Genetics of PTEN in Cowden Syndrome and Sporadic Breast Cancer

Abstract

Abstract : Germilne mutations in PTEN, a tumor suppressor gene located on 10q23.3, is associated with 80% of Cowden syndrome (CS) probands ascertained by the strict operational diagnostic criteria of the International Cowden Consortium. CS is an inherited multiple hamartoma syndrome with a high risk of breast and thyroid cancer. The PT has found that 5% of unselected apparently sporadic breast cancer patients diagnosed under the age of 40 carry occult germline PTEN mutations. Therefore, this DAMD project sought to determine if PTEN played a role in non-BRCA/2 familial site-specific breast cancer and patients and families who have partial features of CS but who do not meet full Consortium criteria. To date, the PT has found that germline PTEN mutations do not play a role in familial site-specific breast cancer. However, CS-like individuals and families have at least a 5% probability of carrying germline PTEN mutations, with full implications for cancer risk and surveillance for that individual and the family. The presence of endometrial cancer seems to increase the likelihood of finding a PTEN mutation in a CS-like family or case. These findings have helped revise the Consortium diagnostic criteria which will be adopted into the NCCN guidelines for their next version. Further, because of the apparent importance of endometrial carcinoma, despite its relatively low frequency, in CS, the PT extended her work to examine PTEN mutation and expression in sporadic endometrial cancer and precancers and discovered that at least 93% of all endometrial carcinomas are due to PTEN mutation or epigenetic PTEN silencing, and that PTEN alterations already are present in a subset of the earliest endometrial precancers.