Hereditary Cancer Syndromes: Cancer Genetics & Genomics

• Distinguish hereditary and sporadic cancer based on clinical presentation and family history of cancer.

• Explain the Knudson two-hits hypothesis and how it relates to tumorigenesis in hereditary and sporadic cancers.

• Describe the process of loss of heterozygocity in the transition of a constitutional to a tumor genotype in the context of a hereditary cancer.

• Associate loss-of-function mutations in hereditary cancer genes with clinical presentation and family history of cancer.

• Discuss the available risk management strategies for carriers of a hereditary cancer mutation.

• Select the most efficient strategy for genetic testing in a family suspected of carrying a hereditary cancer mutation.

• Choose the most likely causative gene/hereditary cancer syndrome from reading pedigrees of cancer family history.

Distinguishing Hereditary vs. Sporadic Cancer (Based on Clinical Presentation and Family History)

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🔷 HEREDITARY CANCER

1. Family History Pattern

• Multiple affected family members, typically first-degree or second-degree relatives.

• Cancer follows a Mendelian pattern, often autosomal dominant (e.g., BRCA1/2, Li-Fraumeni, Lynch).

• Cancers appear across several generations (“vertical transmission”).

• Family members often have multiple different cancers tied to the same syndrome (e.g., breast + ovarian in BRCA; sarcomas + brain tumors + breast in Li-Fraumeni).

• Family history often shows early age of onset in multiple individuals.

2. Clinical Presentation

• Early onset of cancer — usually decades earlier than sporadic cases.

• Patients may develop multiple primary cancers, either simultaneously or sequentially
  (e.g., bilateral breast cancers; colon + endometrial cancers).

• Rare tumors occur more commonly (e.g., adrenocortical carcinoma in Li-Fraumeni).

• Tumors often show distinctive molecular signatures (e.g., mismatch repair deficiency in Lynch syndrome).

• Penetrance varies but is often high, leading to high lifetime risk.

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🔶 SPORADIC CANCER

1. Family History Pattern

• No strong family history of cancer.

• One or zero relatives affected, usually at older ages.

• No Mendelian inheritance pattern — cases appear isolated.

• Family members’ cancer types are typically unrelated (e.g., grandmother’s lung cancer, uncle’s prostate cancer etc.).

• No clustering of early-onset disease.

2. Clinical Presentation

• Later age of onset (e.g., colon cancer in 70s vs. 40s in Lynch).

• Usually single primary tumor, in one organ.

• Tumors are common types that arise due to accumulated somatic mutations (environmental exposures, diet, smoking, aging).

• No characteristic constellation of rare tumors.

• Molecular studies show no inherited pathogenic variant.

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📌 Side-by-Side Summary Table

Feature	Hereditary Cancer	Sporadic Cancer
Family history	Strong clustering; multiple close relatives	Usually absent or minimal
Generational pattern	Vertical (multiple generations)	Not present
Age of onset	Early	Late
Number of primary tumors	Frequent multiple primaries; bilateral	Usually single
Tumor types	Syndrome-specific combinations	Common age-related cancers
Penetrance	High	Low
Molecular hallmark	Germline pathogenic variant + second hit	Solely somatic mutations
Examples	BRCA breast/ovarian, Lynch colorectal/endometrial, Li-Fraumeni	Most breast, colon, lung, prostate cancers

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🔥 Key Mnemonic

Hereditary = “E-M-M-R”

• Early

• Multiple family members

• Multiple cancers in one person

• Rare tumors

Sporadic = “O-S-I”

• Older age

• Single tumor

• Isolated case

Below is a precise, mechanistic, exam-ready explanation of Knudson’s two-hit hypothesis and its relationship to hereditary vs. sporadic cancers.

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⭐ Knudson’s Two-Hit Hypothesis (How Tumor Suppressor Genes Become Inactivated During Tumorigenesis)

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🔷 What the Two-Hit Hypothesis States

Proposed by Alfred Knudson (based on studies of retinoblastoma), the hypothesis states:

Both alleles of a tumor suppressor gene must be inactivated (“two hits”) for a cell to become cancerous.

Tumor suppressor genes (e.g., RB1, TP53, APC, BRCA1, etc.) follow a loss-of-function pattern:

• Losing one allele reduces protection but is not enough for cancer.

• Losing both causes loss of growth control → tumor initiation.

The two hits are typically:

1. Hit #1: Mutation or deletion of the first allele

2. Hit #2: Loss, mutation, or epigenetic silencing of the remaining allele

The second hit often occurs through mechanisms like:

• Loss of heterozygosity (LOH)

• Mitotic recombination

• Nondisjunction

• Promoter methylation

• Point mutations

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🔵 WHY TWO HITS?

Because tumor suppressor genes are recessive at the cellular level.

• A single normal allele usually produces enough protein to maintain function.

• Only complete biallelic loss leads to uncontrolled proliferation.

(Contrast: oncogenes need just one activating mutation, a “gain-of-function.”)

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🔥 APPLICATION: HEREDITARY vs. SPORADIC CANCER

Knudson’s hypothesis perfectly explains why hereditary cancers occur earlier and more frequently, while sporadic cancers occur late.

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🔷 HEREDITARY CANCER: One Hit Is Inherited (Germline)Mechanism

• Individuals inherit a germline mutation in one allele of a tumor suppressor gene.

• Every cell in the body already has Hit #1 at birth.

• Only one remaining allele needs to be lost in any particular cell → Hit #2.

Consequences

• Much faster tumorigenesis: only one somatic event needed.

• Cancer develops at younger ages.

• Often multiple tumors or bilateral tumors (e.g., bilateral retinoblastoma).

• Strong family history due to autosomal dominant transmission.

Classic example

Hereditary retinoblastoma

• Born with one mutated RB1 allele (1st hit).

• Second hit in retinal cells → tumor.

• Multiple tumors, bilateral, early childhood.

Key concept

Hereditary tumor suppressor syndromes are autosomal dominant clinically but recessive at the cellular level.

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🔶 SPORADIC CANCER: Both Hits Are SomaticMechanism

• Person inherits two normal alleles.

• Must acquire two independent somatic mutations in the same cell:

  • Hit #1: somatic mutation (environmental, replication error, etc.)

  • Hit #2: second somatic “loss of heterozygosity,” mutation, or epigenetic silencing.

Consequences

• Much slower: two independent random events must happen in the same cell.

• Typically unilateral and single tumors.

• Later onset, usually decades after birth.

• No family history.

Classic example

Sporadic retinoblastoma

• Both “hits” occur somatically in one retinal cell → rare, unilateral, single tumor.

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🧬 Why the Two-Hit Model Explains Epidemiologic Differences

Feature	Hereditary	Sporadic
First hit	Germline, present in all cells	Somatic, random
Second hit	Somatic	Somatic
Age of onset	Early	Late
Tumor multiplicity	Common, bilateral	Rare, unilateral
Cancer risk	Very high	Low (background population risk)
Family history	Strong	Usually absent
Mechanistic reason	Only 1 somatic event needed	2 independent somatic events needed

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🔥 Example: TP53 vs. RB1 Special Case

• RB1 follows the classic two-hit model.

• TP53 is also a tumor suppressor, but loss of one allele severely compromises function, meaning even dominant-negative effects occur.

  • In Li-Fraumeni (germline TP53 mutation), the second hit still leads to full loss, but the penetrance is even higher.

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Summary (Exam Ready)

Knudson’s two-hit hypothesis:

Tumor suppressor genes must lose both alleles for tumorigenesis.
In hereditary cancer, patients start life with one hit, requiring only one more somatic event → early, multiple, high-risk cancers.
In sporadic cancer, both hits occur somatically → later onset, single tumors, low risk.

Below is an accurate, mechanistic, exam-ready explanation of loss of heterozygosity (LOH) and how it converts a constitutional (germline) genotype into a tumor genotype in hereditary cancer.

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⭐ Loss of Heterozygosity (LOH): Core Concept

Loss of heterozygosity (LOH) is the process whereby a cell that is originally heterozygous for a tumor suppressor gene

• one normal (wild-type) allele

• one mutant allele (inherited germline mutation)

loses the remaining wild-type allele, resulting in complete loss of tumor suppressor function.

This transition is essential because tumor suppressor genes require BOTH alleles to be inactivated for tumorigenesis (Knudson’s two-hit hypothesis).

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🔷 Step-by-step: From Constitutional Genotype → Tumor Genotype1. Constitutional (Germline) Genotype = Heterozygous

In a hereditary cancer syndrome:

• Individuals inherit a germline mutation in one allele of a tumor suppressor gene:
  (mutant/wild-type) = heterozygous.

• Every cell in the body carries this heterozygosity.

This inherited mutation = Hit #1.

The cell is still normal because the remaining wild-type allele provides enough tumor suppressor activity.

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🧬 2. A Somatic “Second Hit” Removes the Wild-Type Allele → LOH

The crucial pathogenic event is the somatic loss of the wild-type allele, resulting in:

(mutant / mutant)
→ homozygous mutant
→ functionally null for the tumor suppressor gene.

This event = Loss of Heterozygosity (LOH) and corresponds to Hit #2.

Once LOH occurs, the cell transitions to a tumor genotype.

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🔥 Mechanisms that Produce LOH

LOH can occur by multiple genomic mechanisms that eliminate the wild-type allele:

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1. Chromosomal Deletion (Hemizygous deletion)

A segment of the chromosome containing the wild-type allele is lost.
Example: deletion of 13q14 removing the WT RB1 allele.

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2. Mitotic Recombination

During mitosis:

• The chromosome with the mutant allele is copied

• Recombination leads to both daughter chromatids carrying the mutant allele only

• The normal allele is lost through replacement or segregation errors.

This produces a region of copy-neutral LOH (no net deletion, but the alleles become identical).

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3. Nondisjunction + Duplication (“Uniparental Disomy”)

Steps:

1. Chromosome with WT allele is lost due to nondisjunction.

2. The chromosome with the mutant allele duplicates to restore disomy.

Result: both chromosomes now carry only the mutant allele.

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4. Gene Conversion

During DNA repair, the sequence of the wild-type allele is replaced by copying from the mutant allele.

Thus the normal allele is literally “converted” into the mutant sequence.

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5. Somatic Point Mutation in the Wild-Type Allele

The remaining WT allele is hit by:

• Point mutation

• Small deletion

• Inactivating frameshift

• Promoter methylation → epigenetic silencing

This also constitutes LOH because the heterozygosity is functionally lost.

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6. Promoter Hypermethylation (Epigenetic LOH)

Methylation of the wild-type allele silences transcription without altering DNA sequence.

This results in functional loss of the WT copy → “epigenetic second hit.”

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🔷 3. After LOH: Transition to Tumor Genotype (Homozygous Loss)

Once the wild-type allele is lost:

• The cell loses ALL tumor suppressor function.

• Checkpoints (RB1, TP53), DNA repair (BRCA1/2, MLH1/MSH2), or APC-mediated Wnt regulation fail.

• Genomic instability increases.

• The cell acquires additional mutations → tumor initiation and progression.

Thus:

Constitutional genotype (germline):

mut / WT

After LOH:

mut / mut = tumor genotype

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🔥 Why LOH Is Central in Hereditary Cancer 1. Explains early age of onset

Only one somatic event needed (LOH) instead of two.

2. Explains tumor multiplicity

Different cells independently undergo LOH at different times → multiple primary tumors.

3. Explains why the inheritance is autosomal dominant

• Inheritance of one mutated allele predisposes to cancer, even though biallelic loss is required at the cellular level.

4. Explains familial clustering

The first hit is shared across all family members with the mutation.

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📌 Classic Example: RB1 and Retinoblastoma

• Constitutional genotype: one germline mutation in RB1 (heterozygous).

• LOH in retinal precursor cells results in:

  • full loss of RB1

  • unregulated E2F activity

  • progression through G1/S

  • malignant transformation

LOH in RB1 explains:

• Bilateral tumors

• Multiple tumors

• Early childhood onset

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⭐ Final Summary (Exam-Perfect)

Loss of heterozygosity (LOH) is the somatic loss or inactivation of the remaining wild-type allele in a tumor suppressor gene in a person who already inherited a germline mutation. It converts a constitutional heterozygous genotype (mut/WT) into a tumorigenic genotype (mut/mut).
LOH can occur by deletion, mitotic recombination, nondisjunction, gene conversion, point mutation, or promoter methylation.
This event is the second hit in Knudson’s model and is the key step that initiates tumor formation in hereditary cancers

Below is a sharp, exam-ready, mechanism → phenotype map linking loss-of-function (LOF) mutations in hereditary cancer genes to their clinical presentations and the family history patterns that arise from them.
This is exactly what examiners want you to understand: how a LOF in a tumor suppressor gene creates the characteristic features of hereditary cancer syndromes.

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⭐ OVERVIEW

Hereditary cancers = germline LOF in tumor suppressor genes + somatic second hit (LOH).
This biology directly produces the clinical presentation and family history pattern.

Key concepts to hold in mind:

• Tumor suppressor → requires biallelic loss → Knudson two-hit model

• Germline LOF = first hit already present

• Somatic LOH = second hit → tumor

• Explains: early onset, bilateral/multiple tumors, vertical transmission, high penetrance

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🔷 HOW LOSS-OF-FUNCTION PRODUCES A HEREDITARY CANCER PHENOTYPE 1. LOF in a tumor suppressor gene → constitutional heterozygosity

Every cell in the body is:

• mut/WT for the gene

• Has only half of normal tumor suppressor function (“haploinsufficiency” varies by gene)

This creates a lifelong field of susceptibility.

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2. Somatic LOH → transition to tumor genotype

When the wild-type allele is lost (via deletion, recombination, epigenetic silencing, etc.), the cell becomes:

• mut/mut

• Completely lacks checkpoint, DNA repair, or cell-cycle restraint

This → cancer initiation.

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Resulting Clinical Features

Because only one somatic hit is required:

✔ Earlier age of onset

• Cancers appear decades earlier than sporadic counterparts.

✔ Multiple primary tumors

• Each tumor arises independently when a different cell acquires LOH.

✔ Bilateral or multifocal tumors

• Particularly in paired organs (eyes, breasts, kidneys).

✔ Characteristic tumor spectrum

• Depends on the specific gene (e.g., BRCA → breast/ovarian; APC → colon; PTEN → thyroid, breast, endometrium).

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Resulting Family History Features

Because the germline LOF mutation is inherited:

✔ Autosomal dominant transmission of susceptibility

(But recessive at the cellular level.)

✔ Vertical transmission across generations

• Affected parent → ~50% of children.

✔ Multiple relatives affected

• Especially first-degree relatives.

✔ Same tumor types cluster in the family

• “Signature tumor types” help identify the syndrome.

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⭐ GENE-BY-GENE ASSOCIATIONS

Below are major hereditary cancer genes, the LOF mechanism, and how this explains the clinical and pedigree patterns.

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🔶 1. RB1 (Retinoblastoma, Osteosarcoma) Mechanism

• Germline LOF = missing one functional RB1 allele.

• LOH in retinal cells → uncontrolled E2F → retinoblastoma.

Clinical Presentation

• Bilateral retinoblastoma

• Multiple tumors in one eye

• Early infancy

• ↑ risk of osteosarcoma, sarcomas (same mechanism)

Family History

• Strong vertical transmission

• A parent often had retinoblastoma as a child

• ~50% offspring affected

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🔶 2. TP53 (Li-Fraumeni Syndrome) Mechanism

• Germline LOF in TP53 removes the universal DNA damage checkpoint.

• Dominant-negative effect increases penetrance.

Clinical Presentation

• Very early onset cancers

• Multiple primary tumors

• Sarcomas, breast cancer, brain tumors, leukemias, adrenocortical carcinoma

• Cancers even in childhood/adolescence

Family History

• “Pedigree full of rare tumors”

• Multiple relatives with different tumors, all at young ages

• High penetrance → nearly every generation has affected members

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🔶 3. BRCA1 / BRCA2 (Hereditary Breast–Ovarian Cancer Syndrome) Mechanism

• LOF in homologous recombination repair → genomic instability → breast/ovarian cancer.

Clinical Presentation

• Early-onset breast cancer (20s–40s)

• Bilateral breast cancer

• Ovarian, pancreatic, prostate cancers

• Triple-negative breast cancer (BRCA1)

Family History

• Multiple affected women in successive generations

• Clustering of breast and ovarian cancers

• Men may show early prostate cancer

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🔶 4. APC (Familial Adenomatous Polyposis – FAP) Mechanism

• APC LOF → dysregulated β-catenin and Wnt signaling → uncontrolled proliferation in colonic crypts.

Clinical Presentation

• Hundreds to thousands of colonic polyps in adolescence

• Near-100% progression to colon cancer

• Duodenal, thyroid tumors

Family History

• Parent often had colectomy

• Siblings also affected

• Strong vertical transmission due to high penetrance

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🔶 5. MLH1, MSH2, MSH6, PMS2, EPCAM (Lynch Syndrome / HNPCC) Mechanism

• Germline LOF in mismatch repair → microsatellite instability → hypermutable cells.

• Second hit creates MMR-null cells → rapid tumor progression.

Clinical Presentation

• Early-onset colorectal cancer (proximal colon)

• Endometrial cancer

• Ovarian, stomach, urinary tract cancers

• Synchronous or metachronous colorectal tumors

Family History

• “Amsterdam criteria”:

  • ≥3 relatives with Lynch-associated tumors

  • Across ≥2 generations

  • At least one <50 years old

• Family clusters of colon + endometrial cancers

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🔶 6. VHL (von Hippel–Lindau Disease) Mechanism

• VHL LOF → inability to suppress HIF → angiogenesis and tumor formation.

Clinical Presentation

• Hemangioblastomas (CNS/retina)

• Renal cell carcinoma (clear cell)

• Pheochromocytomas

• Pancreatic cysts

Family History

• Same spectrum of tumors appears repeatedly in family members

• Early onset RCC is common

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🔶 7. PTEN (Cowden Syndrome) Mechanism

• LOF leads to hyperactive PI3K/AKT signaling → cell survival + proliferation.

Clinical Presentation

• Multiple hamartomas

• Early breast cancer

• Thyroid cancer (follicular)

• Endometrial cancer

• Macrocephaly

Family History

• Breast + thyroid + endometrial cancers in multiple relatives

• Often with subtle mucocutaneous findings

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⭐ WHY LOF MUTATIONS PRODUCE THESE FAMILY PATTERNS

1. Autosomal dominant inheritance of risk

   • One mutant allele enough for high lifetime cancer susceptibility.

   • Pedigree appears dominant because risk is dominant; the molecular mechanism is recessive.

2. Second hit is the rate-limiting event

   • Happens early (childhood/adolescence) → early cancer onset.

3. Tumors arise independently

   • Different cells lose WT allele separately → multiple primary tumors.

4. Characteristic tumor spectrum

   • Determined by the tissue in which the gene plays the dominant tumor-suppressive role.

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⭐ SUMMARY (EXAM-READY SENTENCE)

Loss-of-function germline mutations in hereditary cancer genes produce a constitutional heterozygous state (first hit). When tissues acquire somatic loss of heterozygosity (second hit), tumor suppressor function is lost completely, leading to early-onset, multiple, bilateral, and syndrome-specific cancers. Family pedigrees show autosomal dominant transmission of susceptibility with clustering of cancers typical for the mutated gene.

• Discuss the available risk management strategies for carriers of a hereditary cancer mutation.

Below is an organized, comprehensive, exam-ready overview of risk-management strategies for individuals who carry a hereditary cancer mutation (e.g., BRCA1/2, TP53, APC, Lynch MMR genes, PTEN, VHL).
This covers surveillance, chemoprevention, risk-reducing surgery, lifestyle modifications, and family-directed strategies — exactly the categories expected in medical exams and clinical genetics discussions.

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⭐ Risk Management Strategies for Hereditary Cancer Mutation Carriers

Management strategies aim to:

1. Reduce cancer incidence (prevent tumors from forming)

2. Detect cancer earlier (when curable)

3. Reduce morbidity/mortality

4. Support family planning and identify at-risk relatives

These strategies vary depending on the gene, but the general categories are universal.

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🔷 1. Enhanced Surveillance / Screening

Key principle:

Carriers start screening earlier, more frequently, and with more sensitive modalities than the general population.

Examples by syndrome: BRCA1/BRCA2

• Annual breast MRI starting at 25

• Annual mammogram + MRI from 30–75

• Transvaginal ultrasound + CA-125 (limited utility but used)

Lynch Syndrome (MLH1, MSH2, MSH6, PMS2)

• Colonoscopy every 1–2 years, starting at 20–25

• Endometrial biopsy periodically

• Urinalysis for urinary tract cancers

Li-Fraumeni (TP53)

• Comprehensive annual whole-body MRI

• Annual brain MRI

• Avoid radiation exposure due to radiosensitivity

VHL

• Annual abdominal MRI for renal cell carcinoma

• Yearly ophthalmologic exam

• Annual plasma metanephrines for pheochromocytoma

APC (Familial Adenomatous Polyposis)

• Annual sigmoidoscopy beginning in childhood

• Upper endoscopy for duodenal cancers

Purpose: early detection → improved prognosis or curative intervention.

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🔷 2. Risk-Reducing (Prophylactic) Surgery

Used when:

• Cancer risk is extremely high, or

• Screening is inadequate to detect early disease.

Examples: BRCA1/2

• Bilateral mastectomy reduces breast cancer risk by >90%

• Bilateral salpingo-oophorectomy (BSO) reduces ovarian cancer risk by 80–90% and breast cancer risk by ~50%

Lynch Syndrome

• Prophylactic hysterectomy + bilateral salpingo-oophorectomy after childbearing for high-risk MMR mutations

APC (FAP)

• Total proctocolectomy when polyp burden is unmanageable

TP53 (Li-Fraumeni)

• Prophylactic mastectomy often considered due to early breast cancer risk

• Avoid radiation → mastectomy preferred over lumpectomy + radiation

VHL

• Partial nephrectomy when renal tumors exceed specific size thresholds

Purpose: eliminate the tissue at risk → prevent cancer entirely.

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🔷 3. Chemoprevention

Drugs that reduce cancer risk in genetically high-risk individuals.

BRCA Carriers

• Tamoxifen or raloxifene reduces estrogen receptor–positive breast cancer risk
  (Less effective for BRCA1 due to high rate of ER-negative tumors)

Lynch Syndrome

• Daily aspirin shown in CAPP2 trial to reduce colorectal cancer risk

• Possible role for OCPs in reducing endometrial/ovarian cancer risk

FAP

• COX2 inhibitors (celecoxib) reduce polyp number
  (Used adjunctively, not as alternative to surgery)

Purpose: reduce carcinogenesis in high-risk tissues.

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🔷 4. Lifestyle Modifications

Although not a substitute for genetic-specific interventions, modifiable risk factors improve overall outcomes.

Key strategies:

• Avoid smoking

• Maintain normal BMI

• Limit alcohol

• Regular exercise

• Diet high in fiber and low in processed meats (particularly important in Lynch)

Purpose: reduce background risk and improve overall health.

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🔷 5. Genetic Counseling

An essential component at every stage.

What is provided:

• Interpretation of genetic test results

• Personalized risk estimates

• Discussion of surveillance vs. prophylactic surgery

• Psychological support

• Guidance on informing family members

• Implications for insurance, employment, reproductive choices

Purpose: empower informed decision-making.

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🔷 6. Family Screening / Cascade Testing

Once a pathogenic variant is identified:

Strategies:

• Test all first-degree relatives (50% chance of inheriting)

• Testing may extend to second-degree relatives depending on pedigree

• Early identification → early surveillance → reduced mortality

Purpose: detect carriers early and prevent late diagnoses in relatives.

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🔷 7. Reproductive Options

For individuals wishing to avoid transmitting the mutation.

Options:

• Preimplantation genetic testing (PGT-M) with IVF to implant unaffected embryos

• Prenatal diagnosis (CVS or amniocentesis)

• Use of donor gametes

• Adoption options

• Timing of prophylactic surgery relative to reproductive goals

Purpose: allow planning to avoid passing on high-risk alleles.

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🔷 8. Avoidance of Specific Exposures

Certain hereditary mutations confer unique sensitivities.

Examples: TP53 (Li-Fraumeni)

• Avoid therapeutic radiation due to high risk of radiation-induced malignancy.

RB1 survivors

• Avoid radiation when possible due to risk of second primary tumors.

VHL

• Avoid high altitude in those with hemangioblastomas

• Avoid smoking and certain chemicals for RCC risk

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⭐ SUMMARY (Exam-Perfect Statement)

Carriers of hereditary cancer mutations require a comprehensive management strategy including enhanced surveillance, risk-reducing surgery, chemoprevention, lifestyle modification, genetic counseling, cascade testing of relatives, and reproductive planning.
These interventions reduce cancer incidence, allow earlier detection, and improve survival in individuals predisposed by germline loss-of-function mutations in tumor suppressor genes.