How Do Inherited Gene Mutations Cause Cancer? A New Database Will Help Researchers Find Out

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Geneticist Michael Berger

Geneticist Michael Berger and his colleagues are conducting research that brings together two related but historically separate fields: tumor sequencing and the study of inherited genetic mutations.

Hereditary genetic mutations are a key cause of cancer. One recent study estimated that about 17% of patients with cancer harbor inherited defects in key cancer genes. But it is not well understood how or why — or even whether — these genetic changes contribute to cancer.

Thanks to MSK-IMPACTTM, a diagnostic gene sequencing test developed at Memorial Sloan Kettering Cancer Center, scientists are now able to take a closer look. In a new study, a team of investigators is reporting how information about inherited genetic mutations (called germline mutations) can be combined with data from mutations found only in tumors (called somatic mutations) to create a deeper understanding of how tumors grow. In the paper, published November 5, 2021, in Nature Genetics, the researchers explain that the influence of germline mutations on each patient’s cancer is varied and based on multiple factors.

“Most of what we know about hereditary cancer genes comes from decades of family and population studies, which don’t always tell us how these genes actually affect a cell’s functions,” says co-senior author Michael Berger, a geneticist at MSK and an Associate Director of the Marie-Josée & Henry R. Kravis Center for Molecular Oncology (CMO). “This new research is important because it brings together related but historically separate fields: tumor sequencing and the study of inherited genetic mutations.”

Marie-Josée and Henry R. Kravis Center for Molecular Oncology
This center is a unique and intensive endeavor to transform cancer care through genomic analysis of patient-derived tumors.

Gaining a Deeper Understanding of Cancer

MSK-IMPACT scans patients’ tumors for mutations in more than 500 genes linked to cancer. Since 2014, more than 50,000 patients have had their tumors analyzed with it. Results from MSK-IMPACT are used to match patients with treatments targeted to their particular cancer. After the test reveals which mutation is causing the cancer to grow, doctors can often prescribe drugs to block that growth.

From the beginning of the development of MSK-IMPACT, Dr. Berger and his colleagues realized that in addition to using the tool to sequence the tumor itself, it would also be valuable to analyze patients’ normal tissue for comparison. Normal tissue is usually collected in the form of a blood sample. Having both normal and tumor tissues gives doctors more information about the genetic changes in the patient’s body.

The new study looks at data from more than 17,000 patients who had both their tumor and normal tissues sequenced with MSK-IMPACT. The researchers say that by evaluating both germline and somatic mutations — and, more important, the interplay between the two — they will gain a deeper understanding of how cancer forms. This could contribute to the development of better treatments.

“Currently, we report when patients have germline mutations in key cancer genes, but it’s been hard to say much about what they mean,” says co-first author Chaitanya Bandlamudi, a faculty member in the Department of Pathology and computational biologist on Dr. Berger’s research team. “The premise of this new research is that we can better integrate somatic and germline information so that we can ask questions about what role a germline mutation played in the formation of the tumor.”

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Finding New Ways to Target Hereditary Genes

A few well-known hereditary cancer genes illustrate the utility of germline sequencing data. BRCA1 and BRCA2 mutations were the first inherited genes ever linked to cancer, and they are likely the most studied. Thanks to lab research from a number of scientists, including Sloan Kettering Institute molecular biologist Maria Jasin, it’s now known that these genes contribute to cancer by preventing cells from being able to repair DNA damage. The findings about how BRCA genes cause cancer led to the development of a class of drugs called PARP inhibitors, which are now widely used to treat certain patients with breast, ovarian, prostate, and pancreatic tumors caused by BRCA1 and BRCA2 mutations.

 

The premise of this new research is that we can better integrate somatic and germline information so that we can ask questions about what role a germline mutation played in the formation of the tumor.
Chaitanya Bandlamudi computational biologist

Similarly, a class called mismatch repair genes is associated with an inherited condition called Lynch syndrome. Defects in mismatch repair can cause the formation of cancers that have a large number of mutations. Research by MSK physician-scientists Luis Diaz and Jedd Wolchok, among others, led to the discovery that these cancers respond especially well to immunotherapy drugs called checkpoint inhibitors.

As researchers learn more about the connections between inherited genes and the formation of cancer, they expect they will be able to develop more therapies, too.

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Shared Database Will Enable New Research

To make the connection between inherited mutations, somatic mutations, and the characteristics of individual tumors, much more research is needed. Therefore, Dr. Berger and Dr. Bandlamudi say that one of the most significant parts of this new work is the launch of a database called SignalDB, which can be used by scientists at MSK and beyond to characterize the interplay of germline and somatic mutations.

“There’s nothing like this out there right now,” Dr. Berger says. “As information from more patients is added to this database, it will only become more powerful.”

Dr. Bandlamudi adds that there also may be cases in which researchers learn that hereditary gene mutations don’t actually contribute to cancer. “There are currently many mutations, or variants, that have unknown significance. It may turn out that they don’t contribute to cancer, in which case families that carry these mutations don’t need to worry about them. This will be a resource that will help with many kinds of studies.”

 

As information from more patients is added to this database, it will only become more powerful.
Michael F. Berger geneticist

“One of the most rewarding aspects of this research was the opportunity to collaborate with so many experts representing MSK’s strengths in clinical genetics and genomics,” Dr. Berger says. The project included contributors from the CMO, the Diagnostic Molecular Genetics Laboratory in the Department of Pathology (led by Diana Mandelker), the Robert and Kate Niehaus Center for Inherited Cancer Genomics (led by Kenneth Offit), and the Clinical Genetics Service (including Dr. Offit and Clinical Director Zsofia Stadler). “It also was specifically enabled by our unique clinical sequencing program and large, unparalleled data set from matched tumor and normal sequencing,” Dr. Berger adds.

The other co-first author of the study is Preethi Srinivasan, a former graduate student in Dr. Berger’s lab who is now at the Stanford Cancer Institute. The other co-senior author is Barry Taylor, a former Associate Director of the CMO who now works at a pharmaceutical company.

 

Key Takeaways
  • Because MSK-IMPACT sequences patients’ normal DNA in addition to their tumors, it is a valuable research tool.
  • As researchers learn more about inherited mutations, they can increasingly use that information to also shape treatment for patients.
  • MSK researchers have created a website called SignalDB to share their data with other scientists. 
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This work was supported by National Institutes of Health grants P30 CA008748 and R01 CA227534, the Breast Cancer Research Foundation, the Fund for Innovation in Cancer Informatics, and Cycle for Survival.

Dr. Berger discloses relationships with or financial interests in Advances in Genome Biology and Technology, the American Society of Clinical Oncology, Eli Lilly and Company, JCO Precision Oncology, the Journal of Molecular Diagnostics, the Journal of Visualized Experiments, and PetDx Inc.