A 35-year-old woman is found to carry a germline mutation in the TP53 gene. Which syndrome is she at risk for, and what is the characteristic feature of this inherited cancer predisposition?

Question

Accepted Answer

A. Li-Fraumeni syndrome with multiple early-onset malignancies across diverse tissue types. ## Li-Fraumeni Syndrome (LFS)

**Key Point:** Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by germline TP53 mutations. It is characterized by early-onset malignancies across multiple organ systems.

**High-Yield:** TP53 mutations account for ~70% of LFS cases. Affected individuals have ~90% lifetime cancer risk by age 70, with multiple independent primary cancers being common.

### Spectrum of Malignancies in LFS

| Cancer Type | Frequency | Age of Onset |
| --- | --- | --- |
| Breast cancer | Most common in women | <40 years |
| Soft tissue sarcoma | 15–20% | Childhood/young adult |
| Osteosarcoma | 5–10% | Childhood |
| Brain tumors | 5–10% | Childhood |
| Adrenocortical carcinoma | 5–10% | Childhood |
| Leukemia | 5% | Childhood |
| Gastric, pancreatic, lung cancers | Variable | Adult |

**Clinical Pearl:** The "classic" LFS triad is: (1) early-onset breast cancer in women, (2) soft tissue sarcoma, and (3) adrenocortical carcinoma in children. However, any early-onset or multiple primary malignancies in a family should raise suspicion.

**Mnemonic:** **TP53 = "The Protector" Gene** — when mutated, it loses its ability to suppress tumors across all tissues, leading to diverse malignancies.

### TP53 Function

1. **DNA damage sensing:** Detects genomic stress
2. **Cell cycle arrest:** Activates p21 to halt G1/S progression
3. **Apoptosis:** Triggers programmed cell death if damage is irreparable
4. **Loss in LFS:** Cells escape checkpoint control → accumulation of mutations → cancer

**Warning:** Patients with LFS should avoid unnecessary radiation (including screening mammography before age 40 unless clinically indicated) and chemotherapy when possible, as these can trigger secondary malignancies.

Answer

B. Familial adenomatous polyposis with APC mutations and colorectal cancer

Answer

C. Hereditary breast and ovarian cancer syndrome with BRCA1/BRCA2 mutations

Answer

D. Hereditary nonpolyposis colorectal cancer with mismatch repair gene mutations

A 35-year-old woman is found to carry a germline mutation in the TP53 gene. Which syndrome is she at risk for, and what is the characteristic feature of this inherited cancer predisposition?

Explanation

Li-Fraumeni Syndrome (LFS)

Spectrum of Malignancies in LFS

TP53 Function

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Cancer Type	Frequency	Age of Onset
Breast cancer	Most common in women	<40 years
Soft tissue sarcoma	15–20%	Childhood/young adult
Osteosarcoma	5–10%	Childhood
Brain tumors	5–10%	Childhood
Adrenocortical carcinoma	5–10%	Childhood
Leukemia	5%	Childhood
Gastric, pancreatic, lung cancers	Variable	Adult