N.C. – July 25, 2017 – African-Americans typically have worse
outcomes from smoking-related cancers than Caucasians, but the reasons for this
remain elusive. However, scientists at Wake Forest Baptist Medical Center have
taken a big step toward solving this puzzle.
The scientists found that African-American patients had
an increased mutation rate in several genes, including the best known in
tobacco-related tumors, TP53. The findings are published in the current online
issue of the journal Theranostics.
“We know TP53 mutation happens in 55 percent of all
cancer patients,” said the study’s lead author, Wei Zhang, Ph.D., Hanes and Willis Family Professor in
Cancer at Wake Forest School of Medicine, part of Wake Forest Baptist.
“In our study, we found that the African-American population had close to a 70
percent mutation rate.
“This data suggests that increases in TP53 mutation in
African-Americans may be responsible for the observed resistance to
chemotherapy and a poorer prognosis overall.”
The trial at Wake Forest Baptist enrolled 431 cancer
patients from March 2015 to May 2016. The majority of the patients had advanced
tobacco-related cancers – lung, colorectal and bladder – and 13.5 percent were
Tumors from study participants were sequenced to identify
mutations and genetic alterations associated with smoking and/or
African-American ancestry. The proportion of smokers was similar among
African-American and Caucasian participants. Scientists validated their
findings through the Cancer Genome Atlas dataset that includes 2,821 cases with
known smoking status.
Both the Wake Forest Baptist and Cancer Genome Atlas
cohorts revealed a significantly increased mutation rate in the TP53 gene in
the African-American groups studied. The researchers also found that a number
of genes – including those that repair DNA damage and remodel chromatin –
mutated at higher frequencies in the African-American cancer patients.
Additionally, the Wake Forest Baptist team identified
other genes that were highly mutated in current and former smokers, regardless
“These results provide strong evidence that genomic
instability is a fundamental hallmark of cancer and the events underlying the
regulation of genome stability are centered on interactions with environmental
factors and lifestyle, such as smoking,” Zhang said.
Due to the relatively small number of participants in the
Wake Forest Baptist study, the findings need further validation in a larger
trial, Zhang said.
However, he added, this study provides an understanding
of the molecular basis of smoking-related cancers and how doctors can use this
information to treat patients by knowing what genes to target with drugs. The
essence of precision oncology is to match mutational information with drugs
that have shown therapeutic efficacy in targeting the mutated protein.
“These exciting findings uncover new genetic information
related to smoking that may lead to the development of novel diagnostic and
therapeutic options for patients,” said the study’s co-corresponding author, Boris
Pasche, M.D., Ph.D., director of the Comprehensive Cancer Center at Wake Forest
The study was partially supported by the Cancer Center
Support Grant from the National Cancer Institute to the Comprehensive Cancer
Center of Wake Forest Baptist and funding for the Genome Data Analysis Centers
from the National Institutes of Health. Zhang is supported by Hanes and Willis
Professorship in Cancer and a fellowship by the National Foundation for Cancer
Research. Co-author Pasche is supported by the Charles L. Spurr Professorship
in Cancer Research.
Co-authors are: Ville Kytola, M.S.,
Umit Topaloglu, Ph.D., Lance D. Miller, Ph.D., Rhonda L. Bitting, M.D., Michael
M. Goodman, M.D., Ralph B. D`Agostino Jr, Ph.D., Rodwige J. Desnoyers, M.D.,
Carol Albright, M.D., George Yacoub, M.D., Shadi A. Qasem, M.D., Barry DeYoung,
M.D., Meng Yang, B.S., Anastasia Shcherban, M.S., Matthew Pagni, M.D., Liang
Liu,Ph.D., Gregory A. Hawkins, Ph.D., Stefan C. Grant, M.D., J.D., W. Jeffrey
Petty, M.D., Angela Tatiana Alistar, M.D.,
Edward A. Levine, M.D., Edgar D.
Staren, M.D., Ph.D., Carl D.Langefeld, Ph.D., Robin M. Petro, R.N., Mac
Robinson, Ph.D., William Blackstock, M.D., Bayard L. Powell, M.D., Lynne I.
Wagner, Ph.D., Kristie L. Foley, Ph.D., and Edward Abraham, M.D.,
of Wake Forest Baptist; Vesteinn
Thorsson, Ph.D., and Ilya Shmulevich, Ph.D., of the Institute for Systems
Biology, Seattle; Matti Nykter, Ph.D., of the University of Tampere, Tampere,
Finland; Kexin Chen, M.D., Ph.D, of Tianjin Medical University Cancer Institute
and Hospital, Tianjin, China; and Vincent Miller, M.D.; ,and Gaurav Singal,
M.D., of Foundation Medicine, Cambridge, Mass.