Somatic mutations in leukocytes infiltrating primary breast cancers

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Malignant transformation involves cancer cell interactions with the tumor microenvironment, including infiltrating leukocytes.
• Somatic mutational studies traditionally focus on cancer cells, assuming a genetically normal microenvironment.
• This study investigates the genetic landscape of tumor-associated leukocytes in breast cancer.

Purpose of the Study:

• To investigate the presence of pathogenic mutations in tumor-associated leukocytes within primary breast cancers.
• To determine if the tumor microenvironment's immune cells harbor somatic mutations.
• To explore the potential genetic alterations in leukocytes infiltrating breast tumors.

Main Methods:

• Utilized targeted sequencing and exome sequencing on sorted tumor-infiltrating CD45-positive cells from untreated breast cancers.
• Employed high-depth sequencing to confirm mutations in infiltrating leukocytes, purified tumor cells, and circulating blood cells.
• Analyzed 15 paired tumor-infiltrating leukocytes and matched germline DNA samples.

Main Results:

• Identified variants in known cancer genes within all 15 primary breast cancer patients' infiltrating leukocytes.
• Confirmed mutations in infiltrating leukocytes via orthogonal exome sequencing.
• Observed somatic mutations, including in leukemia-associated genes (DNTM3A, TET2, BCOR), in ten patients; one mutation was also found in circulating leukocytes.

Conclusions:

• Demonstrated the presence of somatic mutations, including in cancer genes, within leukocytes infiltrating a subset of primary breast cancers.
• Highlights the potential for cancer cells to interact with genetically altered infiltrating leukocytes.
• Suggests significant clinical implications arising from mutant immune cell infiltration in breast cancer.