Early clinical signs of ovarian cancer
November 19, 2017
Although patient complaints of abdominal pain and swelling are not specific for ovarian cancer, the researchers found that only about one quarter of women with these symptoms underwent pelvic imaging, or other tests to diagnose ovarian cancer, in a timely manner.
Ovarian cancer has been thought of as a silent killer, coming to the attention of physicians only at its late stages when prognosis is poor. Adding to ovarian cancer's deadly pattern is that it is a fast growing tumor, progressing from early to advanced disease in as little time as a year. There has been increasing evidence for this poorly studied disease to indicate patients may exhibit symptoms many months before advanced disease and diagnosis occurs.
Lloyd H. Smith, M.D., Ph.D. from the University of California, Davis Medical Center in Sacramento and colleagues compared diagnosis codes and claims for diagnostic procedures among 1,985 elderly women with ovarian cancer, 6,024 elderly women with localized breast cancer, and 10,941 age-matched Medicare-enrolled women without cancer.
As early as 12 months before diagnosis, women with ovarian cancer were at least twice as likely to present to a physician with abdominal swelling or pelvic pain. As early as nine months before diagnosis, women with ovarian cancer were also more likely to complain of abdominal pain. Overall, about 40 percent of these women had physician claims indicating one or more visits for abdominal or pelvic symptoms between 36 and 4 months before their ovarian cancer was diagnosed.
Only 25 percent of ovarian cancer patients had diagnostic pelvic imaging or CA125 serum tests during the period from 36 to 4 months before diagnosis. Most received abdominal imaging or diagnostic gastrointestinal studies, which would be less likely to help establish the correct diagnosis. By contrast, 54 percent of ovarian cancer patients received pelvic imaging or CA125 serum testing within 3 months before their ovarian cancer was diagnosed.
"Our findings suggest that ovarian cancer could be diagnosed earlier in some patients whose diagnosis is currently delayed by at least 4 months because physicians order abdominal imaging or perform gastrointestinal procedures before they order a test more likely to diagnose ovarian cancer, such as pelvic imaging and/or CA125," conclude the authors.
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The researchers first applied a test that could tell them whether the offending gene was "upstream" or "downstream" from activated FANCD2 -- that is, did action of the mutant gene fall in the molecular pathway before FANCD2 was activated, or after, respectively? The answer was that the problem was located downstream from a normally functioning FANCD2.
The researchers then mapped SNPs in the genome of those patients and families, looking for changes in which a single chemical building block in the DNA differs from the usual building block at that position. Because FA is a recessive genetic disease, an affected child needs to inherit two copies of an errant gene, each from a parent that carried a single mutation.
They were startled to find only one suspect location in the entire genome, on chromosome 17, that was present in all four families. Further research uncovered two candidate genes within that region, and none of the patients had an abnormality in one of them. But they all had mutations in the second gene, BRIP1.
"What was very surprisingly to us is that while all five patients were homozygous for a mutation in the gene, as expected, all had the same mutation in this gene," Auerbach says. In other words, the five patients each inherited two copies of the same mutation, one from each parent.
When the researchers looked at the other families in their registry with no known mutations in any of the genes associated with the disease, they found six more patients with this same BRIP1 mutation, three of whom were homozygous.
Now the story began to make sense to the researchers, since the protein, BACH1, produced by BRIP1, was known to be a DNA helicase, a class of enzymes which unwind the two strands of the DNA double helix so that DNA synthesis can take place. And they knew from the scientific literature that BACH1 interacts with BRCA1 protein.
"This is the first gene associated with Fanconi anemia that we have a defined function for," says Auerbach. "It interacts directly with BRCA1, and is known to play a role in the repair of DNA double-strand breaks."
BACH1 could be the link between FANCD2 and BRCA1, the researchers say.
"It may be that DNA can't be repaired without a normally functioning BACH1," says Auerbach. "So perhaps FANCD2 activation isn't the endpoint, as had been thought, but that it has to do something downstream that can't be accomplished if BACH1 is not present."
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