Background: Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2). The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. Methods: We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT) and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE). All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. Results: Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%). Conclusion: Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer.

The phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a grouping of related genetic disorders that has been linked to germline mutations in the PTEN gene. These disorders include Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, adult Lhermitte–Duclos disease, and autism spectrum disorders associated with macrocephaly. The majority of the clinical information available on PHTS, however, is related to individuals diagnosed with CS. There is still much to be learned about this disorder, since diagnostic criteria for CS were only established in 1996, before the identification of the PTEN gene, and were based primarily on features seen in cases reported in the existing literature. More recently, however, data from several large series of patients have shown that a number of the clinical features associated with PTEN mutations are either more or less common than previously reported. In addition, we now know that only about 30–35% of patients meeting clinical diagnostic criteria for Cowden syndrome actually have a detectable PTEN mutation. Thus, our understanding of PTEN-related diseases and their management has evolved significantly over time. The United States National Comprehensive Cancer Network (NCCN) has produced and regularly updates practice guidelines which include clinical diagnostic criteria as well as guidelines for PTEN testing and management of patients with mutations. This review will summarize the overall literature on PHTS as well as recent findings which are broadening our understanding of this set of disorders.

Background: Cowden syndrome (CS) is associated with benign hamartomatous lesions and risks for thyroid, breast and endometrial cancers. Bannayan–Riley–Ruvalcaba syndrome is an allelic disorder characterised by macrocephaly, intestinal polyps, lipomas, and pigmented penile macules. Diagnostic criteria for CS are based on the presence of a range of clinical features. However, prior data on the component clinical features have been based primarily on compilations of cases reported before development of consensus diagnostic criteria. Objective: This study sought to determine the clinical features most predictive of a mutation in the largest single cohort of patients with clinical testing for PTEN mutations reported to date. Methods: Molecular and clinical data were reviewed on 802 patients referred for PTEN analysis by a single laboratory. Results: Deleterious mutations were found in 172 (21.4%) subjects. Among mutation carriers significant differences from previous reports were found for the frequencies of several clinical features, including macrocephaly, uterine fibroids, benign breast disease, and endometrial cancer. Logistic regression analyses indicated that female mutation carriers were best identified by the presence of macrocephaly, endometrial cancer, trichilemmomas, papillomatous papules, breast cancer, benign thyroid disease, and benign gastrointestinal (GI) lesions. For males, the most discriminating features were macrocephaly, lipomas, papillomatous papules, penile freckling, benign GI lesions, and benign thyroid disease. Age related differences were also identified. Conclusion: The mutation frequency in patients meeting CS diagnostic criteria (34%) was significantly lower than previously reported, suggesting a need for reevaluation of these criteria. A mutation prediction model has been developed which can help identify patients appropriate for PTEN testing in clinical practice.