern. [1] More precisely, biallelic ATM variants cause A-T; a heterozygous ATM pathogenic variant is a distinct moderate cancer-susceptibility state and does not mean the person has ataxia-telangiectasia [18].
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 relatives who test negative for a known familial variant: they cannot transmit that variant. Their remaining screening still reflects ordinary population risk, personal history and any unexplained risk in the wider pedigree.
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; selected surveillance biomarkers in defined high-risk settings. CA-125 is not an effective ovarian population-screening test |
| 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)
- Use tumour testing when it answers a defined diagnostic, hereditary-triage or treatment question:
- MSI analysis / IHC for MMR proteins in CRC and endometrial cancer
- Somatic mutation profiling for tumour classification or therapy
- Germline testing (blood or saliva) when clinical criteria are met:
- BRCA1/2
- MMR genes (MLH1, MSH2, MSH6, PMS2, EPCAM)
- APC, TP53, CDH1, etc., depending on clinical suspicion
- Prefer an affected relative first when investigating an unexplained family → then targeted cascade testing; if none is available, unaffected-person testing can still be considered with counselling
- 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]
This slide distinction is too absolute. Formal hereditary-cancer counselling and informed consent are central to germline testing because the result is constitutional and familial. Tumour testing still requires an ordinary informed clinical discussion; moreover, tumour BRCA/MMR findings can reveal a possible germline variant that needs confirmatory testing and counselling [13].
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—sporadic MLH1 methylation and biallelic somatic MMR alterations also cause dMMR/MSI-H; BRAF helps only in the CRC MLH1/PMS2-loss context |
| "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" | Distinguish a true negative for a known familial variant from an uninformative negative; neither erases ordinary cancer risk |
| "All familial cancers are autosomal dominant" | Biallelic ATM causes autosomal-recessive ataxia-telangiectasia; heterozygous ATM susceptibility is a different state |
| "A VUS should trigger prophylactic surgery" | A VUS is non-actionable; manage from personal and family risk until reclassification |
| "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 |
| "MMR IHC/MSI on tumour tissue" | Screen for dMMR; it does not by itself diagnose germline Lynch syndrome |
| "Prophylactic colorectal surgery" | Classic FAP; operation and timing are individualised |
| "Risk-reducing salpingo-oophorectomy" | BRCA1/2 after childbearing, with gene-specific timing; no screening test is an equivalent substitute |
| "Hereditary-cancer counselling" | Central to germline testing; tumour tests still need clinical consent and can reveal possible germline findings |
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.
-
Lynch syndrome
- AD, germline MMR gene variants (MLH1, MSH2, MSH6, PMS2; EPCAM deletion can silence MSH2) and a wide tumour spectrum. Universally screen newly diagnosed CRC with MMR IHC and/or MSI, then distinguish sporadic dMMR from heritable disease. Colonoscopy is every 1–2 years with gene-specific starting age.
-
FAP
- AD, APC gene; classic disease usually causes hundreds of adenomas and near-100% untreated CRC risk. Plan colorectal surgery according to phenotype and continue surveillance of retained mucosa and upper GI tract.
-
BRCA1/2
- AD homologous-recombination repair syndromes. Current NCI ranges: female breast risk > 60%; tubo-ovarian risk 39–58% (BRCA1) and 13–29% (BRCA2).
- BRCA1-associated cancers are often basal-like/triple-negative, but morphology is not a germline test.
- Breast surveillance uses MRI plus mammography. TVUS/CA-125 is not an effective ovarian-screening substitute; discuss RRSO after childbearing with gene-specific timing.
- Prefer testing an affected relative first, then targeted cascade testing. A VUS is non-actionable.
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Germline and somatic tests have different implications
- Germline testing requires hereditary-cancer counselling and informed consent. Tumour testing still requires clinical consent and can uncover a possible germline finding needing confirmation.
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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) [12] National Cancer Institute: Genetics of Colorectal Cancer (PDQ) [13] National Cancer Institute: BRCA Gene Changes—Cancer Risk and Genetic Testing [14] National Cancer Institute: Surgery to Reduce the Risk of Breast Cancer [15] ASCO–Society of Surgical Oncology Guideline: Germline Testing in Patients With Breast Cancer [16] ASCO Guideline: Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer [17] NICE NG241: Ovarian cancer—identifying and managing familial and genetic risk [18] GeneReviews: Ataxia-Telangiectasia
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.