Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation.

BACKGROUND: Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described. METHODS: Constitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432). RESULTS: No cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher's exact test). There were no gross relationships with mutation position. Forty-five (64.3%; HR 6.4-83) of the 70 different mutations were more frequent than expected (p<0.05), while 52 (74.3%; HR 5.3-83) were significant when adjusted for multiple comparisons (adjusted p≤0.125; Benjamini-Hochberg). Higher proportions of both nonsense and missense mutations were also observed (adjusted p=0.254; Benjamini-Hochberg). Ten of the 11 missense cases with known age of BC occurred at <50 years (p=0.041). Eighteen cases had BRCA1/2 testing, revealing one BRCA2 mutation. DISCUSSION: These data strongly support the hypothesis that certain constitutional mutation types, and indeed certain specific variants in NF1 confer different risks of BC. The lack of large deletions and excess of nonsenses and missenses is consistent with gain of function mutations conferring risk of BC, and also that neurofibromin may function as a dimer. The observation that somatic NF1 amplification can occur independently of ERBB2 amplification in sporadic BC supports this concept. A prospective clinical-molecular study of NF1-BC needs to be established to confirm and build on these findings, but regardless of NF1 mutation status patients with NF1-BC warrant testing of other BC-predisposing genes.

Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results.

PURPOSE: Genetic predisposition to male breast cancer (MBC) is not well understood. The aim of this study was to better define the predisposition genes contributing to MBC and the utility of germline multi-gene panel testing (MGPT) for explaining the etiology of MBCs. METHODS: Clinical histories and molecular results were retrospectively reviewed for 715 MBC patients who underwent MGPT from March 2012 to June 2016. RESULTS: The detection rate of MGPT was 18.1% for patients tested for variants in 16 breast cancer susceptibility genes and with no prior BRCA1/2 testing. BRCA2 and CHEK2 were the most frequently mutated genes (11.0 and 4.1% of patients with no prior BRCA1/2 testing, respectively). Pathogenic variants in BRCA2 [odds ratio (OR) = 13.9; p = 1.92 × 10-16], CHEK2 (OR = 3.7; p = 6.24 × 10-24), and PALB2 (OR = 6.6, p = 0.01) were associated with significantly increased risks of MBC. The average age at diagnosis of MBC was similar for patients with (64 years) and without (62 years) pathogenic variants. CHEK2 1100delC carriers had a significantly lower average age of diagnosis (n = 7; 54 years) than all others with pathogenic variants (p = 0.03). No significant differences were observed between history of additional primary cancers (non-breast) and family history of male breast cancer for patients with and without pathogenic variants. However, patients with pathogenic variants in BRCA2 were more likely to have a history of multiple primary breast cancers. CONCLUSION: These data suggest that all MBC patients regardless of age of diagnosis, history of multiple primary cancers, or family history of MBC should be offered MGPT.

Cancer Genetic Counseling and Testing in an Era of Rapid Change.

The impacts of the Association for Molecular Pathology vs. Myriad Supreme Court decision regarding patenting DNA segments and multi-gene testing on cancer genetic counseling practice have not been well described. We aimed to assess genetic counselors' perceptions of how their genetic testing-related practices for hereditary breast and/or ovarian cancer (HBOC) changed after these events. One-hundred fifty-two genetic counselors from the National Society of Genetic Counselors Cancer Special Interest Group completed an anonymous, online, mixed-methods survey in November 2013. The survey presented four hypothetical patients and asked about changes in testing practice. Across the vignettes, a majority of participants reported specific changes in testing decisions following Association for Molecular Pathology vs. Myriad and availability of multi-gene testing. Ninety-three percent of participants reported changing the types of first- and second-line tests they order for HBOC; the degree of change varied geographically. Qualitative analysis indicated that some counselors have altered the counseling session content, trading depth of information for breadth and spending more time counseling about uncertainty. This study shows that cancer genetic counselors are adapting quickly to genetic testing changes, but with wide variability. Findings suggest future research to elucidate clinicians' and patients' preferences for guidance on the clinical implementation of next-generation sequencing.

Implementation of routine screening for Lynch syndrome in university and safety-net health system settings: successes and challenges.

PURPOSE: Routine screening for evidence of DNA mismatch repair abnormalities can identify colorectal cancer patients with Lynch syndrome, but impact in usual care settings requires study. After implementing routine screening at our university and safety-net health systems as usual practice, our aims were to determine outcomes, including screening process quality. METHODS: We conducted a retrospective cohort study from 1 May 2010 to 1 May 2011. Screening included reflexive immunohistochemistry to evaluate DNA mismatch repair protein expression for patients with colorectal cancer aged ≤70 years, with a cancer genetics team following up results. Screening outcomes, as well as challenges to a high-quality screening process were evaluated. RESULTS: We included 129 patients (mean age 56 years, 36% female); 100 had immunohistochemistry screening completed. Twelve patients had abnormal immunohistochemistry: four with definite Lynch syndrome, four with probable Lynch syndrome, and three without Lynch syndrome; one patient had an incomplete work-up. Lynch syndrome was confirmed for 6/13 asymptomatic relatives tested. Screening process quality was optimal for 77.5% of patients. Barriers to optimal quality screening included ensuring reflexive immunohistochemistry completion, complete follow-up of abnormal immunohistochemistry, and timely incorporation of results into clinical decision making. CONCLUSION: Usual care implementation of routine screening for Lynch syndrome can result in significant rates of detection, even in a largely safety-net setting. To optimize implementation, challenges to high-quality Lynch syndrome screening, such as ensuring reflexive screening completion and clinically indicated genetic testing and follow-up for abnormal screens, must be identified and addressed.

BAP1 loss defines a new class of renal cell carcinoma.

The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10(-5)), [corrected] and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.