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PTEN Mutation Syndrome Leads to Breast Cancers With Distinct Molecular Alterations

NEW YORK – Forms of breast cancer that arise in individuals with a cancer predisposition syndrome stemming from germline mutations in the PTEN gene — alterations behind a condition called "PTEN hamartoma tumor syndrome" (PHTS) — have molecular features that are distinct from those found in tumors occurring in sporadic breast cancer cases, new research suggests.

"Our findings reveal a distinct breast cancer biology in the context [of] germline PTEN mutations that spotlights the need to develop more targeted, personalized strategies to effectively treat and, in time, prevent PHTS-associated breast cancers," senior and corresponding author Charis Eng, a researcher affiliated with the Cleveland Clinic and Case Western Reserve University and chair of the Cleveland Clinic's Genomic Medicine Institute, said in a statement.

As they reported in the American Journal of Human Genetics on Thursday, the researchers performed exome sequencing on tumor samples from 44 breast cancer patients with PHTS, comparing the protein-coding sequences to sequence data available for 497 sporadic breast cancers profiled for the Cancer Genome Atlas project.

"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," Eng explained.

In contrast to tumors from sporadic breast cancer cases, which are often marked by somatic mutations in the tumor suppressor gene TP53, the researchers noted that mutually exclusive somatic mutations from the PHTS-related breast cancers most often fell in the PIK3CA and PTEN genes.

The latter finding was consistent with the "two-hit" model of cancer development, which links tumor development to distinct germline and somatic mutations that independently impact each allele of a gene, the team explained.

"Following this hypothesis, individuals with PHTS inherit the first PTEN mutation, or the first hit, and then acquire the second hit via a somatic mutation on their other PTEN gene," Eng explained. "In contrast, sporadic cancers would occur when both tumor suppressor genes are mutated randomly, which is less likely or takes longer, thus helping to explain why the risk for developing cancer at an earlier age is greater for those with germline mutations."

The team identified somatic PTEN mutations in almost 23 percent of the PHTS-related breast cancers profiled. In contrast, sequences from sporadic breast cancers suggested that PTEN mutations are found in fewer than 6 percent of those tumors. Sporadic mutations in PIK3CA turned up in almost 23 percent of breast tumors from individuals with PHTS, and in more than 33 percent of tumors from sporadic breast cancers.

"Although targeting PTEN-associated alterations for therapeutic purposes has tremendous challenges, our findings call for more targeted, personalized strategies to effectively treat PHTS-related cancers," the authors concluded, "a population that will only rise in incidence as clinical genetic testing becomes more widely accessible in the clinic."