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The Genomic Landscape of Male Breast Cancers
Salvatore Piscuoglio1, Charlotte K Y Ng1, Melissa P Murray1
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Purpose:
Male breast cancer is rare, and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of males with breast cancer is extrapolated from results in females with breast cancer. We sought to define whether male breast cancers harbor somatic genetic alterations in genes frequently altered in female breast cancers.
Experimental Design:
All male breast cancers were estrogen receptor-positive, and all but two were HER2-negative. Fifty-nine male breast cancers were subtyped by immunohistochemistry, and tumor-normal pairs were microdissected and subjected to massively parallel sequencing targeting all exons of 241 genes frequently mutated in female breast cancers or DNA-repair related. The repertoires of somatic mutations and copy number alterations of male breast cancers were compared with that of subtype-matched female breast cancers.
Results:
Twenty-nine percent and 71% of male breast cancers were immunohistochemically classified as luminal A-like or luminal B-like, respectively. Male breast cancers displayed a heterogeneous repertoire of somatic genetic alterations that to some extent recapitulated that of estrogen receptor (ER)-positive/HER2-negative female breast cancers, including recurrent mutations affecting PIK3CA (20%) and GATA3 (15%). ER-positive/HER2-negative male breast cancers, however, less frequently harbored 16q losses, and PIK3CA and TP53 mutations than ER-positive/HER2-negative female breast cancers. In addition, male breast cancers were found to be significantly enriched for mutations affecting DNA repair-related genes.
Conclusions:
Male breast cancers less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative female breast cancers, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of male breast cancers are driven by a distinct repertoire of somatic changes. Given the genomic differences, caution may be needed in the application of biologic and therapeutic findings from studies of female breast cancers to male breast cancers. Clin Cancer Res; 22(16); 4045-56. ©2016 AACR.
Insights
Male breast cancers have distinct genetic alterations compared to female breast cancers, particularly in DNA repair genes. These genomic differences suggest unique drivers and necessitate caution when applying female breast cancer findings to males.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Male breast cancer is rare, with limited genomic characterization.
- Current treatment strategies are extrapolated from female breast cancer studies.
- Understanding the genetic landscape of male breast cancer is crucial for targeted therapies.
Purpose of the Study:
- To define the somatic genetic alterations in male breast cancers.
- To compare the genomic landscape of male breast cancer with subtype-matched female breast cancers.
- To identify potential distinct drivers in male breast cancer.
Main Methods:
- Sequencing of 241 genes in 59 male breast cancers.
- Comparison of somatic mutations and copy number alterations with female breast cancers.
- Immunohistochemical subtyping (luminal A/B) and HER2 status determination.
Main Results:
- Male breast cancers are predominantly estrogen receptor-positive and HER2-negative (luminal subtypes).
- Common mutations include PIK3CA (20%) and GATA3 (15%), similar to female breast cancers.
- Male breast cancers showed fewer 16q losses and PIK3CA/TP53 mutations than female counterparts, but were enriched for DNA repair gene mutations.
Conclusions:
- Male breast cancers exhibit a distinct genomic profile compared to ER-positive/HER2-negative female breast cancers.
- Somatic alterations like PIK3CA, TP53 mutations, and 16q losses are less frequent in males.
- Genomic differences highlight the need for caution in applying female breast cancer research findings to male patients.
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