What type of gene mutation is most likely involved in a male patient with biopsy-proven breast cancer and no family history of breast cancer?

Gene Mutations in Male Breast Cancer

BRCA2 mutations are the most likely genetic alteration in male patients with biopsy-proven breast cancer who have no family history of breast cancer.

Prevalence of Gene Mutations in Male Breast Cancer

• Male breast cancer is strongly associated with BRCA2 mutations, with BRCA2 carriers having a 6-7% lifetime risk of developing breast cancer compared to the general population 1, 2
• BRCA2 mutations are significantly overrepresented in male breast cancer cases (41.7%) compared to female breast cancer cases (8.3%) 3
• BRCA1 mutations are underrepresented in male breast cancer (5%) compared to female breast cancer (14.4%) 3
• The estimated cumulative risk of breast cancer by age 70 is 6.8% for male BRCA2 mutation carriers versus only 1.2% for BRCA1 mutation carriers 2

Genetic Testing Criteria for Male Breast Cancer

• Male breast cancer alone is considered a criterion for genetic testing, regardless of family history 1, 4
• Widely accepted clinical criteria for BRCA testing include male breast cancer with early onset female breast cancer in the family 1
• The presence of male breast cancer significantly increases the likelihood of identifying a BRCA2 mutation, even without a strong family history 5, 6

De Novo Mutations

• While most BRCA mutations are inherited, de novo germline mutations in BRCA2 have been documented in patients with early-onset breast cancer without family history 7
• The absence of family history does not rule out the possibility of a pathogenic BRCA2 mutation, as it could represent a new mutation 7

Other Genetic Considerations

• While BRCA2 is the most common mutation in male breast cancer, other genes have been implicated:
  • TP53 mutations (associated with Li-Fraumeni syndrome) account for <1% of breast cancer families 1, 4
  • PTEN mutations (Cowden syndrome) are rare in male breast cancer 4
  • CHEK2 mutations confer a moderate risk of breast cancer and may contribute to some male cases 1, 4
  • PALB2 mutations have been described in some male breast cancer cases 1, 4

Histopathological Features

• Male breast cancers in BRCA2 carriers may have distinctive histological features, with a trend toward micropapillary differentiation 3
• Most male breast cancers are of the luminal phenotype (89.7%), with infrequent HER2 (8.6%) and basal (1.7%) phenotypes 3
• This contrasts with BRCA1-associated female breast cancers, which are often basal-like 3

Clinical Implications

• Identification of BRCA2 mutations in male breast cancer patients has important implications:
  • Increased risk of other cancers, including prostate (5-25%), pancreatic (up to 2%), and stomach cancers 1
  • Family members should be offered genetic counseling and testing 1
  • Cascade testing of relatives can identify at-risk individuals who may benefit from enhanced surveillance or risk-reducing interventions 4

Common Pitfalls

• Failing to consider genetic testing in male breast cancer patients without family history 5, 6
• Focusing only on BRCA1 testing, when BRCA2 is much more commonly associated with male breast cancer 3, 2
• Overlooking the possibility of de novo mutations when family history is absent 7
• Not recognizing that negative BRCA1/2 testing does not rule out hereditary breast cancer risk if family history is suggestive 4

Based on the evidence presented, the answer to the question is C. BRCA2.