Distinct genomic characteristics of breast cancer in women with PTEN hamartoma tumor syndrome

Cleveland Clinic researchers have uncovered genomic characteristics of breast cancers associated with PTEN hamartoma tumor syndrome (PHTS) that differentiate them from sporadic breast cancers. The findings, published in the American Journal of Human Genetics, have important implications for the personalized management of PHTS-related breast cancers.

"PHTS-associated breast cancers often develop at a younger age and may progress more aggressively than their sporadic counterparts, but they are treated similarly, which underscores the need to better understand any underlining genomic differences between PHTS-associated and sporadic breast cancers."

To address this need, the researchers performed exome sequencing on samples from 44 women with germline PTEN mutations who developed breast cancer and compared the data to samples from women with sporadic breast cancers.

They specifically investigated somatic mutations in both groups because it is posited that both copies of a tumor suppressor gene must be mutated in order for cancer to develop, which is known as Knudson's two-hit hypothesis.

Their analysis revealed that PHTS-associated breast cancers have distinct somatic mutational profiles compared to sporadic breast cancers. For example, they discovered that PTEN and PIK3CA were the most frequently somatically mutated genes in PHTS-associated breast cancers while TP53 was most frequently mutated in sporadic breast cancers.

Notably, the PHTS group had a significantly higher frequency of somatic PTEN mutations compared to the sporadic group, as well as a lower mutational frequency in PIK3CA, indicating that somatic mutations in PTEN are the main drivers of PHTS-associated breast cancers. In addition, they found that somatic mutations in PTEN and PIK3CA were mutually exclusive in the PHTS group but not in the sporadic group.

Ref:

Charis Eng et. al, Exome Sequencing Reveals a Distinct Somatic Genomic Landscape in Breast Cancer from Women with Germline PTEN Variants, American Journal of Human Genetics, 4-Aug-2022, DOI: 10.1016/j.ajhg.2022.07.005