A 38-year-old female presents to her primary care physician with complaints of several episodes of palpitations accompanied by panic attacks over the last month. She also is concerned about many instances over the past few weeks where food has been getting stuck in her throat and she has had trouble swallowing. She denies any prior medical problems and reports a family history of cancer in her mother and maternal grandfather but cannot recall any details regarding the type of cancer(s) or age of diagnosis. Her vital signs at today's visit are as follows: T 37.6 deg C, HR 106, BP 158/104, RR 16, SpO2 97%. Physical examination is significant for a nodule on the anterior portion of the neck that moves with swallowing, accompanied by mild lymphadenopathy. A preliminary work-up is initiated, which shows hypercalcemia, elevated baseline calcitonin, and an inappropriately elevated PTH level. Diagnostic imaging shows bilateral adrenal lesions on an MRI of the abdomen/pelvis. Which of the following is the most likely diagnosis in this patient?

Multiple endocrine neoplasia (MEN) IIa

Familial medullary thyroid cancer (FMTC)

Multiple endocrine neoplasia (MEN) I

Multiple endocrine neoplasia (MEN) IIb

Patient 1 – A 26-year-old woman presents to her primary care physician for an annual exam. She currently does not have any acute concerns and says her health has been generally well. Medical history is significant for asthma, which is managed with an albuterol inhaler. Her last pap smear was unremarkable. She is currently sexually active with one male and consistently uses condoms. She occasionally smokes marijuana and drinks wine once per week. Her mother recently passed away from advanced ovarian cancer. Her sister is 37-years-old and was recently diagnosed with breast cancer and ovarian cancer. Physical examination is remarkable for a mildly anxious woman. Patient 2 – A 27-year-old woman presents to her primary care physician for an annual exam. She says that she would like to be screened for breast cancer since two of her close friends were recently diagnosed. She noticed she has a small and mobile mass on her left breast, which increases in size and becomes tender around her time of menses. Family history is remarkable for hypertension in the father. The physical exam is significant for a small, well-defined, and mobile mass on her left breast that is not tender to palpation. Which of the following is the best next step in management for patient 1 and 2?

Patient 1 – BRCA testing. Patient 2 – Breast ultrasound

Patient 1 – Breast ultrasound. Patient 2 – Return in 3 months for a clinical breast exam

Patient 1 – Reassurance. Patient 2 – Breast ultrasound

Patient 1 – CA-125 testing. Patient 2 – BRCA testing

Patient 1 – Breast and ovarian ultrasound. Patient 2 – Mammography

A 34-year-old woman comes to the physician for a routine health maintenance examination. She has gastroesophageal reflux disease. She recently moved to a new city. Her father was diagnosed with colon cancer at age 46. Her father's brother died because of small bowel cancer. Her paternal grandfather died because of stomach cancer. She takes a vitamin supplement. Current medications include esomeprazole and a multivitamin. She smoked one pack of cigarettes daily for 6 years but quit 2 years ago. She drinks one to two alcoholic beverages on weekends. She appears healthy. Vital signs are within normal limits. Physical examination shows no abnormalities. Colonoscopy is unremarkable. Germline testing via DNA sequencing in this patient shows mutations in DNA repair genes MLH1 and MSH2. Which of the following will this patient most likely require at some point in her life?

Hysterectomy and bilateral salpingo-oophorectomy

Bilateral prophylactic mastectomy

Surgical removal of a desmoid tumor

Prophylactic proctocolectomy with ileoanal anastomosis

A 74-year-old retired female teacher is referred to the endocrinology clinic. She is very concerned about a large mass in her neck that has progressively enlarged over the past 2 weeks. She also reports a 15 pound weight loss over the last 3 months. She now has hoarseness and difficulty swallowing her food, giving her a sensation that food gets stuck in her windpipe when she swallows. There is no pain associated with swallowing. Her speech is monotonous. No other gait or language articulation problems are noted. Testing for cranial nerve lesions is unremarkable. On palpation, a large, fixed and non-tender mass in the thyroid is noted. Cervical lymph nodes are palpable bilaterally. The patient is urgently scheduled for an ultrasound-guided fine needle aspiration to guide management. Which of the following is the most likely gene mutation to be found in this mass?

Inactivating mutation of the p53 tumor suppressor gene

Activating mutation of the Ras protooncogene

A 39-year-old female presents to her gynecologist complaining of a breast lump. Two weeks ago, while performing a breast self-examination she noticed a small firm nodule in her left breast. She is otherwise healthy and takes no medications. Her family history is notable for a history of breast cancer in her mother and maternal aunt. On physical examination, there is a firm immobile nodular mass in the superolateral quadrant of her left breast. A mammogram of her left breast is shown. Genetic analysis reveals a mutation on chromosome 17. This patient is at increased risk for which of the following conditions?

Ductal carcinoma in situ (DCIS)

A 40-year-old man presents with an episode of rectal bleeding. He is concerned because his mother died of colorectal cancer at 50 years of age. He has no further information about his family history. Physical examination and digital rectal examination are normal. He undergoes a colonoscopy and is found to have innumerable adenomas in the left side of the colon ranging in size from 4–15 mm. Which of the following is the most likely underlying mechanism of this patient illness?

Mutation in DNA mismatch repair genes

Inactivation of BRCA1 and BRCA2 genes

A 65-year-old African American man presents for follow-up examination with a 6-month history of urinary hesitancy, weak stream, and terminal dribbling, which is refractory to a combination therapy of finasteride and tamsulosin. The patient’s past medical history is otherwise unremarkable. His father and brother were diagnosed with prostate cancer at the age of 55 years. His vital signs are within normal limits. The patient has a normal anal sphincter tone and a bulbocavernosus muscle reflex. Digital rectal exam (DRE) reveals a prostate size equivalent to 2 finger pads with a hard nodule and without fluctuance or tenderness. Serum prostate-specific antigen (PSA) level is 5 ng/mL. Which of the following investigations is most likely to establish a definitive diagnosis?

Magnetic resonance imaging (MRI)

An excisional biopsy is performed and the diagnosis of superficial spreading melanoma is confirmed. The lesion is 1.1 mm thick. Which of the following is the most appropriate next step in management?

Surgical excision with 1-2 cm safety margins and sentinel lymph node study

Surgical excision with 0.5-1 cm safety margins only

Surgical excision with 1 cm safety margins only

Surgical excision with 1-2 cm safety margins only

Surgical excision with 0.5-1 cm safety margins and sentinel lymph node study

Hereditary breast cancer syndromes — USMLE Lesson

🧬 The Bad Genes Club

BRCA1/2: Most common; account for ~5-10% of all breast cancers.
- BRCA1: ↑ risk of breast (esp. triple-negative), ovarian, pancreatic, prostate cancer.
- BRCA2: ↑ risk of breast (male & female), ovarian, pancreatic, prostate cancer, melanoma.
Other Key Genes:
- TP53 (Li-Fraumeni): 📌 SBLA mnemonic: Sarcoma, Breast, Leukemia, Adrenocortical.
- PTEN (Cowden): Breast, thyroid, endometrial cancer; hamartomas.
- STK11 (Peutz-Jeghers): GI polyps, breast, GI, pancreatic cancer.

Pedigree chart showing autosomal dominant inheritance

⭐ All are Autosomal Dominant mutations in tumor suppressor genes. Inheritance of one mutated allele requires a second somatic "hit" for tumorigenesis (Knudson's two-hit hypothesis).

🧬 Pathophysiology - Broken Blueprints

Most syndromes are autosomal dominant, involving germline mutations in tumor suppressor genes (TSGs). Function is lost via Knudson's "two-hit" hypothesis.

⭐ Knudson's Two-Hit Hypothesis: A germline mutation (1st hit) is inherited. A second, somatic mutation (2nd hit) in the remaining normal allele leads to loss of heterozygosity (LOH) and subsequent tumorigenesis.

Knudson Two-Hit Hypothesis in Hereditary Cancer

Gene	Chromosome	Key Associated Cancers
BRCA1	17q21	Breast (often triple-negative), Ovarian, Pancreatic, Prostate
BRCA2	13q12	Breast (often ER+), Male Breast, Ovarian, Prostate, Melanoma
TP53	17p13	Li-Fraumeni: Sarcoma, Breast, Brain, Adrenocortical (SBLA)
PTEN	10q23	Cowden: Breast, Thyroid (follicular), Endometrial, Hamartomas

🧬 Clinical Manifestations - Cancer Constellations

Recognizing the full cancer spectrum is crucial for appropriate screening and management. Each syndrome has a distinct pattern of associated malignancies beyond breast cancer.

Syndrome	Gene(s)	Key Features & Associated Cancers
HBOC	BRCA1	↑ Ovarian (serous), Pancreatic, Prostate (aggressive). Triple-negative breast cancer common.
	BRCA2	↑ Ovarian, Male Breast, Pancreatic, Prostate, Melanoma.
Li-Fraumeni	TP53	Sarcomas, Brain tumors, Adrenocortical carcinoma, Leukemia. ⚠️ Avoid radiation therapy.
Cowden	PTEN	Thyroid (follicular), Endometrial. Mucocutaneous lesions (trichilemmomas, papillomas).
Peutz-Jeghers	STK11	GI (hamartomatous polyps), Pancreatic, Ovarian (sex-cord). Mucocutaneous pigmentation.
Hereditary Diffuse Gastric Cancer	CDH1	Gastric (diffuse/signet ring), Invasive Lobular Breast Cancer.

⭐ CDH1 mutations are strongly associated with invasive lobular carcinoma of the breast and diffuse gastric cancer (signet ring cell type). Prophylactic gastrectomy is often recommended.

🛡️ Management - Guardians of the Genome

Management focuses on intensive surveillance and risk-reduction strategies. Decisions are highly individualized based on patient preference, age, and specific mutation.

⭐ Prophylactic bilateral mastectomy reduces breast cancer risk by >95% in BRCA carriers. Risk-reducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk by ~80% and also lowers breast cancer risk by ~50%.

⚡ High-Yield Points - Biggest Takeaways

BRCA1/2 are the most common (autosomal dominant) causes of hereditary breast and ovarian cancer.

BRCA1 is strongly associated with triple-negative breast cancer; BRCA2 with male breast cancer.

Li-Fraumeni (TP53): Sarcoma, Breast cancer, Leukemia, Adrenocortical carcinoma (SBLA).

Cowden syndrome (PTEN): Hamartomas, macrocephaly; risk for breast, thyroid, endometrial cancer.

Peutz-Jeghers (STK11): Mucocutaneous pigmentation, GI polyps, increased breast cancer risk.

ATM gene mutations (Ataxia-Telangiectasia) also confer an increased breast cancer risk.

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