Increases in the TP53 mutation in African American men with cancer may be responsible for chemotherapy resistance and a poorer prognosis overall, according to researchers at Wake Forest Baptist Medical Center. The team found that African American patients had an increased mutation rate in several genes, including the best known in tobacco-related tumors, TP53. The findings, which are published in the current online issue of the journal Theranostics, suggest that patients and providers may need to navigate care from a patient-centered framework that includes smoking history and genetic mutation status.
The trial enrolled 431 cancer patients from March 2015 to May 2016. The majority of the patients had advanced tobacco-related cancers and 13.5% were African American. In this study, the researchers report on their comprehensive analysis of their first stage of Precision Oncology Initiative, which has focused on cancers caused by tobacco use and cancers in the underserved African American population.
Study investigator Wei Zhang, PhD, director of cancer genomics and precision oncology at Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina, said the analysis of the next generation sequencing (NGS) data from the 431 patients demonstrated a landscape of gene mutations consistent with the metastatic and advanced stages of the patient cohort. Tobacco-related cancers such as lung, bladder, and colorectal cancer exhibited a high mutation load.
“These tumors are characterized by high frequency mutations in TP53, DNA repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). Mutations in DNA repair response and chromatin remodeling genes are associated with hypermutation and smoking history,” Zhang told OncoTherapy Network.
He said many of the smoking-related gene mutations were validated by the pan-cancer cohort of The Cancer Genome Atlas (TCGA) dataset, which includes 2,821 cases with known smoking status. Both the Wake Forest and the TCGA cohorts also revealed a significantly increased mutation rate in the African American patients in the TP53 gene. Zhang said this may explain why African American cancer patients are often more resistant to therapies and have a poorer prognosis.
TP53 mutation occurs in about 55% of all cancer patients. However, in this study the African American population had close to a 70% mutation rate. “We plan to further validate these findings with our second cohort of patients enrolled in the Precision Oncology Trial as well as the cohort from the Precision Oncology Exchange Consortium,” said Zhang.
He said in the current study a number of patients with identified mutational signatures have responded to poly-ADP-ribose polymerase (PARP) inhibitor or immunotherapy with the anti-PD1 drug nivolumab. NGS data also led to successful treatment of cancers with FGFR3 or BRAF mutations.
Zhang explained that this study provides strong evidence that genomic instability is a fundamental hallmark of cancer and the events underlying the regulation of genomic stability are centered on interactions with environmental factors and lifestyle (smoking). “Clonality analysis through bioinformatics analysis revealed intra-tumor heterogeneity and suggest a need for a design of sequential therapeutics,” he said.