Germline BRCA2 mutations detected in pediatric sequencing studies impact parents' evaluation and care.

There has been no indication to test for BRCA1/2 in children (with the rare exception of Fanconi anemia) as screening begins in adult years and there is a potential to induce anxiety related to adult-onset cancers. However, in the setting of pediatric cancer, with increasing utility and frequency of companion tumor-normal sequencing without regard for phenotype and with BRCA1/2 included in tumor profiling panels, germline mutations in BRCA1/2 and other DNA damage repair genes have been found. When mutations in these genes are revealed, there are implications for immediate family members. Here we present two children in whom BRCA2 mutations identified through tumor sequencing prompted parental genetic testing and medical action. These cases illustrate the potential importance of including a matched normal DNA sample when performing tumor profiling of pediatric cancer patients to ensure optimal care.

Educational and Psychosocial Support Needs in Lynch Syndrome: Implementation and Assessment of an Educational Workshop and Support Group.

Few reports of educational and counseling support resources exist for Lynch syndrome (LS), a disorder requiring multi-organ cancer screening and specialized medical care throughout adult life. Here we describe the development and efficacy of two resources designed to address this need, the Memorial Sloan Kettering Cancer Center Clinical Genetics Service annual Lynch Syndrome Educational Workshop (LSEW), and a quarterly Lynch Syndrome Patient Advocacy Network (LSPAN) support group. The LSEW and LSPAN were implemented beginning in 2012. Participant survey data evaluating satisfaction, clarity, and unmet needs for each event were retrospectively analyzed and summarized using descriptive statistics. Annual LSEW attendance ranged from 53 to 75 total participants. LSEW year 1 participants indicated a need for a support group, and preferred in-person meetings at a frequency of every 3-6 months. For LSEW year 2-5 participants, >96 % reported satisfaction with the LSEW, and >82 % expressed interest in secure online support. Common themes for improvement included increased time for question and answer sessions and additional introductory genetics education. Responding LSPAN participants (n = 57 total survey responses in 11 meetings) found the meetings helpful (100 %), information clear (91 %), and presence of a genetic counselor useful (67 %). Desired discussion topics included coping with stress and anxiety, development of a support network, family communication about LS, genetic testing decisions, and bereavement. Following genetic counseling, a need exists for ongoing educational and emotional support in LS. Implementation of resources such as the LSEW and LSPAN is feasible and perceived as helpful by participants.

Analysis of genetic variants in never-smokers with lung cancer facilitated by an Internet-based blood collection protocol: a preliminary report.

PURPOSE: Germ line polymorphisms may confer susceptibility to lung cancer in never smokers, but studies in the United States have been limited by the low number of cases seen at single institutions. We hypothesized that we could use the Internet to bolster the accrual of appropriate patients. EXPERIMENTAL DESIGN: We established an Internet-based protocol to collect blood and information from patients throughout the United States. To illustrate the power of this approach, we used these samples, plus additional cases and age-matched controls from the Memorial Sloan-Kettering Cancer Center (New York, NY) and the Aichi Cancer Center (Nagoya, Japan), to analyze germ line DNA for genetic variants reportedly associated with lung cancer susceptibility. The genotypes for the polymorphisms rs763317 (intron 1) and T790M (exon 20) in the EGFR gene were determined by direct sequencing, and CHRNA3 nicotinic acetylcholine receptor single nucleotide polymorphisms (rs8034191 and rs1051730) were genotyped as part of a pilot genome-wide association study. RESULTS: We successfully analyzed germ line DNA from 369 cases, including 45 obtained via the Internet, and 342 controls. A germ line EGFR T790M variant was identified in 2 of the 369 cases (0.54%; 95% confidence interval, 0.21-1.29%), and in none of the 292 controls (P = 0.21). No difference was observed in EGFR rs763317 frequency between cases and controls. Similarly, neither CHRNA3 rs8034191 nor rs1051730 were associated with lung cancer risk. CONCLUSIONS: The Internet provides a way to recruit patients throughout the country for minimal risk studies. This approach could be used to facilitate studies of germ line polymorphisms in specific groups of patients with cancer.

The 6q22.33 locus and breast cancer susceptibility.

Recently, we identified a novel breast cancer susceptibility locus at 6q22.33 following a genome-wide association study in the Ashkenazi Jewish genetic isolate. To replicate these findings, we did a case-control association analysis on 6q22.33 (rs2180341) in an additional 487 Ashkenazi Jewish breast cancer cases and in an independent non-Jewish, predominantly European American, population of 1,466 breast cancer cases and 1,467 controls. We confirmed the 6q22.33 association with breast cancer risk in the replication cohorts [per-allele odds ratio (OR), 1.18; 95% confidence interval (95% CI), 1.04-1.33; P = 0.0083], with the strongest effect in the aggregate meta-analysis of 3,039 breast cancer cases and 2,616 Ashkenazi Jewish and non-Jewish controls (per-allele OR, 1.24; 95% CI, 1.13-1.36; P = 3.85 x 10(-7)). We also showed that the association was slightly stronger with estrogen receptor-positive tumors (per-allele OR, 1.35; 95% CI, 1.20-1.51; P = 2.2 x 10(-5)) compared with estrogen receptor-negative tumors (per-allele OR, 1.19; 95% CI, 0.97-1.47; P = 0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in breast cancer susceptibility. Due to the stronger association of 6q22.33 with estrogen receptor-positive breast cancer, we examined the effect of candidate genes on estrogen receptor response elements. Upon transfection of overexpressed RNF146 in the MCF-7 breast cancer cell line, we observed diminished expression of an estrogen receptor response element reporter construct. This study confirms the association of 6q22.33 with breast cancer, with slightly stronger effect in estrogen receptor-positive tumors. Further functional studies of candidate genes are in progress, and a large replication analysis is being completed as part of an international consortium.

Genetics and the young woman with breast cancer.

While many individual risk factors have been defined for breast cancer, a family history was recognized long ago as one of the most potent. Mutations within BRCA1 or BRCA2, both identified about 10 years ago, are responsible for the majority of inherited breast cancer. By virtue of her age alone, a young woman diagnosed with breast cancer has a greatly elevated probability to carry a BRCA mutation. Other risk factors, including a personal or family history of ovarian cancer, bilateral breast cancer or Jewish ancestry, only serve to increase that chance. It is critical that clinicians caring for a young woman understand their patient's elevated risk to carry such a mutation and thoughtfully investigate this risk. Upon identification of a mutation in a young woman there are many consequences which necessitate careful consideration of various treatment and preventative options including prophylactic mastectomy and oophorectomy. Finally, the diagnosis of breast cancer in a young woman and the attendant genetic implications have immediate and serious consequences for her family members. Genetic professionals can help navigate the complex technical and psychosocial issues. This chapter explores the molecular, clinical and ethical intricacies of BRCA genetic testing.