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) mutations, a clinically important subset is inherited (germline). Recognising familial cancer syndromes — principally Lynch syndrome (HNPCC) and FAP — allows you to prevent cancers in at-risk family members through genetic testing, surveillance, and prophylactic surgery. The doctor's role extends beyond treating the index patient to protecting the entire family.
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
How it fits into exams: This is a classic GC pathology/genetics topic. Expect MCQs on Knudson's two-hit hypothesis, Amsterdam/Bethesda criteria, microsatellite instability (MSI), MMR genes, FAP vs Lynch, and SAQs on genetic counselling and screening protocols. Past papers have tested molecular diagnostics in gynaecological cancers (directly relevant to Lynch syndrome's extracolonic cancers) and cytogenetic principles.
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]
Key Distinction: Oncogenes vs TSGs in Familial Cancer
Familial cancers are overwhelmingly caused by inherited TSG mutations, NOT oncogene mutations. Why? Because oncogene activation is a gain-of-function event (one hit suffices → dominant → would cause widespread developmental problems if germline, often lethal). TSG mutations are loss-of-function and require BOTH copies to be lost — making them compatible with normal development when only one copy is mutated in the germline.
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]
Exam Trap: Why Normal Development in Carriers?
Students often ask: "If every cell has a defective TSG, why doesn't the patient have cancer from birth?" Because ONE functioning allele is sufficient for tumour suppression. The carrier is haploinsufficient for that TSG but phenotypically normal — cancer only develops after the second hit knocks out the remaining good copy in a specific cell.
The lecture shows a CRC patient with germline c.1452-1455delAATG in MSH2 and loss of the wild-type allele (LOH) in the tumour tissue [1]. LOH is the classic mechanism for the "second hit" — the remaining normal allele is physically lost (through deletion, mitotic recombination, or chromosomal non-disjunction), leaving only the mutant allele. This is detectable by comparing tumour DNA vs normal (blood) DNA.
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) / Lynch Syndrome
HNPCC is estimated to account for ~4% of total CRC. It features familial occurrence of colorectal cancer with an early age of onset, autosomal dominant inheritance with incomplete penetrance. Some families have extra-colonic cancers (endometrial, ovarian, gastric, hepatobiliary, small bowel, or transitional cell carcinoma of the renal pelvis or ureter). There are no known premonitory phenotypic stigmata — diagnosis requires careful analysis of the family pedigree. [1]
HNPCC cancers are characterised by microsatellite instability (MSI). HNPCC is caused by germline mutation in one of the DNA mismatch repair genes, most commonly MSH2 or MLH1. [1]
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 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).
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]
| Feature | HNPCC/Lynch (Early Onset MSI-H) | Sporadic MLH1 Methylation (Late Onset MSI-H) |
|---|---|---|
| Mechanism | Germline MMR gene mutation | Somatic epigenetic silencing (MLH1 promoter methylation) |
| Age | Young ( < 50) | Elderly |
| Familial | Yes | No |
| IHC pattern | Loss of MSH2 or MLH1 (depending on gene) | Loss of MLH1 (with co-loss of PMS2) |
| Associated mutation | — | BRAF V600E (present in sporadic, ABSENT in Lynch) |
High Yield: BRAF V600E as Discriminator
In clinical practice and exams, if a tumour shows MSI-H with MLH1 loss, testing for BRAF V600E mutation and/or MLH1 promoter methylation helps distinguish sporadic (BRAF+, methylation+) from Lynch syndrome (BRAF−, methylation−). This avoids unnecessary germline genetic testing.
Based on a study of 132 local MSI-H CRCs, 95% show loss of either one of the three MMR proteins [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
| 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 and PMS2 form a heterodimer (MutLα); MSH2 and MSH6 form a heterodimer (MutSα). Loss of the obligate partner (MLH1 or MSH2) destabilises the other, causing paired loss.
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]
This is extremely high yield for Hong Kong exams — it underscores why all young CRC patients should be tested for Lynch syndrome.
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 |
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]
Key difference: Amsterdam criteria are strict (for defining HNPCC families); Bethesda criteria are broader (for selecting individual patients who should undergo MSI/IHC testing).
Histological spectrum of HNPCC-related extra-colonic cancers: [1]
- Endometrial carcinoma
- Ovarian carcinoma
- Gastric adenocarcinoma
- Hepatobiliary/cholangiocarcinoma
- Pancreas adenocarcinoma
- Small bowel adenocarcinoma
- Transitional cell carcinoma of the renal pelvis 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 most common extra-colonic cancer in Lynch syndrome — lifetime risk up to 60% in MLH1/MSH2 carriers.
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:
- CRC patient meets Bethesda criteria → test tumour for MSI (PCR) and/or IHC for MMR proteins
- If MSI-H or MMR protein loss → rule out sporadic (BRAF/methylation testing if MLH1 loss)
- If not sporadic → germline genetic testing (blood DNA) for the suspected MMR gene
- Once mutation found in proband → cascade testing of at-risk family members using a targeted test for that specific mutation
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 | Procedure | Starting Age | Interval |
|---|---|---|---|
| Colon | Colonoscopy | 20-25 yrs; after age 40 | Every 2 yrs; then every 1 yr |
| Uterus/Ovaries | Gynaecological exam, endometrial aspirate, transvaginal US, CA-125 | 30-35 yrs | Every 1-2 yrs |
| Urinary tract | US kidney/bladder, urine cytology | 30-35 yrs | Every 1-2 yrs |
| Stomach | Upper endoscopy (only for families with Hx of gastric cancer) | 30-35 yrs | Every 1-2 yrs |
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 lecture explicitly states that colonoscopic surveillance reduces CRC mortality by 100% in HNPCC gene carriers — meaning no carrier who undergoes regular screening dies of CRC. This is a powerful statistic for exam answers on the value of genetic diagnosis and screening.
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, insurance discrimination, psychological burden [1]
- Patient must understand what a positive result means (not certainty of cancer, but increased risk) and what options exist
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 Pathology slides explicitly test this: genetic counselling and patient consent is necessary for germline mutation tests (e.g. BRCA1/2, Lynch syndrome MMR genes), NOT for somatic mutation tests (e.g. FOXL2 in granulosa cell tumour, DICER1 in Sertoli-Leydig cell tumour) [5]. The key distinction: germline results affect the whole family and have insurance/psychological implications; somatic results only affect tumour management.
FAP is due to germline mutation in the APC gene. Individuals carrying the mutation always develop the disease (complete penetrance). Adenomas start to develop in early teenage ( > 100). If left untreated, will definitely progress to cancer. Prophylactic surgery to resect the whole colon in gene carrier. [1]
| Feature | FAP | Lynch Syndrome |
|---|---|---|
| Gene | APC (chromosome 5q21) | MLH1, MSH2, MSH6, PMS2 |
| Inheritance | AD, ~100% penetrance | AD, incomplete penetrance (~70-80% lifetime CRC risk) |
| Polyp number | Hundreds to thousands ( > 100) | Few (HNPCC is a misnomer!) |
| CRC risk | ~100% if untreated | ~70-80% lifetime |
| Predominant side | Left-sided | Right-sided |
| 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 | Prophylactic total colectomy | Colonoscopic surveillance ± prophylactic gynaecological surgery |
Key points from lecture:
- FAP: complete penetrance → prophylactic colectomy is indicated in ALL gene carriers
- Lynch: incomplete penetrance → surveillance approach; surgery when cancer/polyps detected
- FAP accounts for < 1% of CRC; Lynch accounts for ~4% (lecture) to 5-7% (senior notes) [1][3]
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 = 10-99 polyps, later onset, APC mutation in only ~30%
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]
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 all familial cancer clusters are genetic. HBV-related HCC in Hong Kong is a prime example — shared environment/infection, not inherited gene mutation.
Since the lecture title includes "cytogenetics" and past papers test cytogenetic principles:
- 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]
Past Paper Questions
"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. Same test can serve more than one purpose under (a). (4 marks)" [9]
Markscheme / Rationale:
(a) Applications in gynaecological cancers:
- Lynch syndrome screening — MMR/MSI testing in endometrial cancer to identify Lynch syndrome families → cascade genetic testing
- BRCA1/2 germline testing — in ovarian high-grade serous carcinoma → guide use of PARP inhibitors (e.g. olaparib), prophylactic surgery in carriers
- Diagnosis of specific ovarian tumours — FOXL2 somatic mutation for adult granulosa cell tumour; DICER1 for Sertoli-Leydig cell tumour
- HPV genotyping — cervical cancer screening (hrHPV detection)
- Somatic mutation profiling — KRAS/NRAS for targeted therapy selection
- Tumour mutational burden / PD-L1 — for immunotherapy eligibility
(b) Specific tests:
- IHC for MMR proteins (MLH1, MSH2, MSH6, PMS2)
- PCR-based MSI analysis
- Germline sequencing for BRCA1/2 and MMR genes (NGS panel)
- PCR-based HPV genotyping
- Sanger sequencing / NGS for somatic mutations (FOXL2, DICER1, KRAS)
Discriminators: The question asks about both germline (Lynch, BRCA) and somatic (FOXL2, DICER1) applications. Students who only mention one type lose marks. Remember that genetic counselling is required for germline tests but not somatic tests [5].
"Molecular genetic tests are now commonly used to assist diagnostic pathology particularly in challenging cases. Which of the following gene mutation tests is applied to assist histopathological diagnosis of ovarian Sertoli-Leydig cell tumour, a sex cord stromal tumour? A. BRCA B. DICER C. EGFR D. KRAS" [10]
Answer: B. DICER
Rationale: DICER1 mutations are characteristic of Sertoli-Leydig cell tumours. BRCA is for breast/ovarian high-grade serous carcinoma. EGFR and KRAS are for epithelial carcinomas (lung, CRC). This tests whether you know the specific molecular markers for different ovarian tumour subtypes [5][10].
"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? A. Anaphase B. Metaphase C. Prophase D. Telophase" [10]
Answer: B. Metaphase
Rationale: Karyotyping requires chromosomes to be maximally condensed, which occurs in metaphase. Colchicine is added to arrest cells at metaphase by inhibiting spindle formation [7][8][10].
"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 are detected on cytological examination of the pleural fluid. Which of the following tests on the pleural tap sample is MOST APPROPRIATE to evaluate the doctor's suspicion of metastatic carcinoma? A. Biochemical test on the cell-free component for glucose and protein B. Genetic testing of the cell-free component for EGFR mutation C. Genetic testing of the cellular component for EGFR mutation D. Rapid tumour cell culture of the cellular component" [11]
Answer: B. Genetic testing of the cell-free component for EGFR mutation
Rationale: No malignant cells on cytology → cannot test cellular component. Cell-free DNA (cfDNA) / liquid biopsy can detect tumour-derived EGFR mutations in the acellular fraction of body fluids. This is a key molecular pathology concept — tumour cells shed DNA into body fluids even when intact cells are not recoverable [11].
"A 58-year-old lady had a modified radical mastectomy done for a 5 cm breast mass. Pathology reported a grade 3 invasive ductal carcinoma with lymph node metastases. IHC for ER and PR was negative. HER2 IHC was positive (score 3+). What is the next step? A. Perform HER2 FISH test B. Start tamoxifen C. Start conventional adjuvant chemotherapy D. Start Trastuzumab (Herceptin)" [12]
Answer: D. Start Trastuzumab (Herceptin)
Rationale: HER2 IHC 3+ is definitively positive — FISH is only needed for equivocal results (2+). ER/PR negative → tamoxifen not indicated. Trastuzumab is standard for HER2+ breast cancer. This tests molecular pathology-guided targeted therapy [12].
"Molecular pathology and genomic tests are increasingly used in diagnosis, management, screening and prognosis prediction of cancers including cancers of the female genital tract. Genetic counselling and patient consent is necessary for which of the following tests? A. BRCA1/BRCA2 germline mutation tests in patients with ovarian high-grade serous carcinoma B. DNA mismatch repair (MMR) status of endometrial cancer C. Somatic DICER1 mutations in Sertoli-Leydig cell tumours D. Somatic FOXL2 mutation test for diagnosis of ovarian adult granulosa cell tumour" [5]
Answer: A. BRCA1/BRCA2 germline mutation tests
Rationale: Genetic counselling is required for germline tests because results have implications for the patient AND their family (inheritance, insurance, psychological impact). MMR IHC on the tumour is a somatic screen (though if it triggers germline testing later, counselling would then be needed). DICER1 and FOXL2 are somatic tumour tests — no family implications [5].
Exam Intelligence
| Trap | Correct Understanding |
|---|---|
| "HNPCC = many polyps" | HNPCC is a misnomer — these patients have FEW polyps. "Non-polyposis" distinguishes it from FAP |
| Confusing Amsterdam and Bethesda | Amsterdam = strict diagnostic criteria for HNPCC families; Bethesda = broader screening criteria for selecting patients for MSI testing |
| Thinking all MSI-H CRC = Lynch | Most MSI-H CRC in elderly is sporadic (MLH1 methylation) — must exclude with BRAF/methylation testing |
| Forgetting extra-colonic cancers in Lynch | Endometrial cancer is the #1 extra-colonic cancer — always screen female carriers |
| FAP vs Lynch: penetrance | FAP = ~100% penetrance → prophylactic colectomy; Lynch = incomplete penetrance → surveillance |
| Germline vs somatic testing: counselling | Genetic counselling required for germline (BRCA, Lynch) but NOT for somatic mutation tests |
| Karyotyping phase | Metaphase — not prophase or anaphase |
| Sporadic vs familial: age | Sporadic CRC typically > 50-60 yrs; Lynch CRC typically < 50 yrs (60% of CRC ≤35 yrs in HK is HNPCC!) |
- MSI-H with MLH1 loss: Check BRAF V600E → if present, sporadic; if absent, likely Lynch
- 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: TSGs need BOTH alleles inactivated. Familial cancer carriers inherit one defective allele → only need one somatic hit → earlier onset, higher risk, multiple cancers.
Lynch syndrome (HNPCC): ~4% of CRC, AD inheritance, incomplete penetrance, caused by germline MMR gene mutations (MLH1, MSH2 most common) → MSI. Diagnose with Amsterdam criteria (3-2-1 rule) or Bethesda criteria → MSI/IHC testing → germline sequencing. Extra-colonic cancers: endometrial, ovarian, gastric, urinary tract, brain, sebaceous. Surveillance: colonoscopy from 20-25, gynaecological screening from 30-35. Regular colonoscopy reduces CRC incidence by 60% and mortality by 100%.
FAP: APC gene, 100% penetrance, > 100 polyps, prophylactic colectomy mandatory.
Sporadic MSI-H CRC (elderly): Due to MLH1 promoter methylation, NOT germline — distinguish by BRAF V600E testing.
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) [9] Past papers: 2021 Fourth Summative SAQ.pdf (Question 2) [10] Past papers: 2022 Fourth Summative MCQ.pdf (Questions 22, 23) [11] Past papers: 2024 Fourth Summative MCQ.pdf (Question 19) [12] Past papers: 2025 Fourth Summative MCQ.pdf (Question 18)
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.