Case report: TP53 and RB1 loss may facilitate the transformation from lung adenocarcinoma to small cell lung cancer by expressing neuroendocrine markers.

Introduction: Transformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) is one of the mechanisms responsible for acquired EGFR-TKIs resistance. Although it rarely happens this event determines a rapid disease deterioration and needs specific treatment. Patient and method: We report a case of 75-year-old LUAD female with a p.L858R mutation in Epidermal Growth Factor Receptor (EGFR) who presented with SCLC transformation after responding to first line osimertinib treatment for only 6 months. To understand the underlying molecular mechanism, we retrospectively sequenced the first (LUAD) and the second (SCLC) biopsy using a 56 multi-gene panel. Immunohistochemistry (IHC) staining and Fluorescence In Situ Hybridization (FISH) was applied to confirm the genetic aberrations identified. Results: EGFR p.E709A and p.L858R, Tumor Protein p53 (TP53) p.A159D and Retinoblastoma 1 (RB1) c.365-1G>A were detected in both the diagnostic LUAD and transformed SCLC samples. A high copy number gain for Proto-Oncogene C-Myc (MYC) and a Phosphoinositide 3-Kinase Alpha (PIK3CA) p.E545K mutation were found in the transformed sample specifically. Strong TP53 staining and negative RB1 staining were observed in both LUAD and SCLC samples, but FISH only identified MYC amplification in SCLC tissue. Conclusion: We consider the combined presence of MYC amplification with mutations in TP53 and RB1 as drivers of SCLC transformation. Our results highlight the need to systematically evaluate TP53 and RB1 status in LUAD patients to offer a different therapeutic strategy.

Identification of BRCA1:c.5470_5477del as a Founder Mutation in Chinese Ovarian Cancer Patients.

Predisposition of germline BRCA1/2 mutations (gBRCAMUT ) increases the risk of breast and ovarian cancer in females, but the mutation prevalence and spectrum are highly ethnicity-specific with different recurrent mutations being reported in different populations. Hereby, we performed hybridization-based target sequencing of BRCA1/2 in 530 ovarian cancer patients from Henan, the central region of China, followed by haplotype analysis of six short tandem repeat (STR) markers in the patients with recurrent mutations to determine their founder effect. About 28.3% (150/530) of the OC patients in our cohort harbored gBRCAMUT ; of the 151 mutations, 117 in BRCA1 and 34 in BRCA2, identified in this study, BRCA1:c.5470_5477del, c.981_982del, and c.4065_4068del are the top three mutants, recurrently detected in eight, seven, and six independent patients respectively. Haplotype analysis identified a region of 0.6 MB genomic length covering BRCA1 highly conserved across all eight carriers of BRCA1:c.5470_5477del, but not c.981_982del, suggesting a consequence of founder effect. Retrospective analysis in a subgroup of serous ovarian cancer patients revealed gBRCAMUT status was not associated with the progression-free survival (PFS); instead, an expression of Ki-67% ≥50% was associated with a shorter PFS (p = 0.041). In conclusion, patients with pathogenic or likely pathogenic gBRCAMUT account for 28.3% of the OC cases from Henan, and BRCA1:c.5470_5477del, the most frequently detected mutation in Henan patients, is a founder mutation in the population.

Corrigendum: Identification of BRCA1:c.5470_5477del as a Founder Mutation in Chinese Ovarian Cancer Patients.

[This corrects the article DOI: 10.3389/fonc.2021.655709.].

Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant.

Breast cancer gene 1 (BRCA1) and BRCA2 are tumor suppressors involved in DNA damage response and repair. Carriers of germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 have significantly increased lifetime risks of breast cancer, ovarian cancer, and other cancer types; this phenomenon is known as hereditary breast and ovarian cancer (HBOC) syndrome. Accurate interpretation of BRCA1 and BRCA2 variants is important not only for disease management in patients, but also for determining preventative measures for their families. BRCA1:c.132C>T (p.Cys44=) is a synonymous variant recorded in the ClinVar database with "conflicting interpretations of its pathogenicity". Here, we report our clinical tests in which we identified this variant in two unrelated patients, both of whom developed breast cancer at an early age with ovarian presentation a few years later and had a family history of relevant cancers. Minigene assay showed that this change caused a four-nucleotide loss at the end of exon 3, resulting in a truncated p.Cys44Tyrfs*5 protein. Reverse transcription-polymerase chain reaction identified two fragments (123 and 119 bp) using RNA isolated from patient blood samples, in consistency with the results of the minigene assay. Collectively, we classified BRCA1:c.132C>T (p.Cys44=) as a pathogenic variant, as evidenced by functional studies, RNA analysis, and the patients' family histories. By analyzing variants recorded in the BRCA Exchange database, we found synonymous changes at the ends of exons could potentially influence splicing; meanwhile, current in silico tools could not predict splicing changes efficiently if the variants were in the middle of an exon, or in the deep intron region. Future studies should attempt to identify variants that influence gene expression and post-transcription modifications to improve our understanding of BRCA1 and BRCA2, as well as their related cancers.