In a new analysis, researchers have shed light on these
hereditary elements across 12 cancer types — showing a surprising inherited
component to stomach cancer and providing some needed clarity on the
consequences of certain types of mutations in well-known breast cancer
susceptibility genes, BRCA1 and BRCA2.
The study, from Washington University School of Medicine in
St. Louis, appears Dec. 22 in the journal Nature Communications.
The investigators analyzed genetic information from more than
4,000 cancer cases included in The Cancer Genome Atlas project, an initiative funded
by the National Institutes of Health (NIH) to unravel the genetic basis of
cancer.
“In general, we have known that ovarian and breast cancers
have a significant inherited component, and others, such as acute myeloid
leukemia and lung cancer, have a much smaller inherited genetic contribution,”
said senior author Li Ding, PhD, associate professor of medicine and assistant
director of the McDonnell Genome Institute at Washington University.
“But this
is the first time on a large scale that we’ve been able to pinpoint gene
culprits or even the actual mutations responsible for cancer susceptibility.”
The new information has implications for improving the
accuracy of existing genetic tests for cancer risk and eventually expanding the
available tests to include a wider variety of tumors.
Past genomic studies of cancer compared sequencing data from
patients’ healthy tissue and the same patients’ tumors.
These studies uncovered
mutations present in the tumors, helping researchers identify important genes
that likely play roles in cancer. But this type of analysis can’t distinguish
between inherited mutations present at birth and mutations acquired over the
lifespan.
To help tease out cancer’s inherited components, the new study
adds analysis of the sequencing data from the patients’ normal cells that
contain the “germline” information.
A patient’s germline is the genetic
information inherited from both parents. This new layer of information gives a
genetic baseline of a patient’s genes at birth and can reveal whether
cancer-associated mutations were already present.
In all the cancer cases they analyzed, the investigators
looked for rare germline mutations in genes known to be associated with cancer.
If one copy of one of these genes from one parent is already mutated at birth,
the second normal copy from the other parent often can compensate for the
defect.
But individuals with such mutations are more susceptible to a so-called
“second hit.” As they age, they are at higher risk of developing mutations in
the remaining normal copy of the gene.
“We looked for germline mutations in the tumor,” Ding said.
“But it was not enough for the mutations simply to be present; they needed to
be enriched in the tumor — present at higher frequency. If a mutation is
present in the germline and amplified in the tumor, there is a high likelihood
it is playing a role in the cancer.”
In 114 genes known to be associated with cancer, they found
rare germline mutations in all 12 cancer types, but in varying frequencies
depending on the type. They focused on a type of mutation called a truncation
because most truncated genes can’t function at all.
Of the ovarian cancer cases the investigators studied, 19
percent of them carried rare germline truncations. In contrast, only 4 percent
of the acute myeloid leukemia cases in the analysis carried these truncations
in the germline.
They also found that 11 percent of the stomach cancer cases
included such germline truncations, which was a surprise, according to the
researchers, because that number is on par with the percentage for breast
cancer.
“We also found a significant number of germline truncations in
the BRCA1 and BRCA2 genes present in tumor
types other than breast cancer, including stomach and prostate cancers, for
example,” Ding said. “This suggests we should pay attention to the potential
involvement of these two genes in other cancer types.”
The BRCA1 and BRCA2 genes
are important for DNA repair. While they are primarily associated with risk of
breast cancer, this analysis supports the growing body of evidence that they
have a broader impact.
“Of the patients with BRCA1 truncations in
the germline, 90 percent have this BRCA1 truncation enriched
in the tumor, regardless of cancer type,” Ding said.
Genetic testing of the BRCA1 and BRCA2 genes
in women at risk of breast cancer can reveal extremely useful information for
prevention. When, for example, the genes are shown to be normal, there is no
elevated genetic risk of breast cancer.
But if either of these genes is mutated
in ways that are known to disable either gene, breast cancer risk is
dramatically increased. In this situation, doctors and genetic counselors can
help women navigate the options available for reducing that risk.
But mutations come in a number of varieties. Genetic testing also
can reveal many that have unknown consequences for the function of these genes,
so their influence on cancer risk can’t be predicted.
To help clarify this gray area in clinical practice, Ding and
her colleagues Jeffrey Parvin, MD, PhD, professor and director of the division
of computational biology and bioinformatics at The Ohio State University, and
Feng Chen, PhD, associate professor of medicine at Washington University,
investigated 68 germline non-truncation mutations of unknown significance in the BRCA1 gene.
For each mutation, they tested how well the BRCA1 protein could perform one of
its key DNA-repair functions. The researchers found that six of the mutations
behaved like truncations, disabling the gene completely.
These mutations also
were enriched in the tumors, supporting a likely role in cancer.
“It is important to be able to show that these six mutations
of unknown clinical significance are, in fact, loss-of-function mutations,”
Ding said.
“But I also want to emphasize the contrasting point. Many more show
normal function, at least according to our analysis. Many of these types of
mutations are neutral, and we would like to identify them so that health-care
providers can better counsel their patients.”
Ding said more research is needed to confirm these results
before they can be used to advise patients making health-care decisions.
“Our strategy of investigating germline-tumor interactions
provides a good way to prioritize important mutations that we should focus on,”
she said. “For the information to eventually be used in the clinic, we will
need to perform this type of analysis on even larger numbers of patients.”
Other key contributors to the study include Charles Lu, PhD;
Mingchao Xie; Mike Wendl, PhD; Mike McLellan; Jiayin Wang, PhD; and Kim
Johnson, PhD, from Washington University; and Mark Lerseison from Brown
University.
This work was supported by the National Institutes of Health
(NIH), including the National Cancer Institute (NCI), grants R01CA180006,
R01CA178383, R01CA141090 and PO1CA101937; the National Human Genome Research
Institute (NHGRI), grants U01HG006517, R01HG007069, U54HG003079 and T32
HG000045; the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), grant R01DK087960; the Department of Defense, grant PC130118; a
Ministry of Education in Taiwan Fellowship, and CMB training grant GM 007067.
The Cancer Genome Atlas (cancergenome.nih.gov) was the source of primary data.
Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MDM,
Huang K, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang
Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C,
Bharadwaj M, Koboldt DC, Miller CA, Kanchi KL, Eldred JM, Larson DE, Welch JS,
You M, Ozenberger BA, Govindan R, Walter MJ, Ellis MJ, Mardis ER, Graubert TA,
Dipersio JF, Ley TJ, Wilson RK, Goodfellow PJ, Raphael BJ, Chen F, Johnson KJ,
Parvin JD, Ding L. Patterns and functional implications of rare germline
variants across 12 cancer types. Nature Communications. Dec. 22, 2015.
Washington University School of Medicine’s 2,100 employed and
volunteer faculty physicians also are the medical staff of Barnes-Jewish and
St. Louis Children’s hospitals.
The School of Medicine is one of the leading
medical research, teaching and patient-care institutions in the nation,
currently ranked sixth in the nation by U.S. News & World Report. Through
its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the
School of Medicine is linked to BJC Health
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