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Cancer and exome testing: benefits, despite drawbacks, as we learn more about mutations

Cancer and exome testing: benefits, despite drawbacks, as we learn more about mutations hero image

Personal exome testing regularly highlights the risk of cancer which individuals face, and confronted with the odds, many patients choose surgery to remove at-risk organs.

But what happens when the test is wrong?

That’s what happened to Colorado schoolteacher Katy Mathes and six other women in her family, whose cancer screening test revealed an 84% risk of cancer by the age of 70—well above the average of 7.3%.

Mathes, as recounted in the Wall Street Journal, weighed her odds and made a decision: she had surgery to remove her ovaries and fallopian tubes, and her younger sister, their mother, and four relatives followed suit; Mathes and her sister also had double mastectomies. The recovery was tough, she told CBS; for months she could not pick up her child, do bath time, or even make dinner.

Then, things changed. The company which supplied the test results reclassified Mathes’ genetic variation from “pathogenic” to having “unknown significance.”

“My brain just shut off,” Mathes said about the moment she learned that the test was wrong.

Suggestions for breast cancer screening: Old genetic test results should be updated

“Variants of uncertain significance” present a major challenge when it comes to clinical genetic testing, particularly in breast cancer.

“Their relevance to the cancer risk is unclear and the association with the response to specific BRCA1/2-targeted agents is uncertain,” noted a team of researchers from South Korea.

Despite that, genetic testing, particularly for breast cancer, is a hot topic, according to the American Society of Breast Surgeons. In 2019, the group released an official consensus guideline for hereditary breast cancer genetic testing. Recommendations from the guideline state:

  • Medical professionals can recommend genetic testing to at-risk patients, but there is a wide variety of multi-gene panels available and no real consensus about which is best, or when.
  • Genetic testing should be available to all patients with a personal history of breast cancer.
  • Patients who previously had genetic testing may benefit from updated testing. “In particular, a patient who had negative germline BRCA1 and 2 testing, who is from a family with no pathogenic variants, should be considered for additional testing. Genetic testing performed prior to 2014 most likely would not have had PALB2 or other potentially relevant genes included and may not have included testing for large genomic rearrangements in BRCA1 or BRCA2.”
  • Genetic testing should be made available to patients without a history of breast cancer but who meet National Comprehensive Cancer Network guidelines.
  • Variants of uncertain significance are DNA sequences that are not clinically actionable.

    Data reviewed by the American Society of Breast Surgeons found that in 2018 there were more than 266,000 new cases of invasive breast cancer diagnosed in the US and more than 40,000 deaths from the disease. About one-tenth of breast cancers are associated with a pathogenic germline variant, and more than half of those are mutations of BRCA1/2, but “in the current state of medical practice, a significant number of pathogenic mutation carriers remain undetected and undiagnosed. These are largely women with ‘moderate penetrance’ mutations, but even women with BRCA1 or 2 mutations may not be identified.”

    Cancer screening and the role of whole exome sequencing

    Whole exome sequencing (WES) is critically important, intones the National Cancer Institute, though it’s not yet clear if WES benefits patients more than whole genome sequencing (WGS) tests, since there has not been a head-to-head comparison. (The institute also notes that mRNA expression tests can helpfully gather info about what specific treatments may work for a patient.)

    “Multigene panel tests clearly indicate whether you have a genetic alteration in your tumor that can be targeted by an existing therapy,” the National Cancer Institute explains. “Tumor DNA sequencing tests may also uncover the presence of inherited alterations that increase cancer risk or that are associated with diseases or conditions other than cancer.”

    Limitations of tumor DNA sequencing tests include:

  • The cancer cell sample may not accurately represent a heterogeneous tumor.
  • Since genetic alterations can change over time, the results of a test taken in the past may not accurately reflect the genetic alterations present in cancer cells right now.
  • The test may not identify the DNA alteration causing tumor growth.
  • Personal biological factors may impact how a person responds to therapy.

NGS to the rescue?

Thanks to next generation sequencing (NGS), medicine is offering personalized cancer-patient care, with gene panel testing providing a base for investigating the genetic basis of an individual’s response to therapy.

“Cancer is a disease of the genome, and thus it is reasonable that treatment strategies should be based on genomic change,” noted Nagahashi et. al. (2019) in a Cancer Science article. “Although there are many issues that need to be addressed to fully realize precision cancer medicine, it appears that we are generally headed in the right direction to improve a cancer patient’s prognosis.”

While whole exome—even genome—sequencing is possible, the authors add, it provides more information than can be practically analyzed and interpreted, not to mention the costs involved. NGS-based gene panel tests that only examine clinically important genes have been developed.

When it comes to the breast cancer that Mathes faced, tests are becoming more accurate, notes a study from the Somatic Mutation Working Group of the SEQC-II Consortium, but work remains to be done.

“The reproducibility of cancer mutation detection not only depends on the choice of NGS platform (WGS vs. WES) but also on the selection of mutation callers,” the authors state. “Comparing to WGS, WES is very sensitive to sample processing, PCR effects, and choice of bioinformatics tools and thus less reproducible.”

But that does not mean you should rule out WES, researchers caution, as the practice is highly beneficial in many cases. For example, in a heavily-cited article in JAMA Pediatrics, Tan et. al. (2017) showed that singleton WES in children with suspected monogenic conditions was cost effective and had high diagnostic yields. A study in JAMA posited that WES offered advantages over traditional molecular diagnostics in certain patients, especially when it came to the detection of rare events and new mutations.

“For individuals who have a suspected genetic etiology but for whom the specific genetic alteration is unclear or unidentified by standard clinical work-up, WES may return a likely pathogenic variant,” noted a white paper authored by Wellmark Blue Cross Blue Shield. “A genetic diagnosis for these patients is reported to change management, including medication changes, discontinuation of or additional testing, ending the diagnostic odyssey and family planning. The evidence is sufficient to determine that this testing results in meaningful improvement in the net health outcome for multiple congenital anomalies and neurodevelopmental disorders.”

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