Nonhereditary mutations are the main cause of breast cancer in younger women
September 26, 2018
By Maria Fernanda Ziegler | Agência FAPESP – Up to 80% of breast cancer cases in young women (20-35) may be caused by somatic mutations – spontaneously occurring alterations in breast cells not inherited from a parent and not passed to offspring – according to a study conducted with FAPESP’s support at the Center for Translational Cancer Research (LIM 24), which is part of the São Paulo State Cancer Institute (ICESP) in Brazil.
Breast cancer is the most common type of cancer in women. The number of new cases occurring in Brazil is forecasted to reach 59,000 in 2018. Most women diagnosed with breast cancer are over 50 years of age and postmenopausal.
However, approximately 4.5% of cases occur in young adults aged 20-35. Because the disease is harder to diagnose and is relatively unexpected in this age group, treatment normally begins when the disease is at a more advanced stage, and mortality is higher in these younger patients than in older women.
A paper on the study published in the journal Oncotarget highlights the two most important causes of breast cancer, namely, cancer-predisposing germline mutations inherited from a parent and somatic mutations occurring in breast cells over time.
“We studied this second factor, which is poorly understood even though we also found it to be the most common in young women with breast cancer,” said Maria Aparecida Koike Folgueira, a researcher at the University of São Paulo’s Medical School (FM-USP) and a coauthor of the study.
Derived from PhD research conducted by Giselly Encinas with a scholarship from FAPESP, the study also involved collaboration with other researchers at FM-USP, ICESP and the Brazilian Institute for Cancer Control (IBCC), as well as the Ontario Institute for Cancer Research and the University of Toronto in Canada.
The study analyzed 79 patients under 36 years of age who were diagnosed with breast cancer at the ICESP or IBCC. Pathogenic germline (hereditary) mutations of the genes BRCA1 or BRCA2 were found in 13 patients. Other germline mutations in less common genes were also identified.
Eight patients with somatic mutations and tumors diagnosed as luminal HER2 negative (with few or no hormone receptors) had their tumor and normal exomes sequenced to look for disease-causing variants in exons, the pieces of genes that encode proteins. Their samples were analyzed together with 29 other luminal samples from the COSMIC database of somatically acquired mutations or from the literature.
“Breast cancer accounts for 25% of the tumors found in young patients, and these tumors have not been sufficiently studied,” Folgueira told Agência FAPESP. “While 2,000 sequenced breast cancer tumors are available from databases, only 29 luminal tumors from young women had previously been characterized. Our group sequenced eight and analyzed the data together with the 29 already studied.”
The analysis produced important information on the occurrence of breast cancer due to somatic mutations in younger women. According to Folgueira, breast cells are more likely to mutate by chance than other types of cells because they proliferate (and die naturally through apoptosis) during each ovulation cycle.
“We found somatic mutations in genes that encode DNA repair proteins in over 40% of the cases we studied,” she said. “In other words, cancer arose from a problem with some DNA repair system originating in the breast cells themselves that was not inherited.”
BRCA1 and BRCA2
Mutations occur all the time, via cellular metabolism or duplication (DNA replication), among other causes. Specific enzymes called DNA polymerases create two identical DNA strands from an original DNA molecule, but mistakes in the copying of the genetic message may lead to mutations.
DNA repair can prevent these errors from becoming permanent. The study conducted at ICESP found DNA repair gene mutations in 43% of the tumors in young women.
“If cells proliferate strongly, they’re more likely to mutate accidentally. This appears to be what happened in the cases we studied,” Folgueira said.
An analogous problem explains the frequency of hereditary mutations in BRCA1 and BRCA2, which became famous worldwide in 2013 when the movie star Angelina Jolie disclosed that she had undergone a preventive double mastectomy after discovering in a genetic test that she had a hereditary mutation in BRCA1, placing her in a high-risk group for developing breast cancer in the future.
“BRCA1 and BRCA2 encode key proteins that participate in DNA repair. When this system does not work, DNA is more likely to develop mutations. If there are many mutations, they result in alterations, forming neoplastic cells that can lead to cancer,” Folgueira explained.
In addition to concluding that heredity is not the main cause of breast cancer in younger women, in approximately 50% of the tumors analyzed, the study found somatic mutations in genes that control gene transcription and, therefore, protein synthesis, which is more problematic because it is difficult to determine whether this function is associated with cancer.
“The study also detected pathogenic mutations in genes associated with positive regulation of gene transcription in 54% of the tumors analyzed,” Folgueira said.
She added that while a change in the care or treatment of young women is not immediately advisable on the basis of these findings, they do suggest avenues for future research.
“DNA repair is highly important. For example, PARP inhibitors are used in targeted therapy for metastatic breast cancer in patients with germline mutations in BRCA1 and BRCA2, and clinical studies currently in progress are designed to determine whether this treatment can also benefit patients with somatic mutations in other repair genes besides BRCA1 and BRCA2. This would apply to approximately 40% of young patients with luminal breast cancer,” Folgueira said.
The findings also pave the way for new lines of inquiry in research. “They constitute an important indication that heredity isn’t the problem in most cases,” she stressed. “Even so, the question remains whether only chance somatic mutations are involved. We’re exposed to everything from the moment of birth, aren’t we? Breast cancer is the most frequent cancer in women, and one reason could be abundant breast cell proliferation, with more chances for error.”
The article “Somatic mutations in early onset luminal breast cancer” (doi: 10.18632/oncotarget.25123) by Giselly Encinas, Veronica Y. Sabelnykova, Eduardo Carneiro de Lyra, Maria Lucia Hirata Katayama, Simone Maistro, Pedro Wilson Mompean de Vasconcellos Valle, Gláucia Fernanda de Lima Pereira, Lívia Munhoz Rodrigues, Pedro Adolpho de Menezes Pacheco Serio, Ana Carolina Ribeiro Chaves de Gouvêa, Felipe Correa Geyer, Ricardo Alves Basso, Fátima Solange Pasini, Maria del Pilar Esteves Diz, Maria Mitzi Brentani, João Carlos Guedes Sampaio Góes, Roger Chammas, Paul C. Boutros and Maria Aparecida Azevedo Koike Folgueira can be read at: oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=25123.
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