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Mapping genetic differences in breast cancer can improve care for underserved populations

Largest cancer genomics study to date of women of African ancestry highlights molecular features that could be targeted to reduce the breast cancer mortality gap

University of Chicago Medical Center

A study comparing DNA and RNA data from Nigerian breast cancer patients to patients in a United States database found that certain aggressive molecular features were far more prevalent in tumors from Nigerian women than in black or white American women.

In the Oct. 16, 2018 issue of Nature Communications, the study's authors say those differences in multiple molecular features could in part explain disparities in breast cancer mortality for women from Nigeria, and perhaps other West African nations.

"In the era of precision medicine our data provide insights that could reduce the number of deaths from breast cancer across Sub-Saharan Africa and the developing world," said study author Olufunmilayo Olopade, MD, the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, associate dean for Global Health and director of the Center for Clinical Cancer Genetics at the University of Chicago Medicine.

"Without data, we make wrong policies," she added. "Understanding the molecular mechanisms that trigger lethal breast cancers is the most fundamental question remaining in breast cancer research, and is a crucial first step toward intervention."

The study, "Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features," compares genomic data from 1,037 U.S. patients, provided by The Cancer Genome Atlas (TCGA), to genomic data from 194 Nigerian women with breast cancer. The researchers found multiple, often unexpected, genetic differences between the racial and ethnic groups.

Although the Nigerian patients in the study were much younger, on average, they had more advanced disease at diagnosis and higher mortality rates than women from the TCGA group, most of whom were of European heritage. Breast cancer rates are increasing in Nigeria and across Sub-Saharan Africa at an alarming pace without the necessary infrastructure to stem the epidemic.

In a transnational collaboration to establish a platform for translational breast cancer research in Africa, researchers from the University of Chicago, Novartis Biomedical Research Institute, University of Ibadan and Lagos State University identified 25 different genes from Nigerian patients that were significantly mutated but potentially treatable with novel therapies in clinical trials.

Aggressive features found in these women include the inability to repair damaged DNA -- a mutational process known as homologous recombination deficiency, for which there are emerging therapies. These include drugs in development that target the immune system.

One of the most frequently mutated genes was the tumor-suppressor gene TP53. Sixty-two percent of the African women in the study had TP53 alterations, compared to 46 percent of African-Americans with breast cancer and 29 percent of the TCGA group, primarily U.S. women of European ancestry. The second most frequently mutated gene is human epidermal growth factor receptor 2 (HER2), for which there are highly effective therapies. "Nigerian women," Olopade said, "should be provided access to HER2 targeted therapies."

Overall, younger Nigerian patients had more mutations in TP53, and in GATA3, which is associated with estrogen receptors, than black patients from the TCGA. White TCGA patients had fewer mutations than black TCGA patients.

They also found significant cancer-related mutations in three genes that had not been previously associated with breast cancer: PLK2, KDM6A and B2M. (A fourth gene was identified after the current study was under review.) PLK2 is a presumed tumor suppressor. KDM6A is frequently mutated in other cancers, and B2M inactivation has been associated with lung cancer.

Tumors from Nigerian women were frequently characterized by "molecular features of aggressive disease," said co-senior author Jordi Barretina, PhD, formerly at the Novartis Institutes for Biomedical Research in Massachusetts, now the Director of the Girona Biomedical Research Institute in Spain. "The most prominent was the prevalence of homologous recombination deficiency among women with estrogen-receptor positive disease."

The study, according to the authors, "lays the foundation for a more concerted effort to reduce disparities in cancer outcomes by first closing the knowledge gaps. Nigerian women," they add, "could benefit from increased access to genomically-tailored treatments."


In a related commentary, published Oct. 8, in Cancer Cell, Olopade, Jason Pitt (now at the National University of Singapore), and Yonglan Zheng from the University of Chicago add that "it is now time to develop interventions that promote health equity. Broad access to genomic analysis coupled with improved access to effective evidence-based treatment and innovative clinical trials have the potential to close widespread mortality gaps."

This study was supported by the National Cancer Institute, Susan G. Komen for the Cure, the Breast Cancer Research Foundation, the Novartis Institutes for Biomedical Research and the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council and the Wellcome Trust. Computational resources were provided by the University of Chicago's Computation Institute, the University's Biological Sciences Division and Argonne National Laboratory.

Additional authors include Jason Pitt, Kevin White, Dezheng Huo, Dominic Fitzgerald, Jason Grundstad, Jigyasa Tuteja, Yonglan Zheng, Toshio Yoshimatsu, Shengfeng Wang, Galina Khramtsova, Jing Zhang, Elisabeth Sveen, Wendy Clayton, Christopher Olopade, Odunayo Akinyele, Jiebiao Wang and Lin Chen from the University of Chicago; Markus Riester, Artur Veloso, Emma Labrot, Ryan Johnson, Scott Mahan, Rebecca Leary, Maura Macomber, Wendy Winckler, Bryce Hwang, Kenzie MacIsaac, Dimitris Papoutsakis and Michael Morrissey from Novartis; Ayodele Sanni, Esther Obasi, Victor Aderoju, Nasiru Ibrahim, Mobolaji Oludara, Folusho Omodele, John Obafunwa and Abiodun Popoola from Lagos State University, Nigeria; Mustapha Ajani, Adewunmi Adeeoye, Adeyinka Falusi, Babajide Okedere, Abayomi Odetunde, Chinedum Babalola, Temidayo Ogundiran, Olayiwola Oluwasola, Oladosu Ojengbede, Adeyinka Ademola, Chibuzor Nkwodimmah, Bisola Famooto and Temidayo Ogundiran from the University of Ibadan, Nigeria; and Kerstin Haase and Peter Van Loo from the Francis Crick Institute, London, UK.

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