Search

Introduction Approximately 20% of patients living with colorectal cancer (CRC) have activating mutations in their tumors in the PIK3CA oncogene. Two or more activating mutations (multi-hit) for the PIK3CA allele increase PI3K⍺ signaling compared to single-point mutations, resulting in exceptional response to PI3K⍺ inhibition. We aimed to identify the prevalence of PIK3CA multi-hit mutations in metastatic CRC to identify patients who may benefit from PI3K inhibitors. Methods The Foundation Medicine database (Boston, MA, USA) was analyzed for patients with CRC who underwent genomic profiling on tumor DNA isolated during routine clinical care from 2013 to 2021. Molecular and clinical variables were abstracted for patients with PIK3CA mutations. Results We identified 49 051 patients with CRC who underwent Foundation Medicine testing. 710/41154 (1.7%) patients had multi-hit PIK3CA mutations, of which 53% were male (n  = 448) with a median age of 60. Microsatellite status was available for 697 patients with multi-hit PIK3CA and 17.6% (123/697) were microsatellite instability-high. Clinically relevant mutations in KRAS and BRAF V600E were seen in 459/710 (64.7%) and 65/710 (9.1%), respectively. The 4 most common PIK3CA variants were H1047R (9.8%), E545K (9.2%), E542K (9.0%), and R88Q (7.1%). The most common variant pair was E542K-E545K (4.7%). Conclusions Multi-hit mutations in PIK3CA are seen in 1.7% of advanced CRC, a meaningful prevalence given the high burden of CRC worldwide, and may represent a subset of patients that have enhanced sensitivity to PI3K inhibition. Future investigation regarding the clinical utility of PI3K inhibitors is warranted in multi-hit PIK3CA CRC. [ABSTRACT FROM AUTHOR]

Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology. [ABSTRACT FROM AUTHOR]

Background One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A , and CDKN2B , and has been correlated with worsened outcomes and immunotherapy resistance. MTAP -loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP- loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker. Materials and Methods We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI cancers. We compared the clinical outcomes of patients with GI cancer harboring MTAP- loss and MTAP- intact tumors in a retrospective study. Results The prevalence of MTAP -loss in GI cancers is 8.30%. MTAP -loss was most prevalent in pancreatic ductal adenocarcinoma (PDAC) at 21.7% and least in colorectal carcinoma (CRC) at 1.1%. MTAP -loss tumors were more prevalent in East Asian patients with PDAC (4.4% vs 3.2%, P  = .005) or intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, P  = .036). Significant differences in the prevalence of potentially targetable genomic alterations (ATM , BRAF , BRCA2 , ERBB2 , IDH1 , PIK3CA , and PTEN) were observed in MTAP -loss tumors and varied according to tumor type. MTAP -loss PDAC, IHCC, and CRC had a lower prevalence of microsatellite instability or elevated tumor mutational burden. Positive PD-L1 tumor cell expression was less frequent among MTAP -loss versus MTAP -intact IHCC tumors (23.2% vs 31.2%, P  = .017). Conclusion In GI cancers, MTAP -loss occurs as part of 9p21 loss and has an overall prevalence of 8%. MTAP -loss occurs in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC and is not mutually exclusive with other targetable mutations. [ABSTRACT FROM AUTHOR]

Objective The majority of tumor sequencing currently performed on cancer patients does not include a matched normal control, and in cases where germline testing is performed, it is usually run independently of tumor testing. The rates of concordance between variants identified via germline and tumor testing in this context are poorly understood. We compared tumor and germline sequencing results in patients with breast, ovarian, pancreatic, and prostate cancer who were found to harbor alterations in genes associated with homologous recombination deficiency (HRD) and increased hereditary cancer risk. We then evaluated the potential for a computational somatic-germline-zygosity (SGZ) modeling algorithm to predict germline status based on tumor-only comprehensive genomic profiling (CGP) results. Methods A retrospective chart review was performed using an academic cancer center's databases of somatic and germline sequencing tests, and concordance between tumor and germline results was assessed. SGZ modeling from tumor-only CGP was compared to germline results to assess this method's accuracy in determining germline mutation status. Results A total of 115 patients with 146 total alterations were identified. Concordance rates between somatic and germline alterations ranged from 0% to 85.7% depending on the gene and variant classification. After correcting for differences in variant classification and filtering practices, SGZ modeling was found to have 97.2% sensitivity and 90.3% specificity for the prediction of somatic versus germline origin. Conclusions Mutations in HRD genes identified by tumor-only sequencing are frequently germline. Providers should be aware that technical differences related to assay design, variant filtering, and variant classification can contribute to discordance between tumor-only and germline sequencing test results. In addition, SGZ modeling had high predictive power to distinguish between mutations of somatic and germline origin without the need for a matched normal control, and could potentially be considered to inform clinical decision-making. [ABSTRACT FROM AUTHOR]