Bruce R. Korf

The Alabama Genomic Health Initiative (AGHI), funded by the state of Alabama, aims to provide genomic testing, interpretation, and counseling free of charge to Alabama residents. A 14-member Community Advisory Board (CAB) was convened in 2021 to provide community insight on integrating genomic medicine into clinical care and assessing future perspectives. The CAB was comprised of members from diverse ethnic backgrounds and represented a wide range of age groups, with balanced gender representation from two Alabama counties. The CAB met quarterly, and the team explored the perceptions of members related to genomic medicine through qualitative inquiry with exploratory quantitative findings. Self-administered pre- and post-surveys, completed prior to the first CAB meeting (pre) and after meeting five (post), were utilized to evaluate positive and negative views towards the future of genomic medicine. Five meetings were conducted in a focus group format, and transcripts were coded and analyzed to identify emerging themes. Ten of fourteen (71%) CAB members completed both surveys. Results indicate there was a slight shift in responses related to the future of genomic medicine from pre to post-test, but no significant changes were noted. Eleven of fourteen (80%) CAB members attended four out of five meetings. The prominent themes included barriers to genomic testing, strategies for recruitment, and recommendations for sharing test results. Members believed that participation in the CAB facilitated acquiring new knowledge and insight on genomic medicine.

Purpose: Phenotype-based ascertainment of probands in studies of Mendelian disorders may exclude individuals with mild phenotypes or that lack health care access. We explore this premise in All of Us Research Program participants with pathogenic variation causal for three Mendelian conditions: autosomal dominant polycystic kidney disease (ADPKD), Marfan syndrome, and neurofibromatosis type 1 (NF1). Methods: We identified All of Us Research Program participants with putatively pathogenic variation in NF1 , FBN1 , PKD1 , and PKD2 . Concept terms were extracted from electronic health records to assess participant diagnosis and phenotype. Variant annotation and participant surveys were evaluated to identify biological and social factors differentiating diagnosed and undiagnosed individuals. Results: Large proportions of individuals with pathogenic variation in NF1 , FBN1 , or PKD1/PKD2 lack the associated diagnosis of NF1 (47%), Marfan syndrome (58%), or ADPKD (51%), respectively. Pathogenic variants in diagnosed individuals have greater inferred deleteriousness for NF1 and ADPKD, and undiagnosed individuals had less severe phenotypes compared to diagnosed individuals for all three conditions. Conclusion: A genotype-first ascertainment of individuals in genomic research allows for a more comprehensive assessment of Mendelian disease and removes biases that confound our understanding of the penetrance and presentation of these conditions.

NF1 germline mutation predisposes to breast cancer. NF1 mutations have also been proposed as oncogenic drivers in sporadic breast cancers. To understand the genomic and histologic characteristics of these breast cancers, we analyzed the tumors with NF1 germline mutations and also examined the genomic and proteomic profiles of unselected tumors. Among 14 breast cancer specimens from 13 women affected with neurofibromatosis type 1 (NF1), 9 samples (NF + BrCa) underwent genomic copy number (CN) and targeted sequencing analysis. Mutations of NF1 were identified in two samples and TP53 were in three. No mutation was detected in ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, and STK11. HER2 (ErbB2) overexpression was detected by IHC in 69.2% (9/13) of the tumors. CN gain/amplification of ERBB2 was detected in 4 of 9 with DNA analysis. By evaluating HER2 expression and NF1 alterations in unselected invasive breast cancers in TCGA datasets, we discovered that among samples with ERBB2 CN gain/amplification, the HER2 mRNA and protein expression were much more pronounced in NF1-mutated/deleted samples in comparison with NF1-unaltered samples. This finding suggests a synergistic interplay between these two genes, potentially driving the development of breast cancer harboring NF1 mutation and ERBB2 CN gain/amplification. NF1 gene loss of heterozygosity was observed in 4 of 9 NF + BrCa samples. CDK4 appeared to have more CN gain in NF + BrCa and exhibited increased mRNA expression in TCGA NF1--altered samples. Cancer Prev Res; 11(10); 655–64. ©2018 AACR.

NF1 germline mutation predisposes to breast cancer. NF1 mutations have also been proposed as oncogenic drivers in sporadic breast cancers. To understand the genomic and histologic characteristics of these breast cancers, we analyzed the tumors with NF1 germline mutations and also examined the genomic and proteomic profiles of unselected tumors. Among 14 breast cancer specimens from 13 women affected with neurofibromatosis type 1 (NF1), 9 samples (NF + BrCa) underwent genomic copy number (CN) and targeted sequencing analysis. Mutations of NF1 were identified in two samples and TP53 were in three. No mutation was detected in ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, and STK11. HER2 (ErbB2) overexpression was detected by IHC in 69.2% (9/13) of the tumors. CN gain/amplification of ERBB2 was detected in 4 of 9 with DNA analysis. By evaluating HER2 expression and NF1 alterations in unselected invasive breast cancers in TCGA datasets, we discovered that among samples with ERBB2 CN gain/amplification, the HER2 mRNA and protein expression were much more pronounced in NF1-mutated/deleted samples in comparison with NF1-unaltered samples. This finding suggests a synergistic interplay between these two genes, potentially driving the development of breast cancer harboring NF1 mutation and ERBB2 CN gain/amplification. NF1 gene loss of heterozygosity was observed in 4 of 9 NF + BrCa samples. CDK4 appeared to have more CN gain in NF + BrCa and exhibited increased mRNA expression in TCGA NF1--altered samples. Cancer Prev Res; 11(10); 655–64. ©2018 AACR.

TCGA invasive breast cancer mRNA expression, protein expression, and CNV comparison based on NF1 genetic alterations.

Supplement 2 Figure. NF+BrCa OncoScan CNV Whole Genome Histogram.