Category Archives: Gene Medicine

Using gene sequencing tools, scientists from Johns Hopkins Medicine and the University of British Columbia have found a set of genetic mutations in samples from 24 women with benign endometriosis, a painful disorder marked by the growth of uterine tissue outside of the womb. The findings, described in the May 11 issue of The New England Journal of Medicine, may eventually help scientists develop molecular tests to distinguish between aggressive and clinically indolent, or non-aggressive, types of endometriosis.

Our discovery of these mutations is a first step in developing a genetics-based system for classifying endometriosis so that clinicians can sort out which forms of the disorder may need more aggressive treatment and which may not, said Ie-Ming Shih, M.D., Ph.D., the Richard W. TeLinde Distinguished Professor in the Department of Gynecology & Obstetrics at the Johns Hopkins University School of Medicine and co-director of the Breast and Ovarian Cancer Program at the Johns Hopkins Kimmel Cancer Center.

Endometriosis occurs when tissue lining the uterus forms and grows outside of the organ, most often into the abdomen. The disease occurs in up to 10 percent of women before menopause and half of those with abdominal pain and infertility problems. In the 1920s, Johns Hopkins graduate and trained gynecologist John Sampson first coined the term endometriosis and proposed the idea that endometriosis resulted when normal endometrial tissue spilled out through the fallopian tubes into the abdominal cavity during menstruation.

The new study, Shih said, challenges that view. The presence of the unusual set of mutations they found in their tissue samples, he says, suggests that while the origins of endometriosis are rooted in normal endometrial cells, acquired mutations changed their fate.

For reasons the researchers say are not yet clear, the mutations they identified have some links to genetic mutations found in some forms of cancer. They emphasize that although abnormal tissue growth in endometriosis often spreads throughout the abdominal cavity, the tissue rarely becomes cancerous except in a few cases when ovaries are involved.

For the study, Shih and his colleagues sequenced or figured out the genetic alphabet a part of the genome known as the exome, which contains all of the genes that can be expressed and make proteins. Specifically, they sequenced the exome of both normal tissue and endometriosis tissue removed during laparoscopic biopsies on 24 women, some with more than one abnormal endometrial growth. All had deep infiltrating endometriosis, the type that typically causes pain and infertility.

Seven of the 24 women were from Japan; the rest were patients at Lenox Hill Hospital-Northwell Health in New York City. The use of samples from Japanese women was selected because endometriosis before menopause occurs more often in Asian women (1318 percent) than in Caucasian women (6-10 percent), Shih says.

The scientists looked for mutations, or abnormal changes in the DNA, and filtered out normal variations in genes that commonly occur among humans. Of the 24 women, 19 had one or more mutations in their endometriosis tissue that were not present in their normal tissue.

The type and number of mutations varied per endometriosis lesion and between each of the women. The most common mutations, occurring in five of the women, occurred in genes including ARID1A, PIK3CA, KRAS and PPP2R1A, all known for controlling cell growth, cell invasion and DNA damage repair.

Mutations in these genes have been associated with one of the deadliest types of ovarian cancer, called clear cell carcinoma. Nickolas Papadopoulos, Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, led the team that completed the first sequencing of the clear cell ovarian cancer genome in 2010.

We were surprised to find cancer-linked genes in these benign endometriosis samples because these lesions do not typically become cancer, said Papadopoulos, whose Ludwig Center laboratories performed the sequencing. We don't yet understand why these mutations occur in these tissues, but one possibility is that they could be giving the cells an advantage for growth and spread.

In an additional group of endometriosis samples biopsied from 15 women at the University of British Columbia, the scientists looked specifically for mutations in the KRAS gene, whose expression signals proteins that spur cell growth and replication. They found KRAS mutations in five of the 15 patients.

The scientists make clear that their sequencing studies may have missed mutations in some of the samples. Their data do not at this point reveal the aggressiveness of the lesions.

However, Shih said, he and his team are working on additional studies to determine if the mutations correlate with patients outcomes. He says a molecular test that sorts lesions as more or less aggressive has the potential to help doctors and patients decide how to treat and monitor the progression and control of the disease. We may also be able to develop new treatments for endometriosis that use agents that block a gene-related pathway specific to a persons disease, said Shih.

Women with endometriosis are typically prescribed anti-hormonal treatments that block estrogen to shrink lesions. When the disease occurs in the ovaries and forms a large cyst, which increases the risk of developing ovarian cancer, the lesion is usually surgically removed.

Image: Endometriosis in the peritoneal tissue (left) forming a scar. Under microscopy, it is composed of glands and surrounding stroma with chronic inflammation and fibrosis.

Credit: Ie-Ming Shih

Read the rest here:
Gene Sequencing Study Reveals Unusual Mutations in Endometriosis - Bioscience Technology

Personalized medicine, also known as precision medicine or genomic medicine, is one of the most revolutionary trends shaping the future of healthcare. What is personalized medicine? The simple definition is that it's the customization of care to an individual's genetic profile. Several publicly traded companies stand out as leaders in the field.

Exact Sciences (NASDAQ: EXAS), Illumina (NASDAQ: ILMN), and Vertex Pharmaceuticals (NASDAQ: VRTX) are pioneers in personalized medicine -- each in a different way. Here's why I think these are the three best stocks in personalized medicine right now.

Image source: Getty Images.

Exact Sciences markets the CologuardDNA screening test for colorectal cancer. Cologuard has enjoyed the strongest product launch of any diagnostic test ever, with more than 450,000 people screened since late 2014. But there's much more potential growth. There are around 80 million patients in the U.S. alone who need to be tested for colorectal cancer, but many don't get tested because they don't want a colonoscopy. Exact Sciences hopes to capture around 30% of that market.

Cologuard should continue to drive Exact Sciences stock higher in the near future, but over the long run there are even more opportunities. Exact Sciences is collaborating with the Mayo Clinic to develop a platform for early detection of cancer by identifying DNA methylation markers. (Addition of methyl groups to DNA changes gene expression and potentially lead to cancer.) Significant progress has already been made in what could be a huge new market for Exact Sciences.

Although Exact Sciences isn't profitable yet, it's headed in the right direction. Analysts project the company will grow earnings by an average annual rate of 68% over the next five years. That seems quite possible with Cologuard continuing to pick up momentum.

Illumina is the leader in genomic sequencing, an essential tool that makes the personalized medicine revolution possible. The company began operations in 1998 and launched its first DNA sequencing system in 2007. Since then, Illumina's technological innovations havereduced the cost of sequencing by a factor of more than 10,000 and have reduced sequencing time per gigabase by a factor of approximately 3,500.

The company is continuing its track record of innovation with its recent launch of the NovaSeq sequencing system. Illumina thinks that the NovaSeq architecture could lead to reducing the cost of human genome mapping to $100, which would open up genomic sequencing to more customers than ever before. Selling more systems would be great news for Illumina, but the added consumables revenue would be even better: The company makes around two-thirds of its total revenue from consumables sales.

As a well-established company now, Illumina might not enjoy the tremendous growth that it did in the early days of genomic sequencing. However, Wall Street analysts still estimate that Illumina will grow earnings by an average annual rate of 14% over the next several years, thanks in large part to great prospects for NovaSeq.

Vertex Pharmaceuticals is leading the way in the use of personalized medicine to fight cystic fibrosis (CF). The company won U.S. regulatory approval in 2012 for its first drug, Kalydeco, as a treatment for CF patients with theG551D mutation. Another approval came in 2014 for CF patients with one of 10 other genetic mutations.In 2015, Vertex received approval for Kalydeco in treating children ages two to five with specific gene mutations that cause CF.

While Kalydeco has been successful, Vertex's biggest opportunities lie with other CF drugs. Vertex is still finalizing reimbursement arrangements in several European nations for Orkambi, but Orkambi has already become the company's top-selling product. Even greater prospects could be in store for a combination of Kalydeco and tezacaftor, for which Vertex plans to file for approval in the third quarter of 2017.

Analysts think that Vertex can grow its earnings by nearly 65% annually over the next five years. Although the stock looks expensive right now with shares trading at 39 times expected earnings, Vertex remains a good pick for investors with that kind of growth potential.

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Excerpt from:
3 Best Stocks in Personalized Medicine - Madison.com

Using gene sequencing tools, scientists from Johns Hopkins Medicine and the University of British Columbia have found a set of genetic mutations in samples from 24 women with benign endometriosis, a painful disorder marked by the growth of uterine tissue outside of the womb. The findings, described in the May 11 issue of the New England Journal of Medicine, may eventually help scientists develop molecular tests to distinguish between aggressive and clinically "indolent," or non-aggressive, types of endometriosis.

"Our discovery of these mutations is a first step in developing a genetics-based system for classifying endometriosis so that clinicians can sort out which forms of the disorder may need more aggressive treatment and which may not," says Ie-Ming Shih, M.D., Ph.D., the Richard W. TeLinde Distinguished Professor in the Department of Gynecology & Obstetrics at the Johns Hopkins University School of Medicine and co-director of the Breast and Ovarian Cancer Program at the Johns Hopkins Kimmel Cancer Center.

Endometriosis occurs when tissue lining the uterus forms and grows outside of the organ, most often into the abdomen. The disease occurs in up to 10 percent of women before menopause and half of those with abdominal pain and infertility problems. In the 1920s, Johns Hopkins graduate and trained gynecologist John Sampson first coined the term "endometriosis" and proposed the idea that endometriosis resulted when normal endometrial tissue spilled out through the fallopian tubes into the abdominal cavity during menstruation.

The new study, Shih says, challenges that view. The presence of the unusual set of mutations they found in their tissue samples, he says, suggests that while the origins of endometriosis are rooted in normal endometrial cells, acquired mutations changed their fate.

For reasons the researchers say are not yet clear, the mutations they identified have some links to genetic mutations found in some forms of cancer. They emphasize that although abnormal tissue growth in endometriosis often spreads throughout the abdominal cavity, the tissue rarely becomes cancerous except in a few cases when ovaries are involved.

For the study, Shih and his colleagues sequenced -- or figured out the genetic alphabet -- a part of the genome known as the exome, which contains all of the genes that can be expressed and make proteins. Specifically, they sequenced the exome of both normal tissue and endometriosis tissue removed during laparoscopic biopsies on 24 women, some with more than one abnormal endometrial growth. All had deep infiltrating endometriosis, the type that typically causes pain and infertility.

Seven of the 24 women were from Japan; the rest were patients at Lenox Hill Hospital-Northwell Health in New York City. The use of samples from Japanese women was selected because endometriosis before menopause occurs more often in Asian women (13-18 percent) than in Caucasian women (6-10 percent), Shih says.

The scientists looked for mutations, or abnormal changes in the DNA, and filtered out normal variations in genes that commonly occur among humans. Of the 24 women, 19 had one or more mutations in their endometriosis tissue that were not present in their normal tissue.

The type and number of mutations varied per endometriosis lesion and between each of the women. The most common mutations, occurring in five of the women, occurred in genes including ARID1A, PIK3CA, KRAS and PPP2R1A, all known for controlling cell growth, cell invasion and DNA damage repair.

Mutations in these genes have been associated with one of the deadliest types of ovarian cancer, called clear cell carcinoma. Nickolas Papadopoulos, Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, led the team that completed the first sequencing of the clear cell ovarian cancer genome in 2010.

"We were surprised to find cancer-linked genes in these benign endometriosis samples because these lesions do not typically become cancer," says Papadopoulos, whose Ludwig Center laboratories performed the sequencing. "We don't yet understand why these mutations occur in these tissues, but one possibility is that they could be giving the cells an advantage for growth and spread."

In an additional group of endometriosis samples biopsied from 15 women at the University of British Columbia, the scientists looked specifically for mutations in the KRAS gene, whose expression signals proteins that spur cell growth and replication. They found KRAS mutations in five of the 15 patients.

The scientists make clear that their sequencing studies may have missed mutations in some of the samples. Their data do not at this point reveal the aggressiveness of the lesions.

However, Shih says, he and his team are working on additional studies to determine if the mutations correlate with patients' outcomes. He says a molecular test that sorts lesions as more or less aggressive has the potential to help doctors and patients decide how to treat and monitor the progression and control of the disease. "We may also be able to develop new treatments for endometriosis that use agents that block a gene-related pathway specific to a person's disease," says Shih.

Women with endometriosis are typically prescribed anti-hormonal treatments that block estrogen to shrink lesions. When the disease occurs in the ovaries and forms a large cyst, which increases the risk of developing ovarian cancer, the lesion is usually surgically removed.

See the article here:
Gene sequencing study reveals unusual mutations in endometriosis - Science Daily

Two new studies presented at the Annual Scientific Meeting of the American Urological Association (AUA) offer an improved understanding of some genetic underpinnings of prostate cancer. In one, researchers found that BRCA mutations may raise the risk of the malignancy substantially, while another found a high rate of mutations among other DNA repair genes as well.

These studies reveal new insights into the role genetic mutations play in the development of prostate cancer, particularly metastatic disease, said Scott Eggener, MD, of the University of Chicago Medicine, who moderated the session with these studies, in a press release.

One study focused on male carriers of BRCA genes; previous work has shown increased risk for various cancers, but there are currently no screening guidelines for this population of men. The study was presented by Roy Mano, MD, of Rabin Medical Center in Petah Tikva, Israel.

The study included 154 men known to be BRCA mutation carriers; 92 of them (60%) had BRCA1 mutations, 61 (40%) had BRCA2 mutations, and 1 had a mutation in both genes. Twenty-four participants (16%) were diagnosed with cancer upon enrollment or during initial screening, and they had a median age at diagnosis of 55 years.

Four patients had multiple malignancies; seven patients (8%) had prostate cancer with a BRCA1 mutation, and three (5%) had prostate cancer with a BRCA2 mutation. The researchers noted that these rates appear substantially higher than in the general population for this age group; also, these results suggest that prostate cancer risk may not be restricted to BRCA2 mutation carriers, as previous work has shown.

In the other study, presented by Allison Glass, MD, of the University of California, Davis, researchers analyzed samples from 936 localized and metastatic prostate cancers to study the distribution of DNA repair gene mutations.

Of the full cohort, 228 samples (24.4%) showed at least one likely functional mutation of a DNA repair gene. Those mutations were found in 20.1% of prostate tumors, and in 18.8% of bone metastases, and the highest rates of DNA repair mutations were seen in visceral metastases including brain, pelvis, and liver.

The genes most commonly mutated included BRCA2 (11% of samples), ATM (6.6%), MSH6 (2.5%), MSH2 (2%), ATR (1.6%), MLH1 (1.3%), and BRCA1 (1.2%). The authors noted that genomic profiling could potentially identify prostate cancer patients that are sensitive to platinum-based chemotherapy or to PARP inhibition.

For some patients, a detailed understanding of these mutations could have a meaningful impact on the timely diagnosis and treatment of their disease, Eggener said.

Read more from the original source:
AUA: Prostate Cancer Studies Highlight DNA Repair Gene Involvement - Cancer Network

Endometriosis is a fairly common gynecological disorder that can cause a number of unpleasant symptoms such as pelvic pain, menstrual problems, and infertility. However, a new study has also found cancer-causing gene mutations in some women with endometriosis, suggesting that the condition may be even more serious than previously known.

In a study, published in the New England Journal of Medicine, researchers from Canada found cancer-causing gene mutations in the pelvic lesions of women with endometriosis, The Vancouver Sun reported. Although a low number of endometriosis cases are linked to ovarian cancer, the condition is typically considered to be non cancerous.The new findings suggests that doctors may now have to take a new approach to this condition.

Read:Women With Endometriosis Have Greater Risk Of Pregnancy Complications, Including Miscarriage and Ectopic Pregnancy

Finding these mutations in non-cancer conditions is largely uncharted territory, said co-author Michael Anglesio, The Vancouver Sun reported. Its not just inflammation around endometrial tissue in the wrong place, its that there are genetic changes hardwired into the biology of the disorder.

Endometriosis is a condition that affects around one in 10 women. Photo Courtesy of Pixabay

For the study, the Vancouver team used gene-sequencing technology to analyze tissue from the lining of the womb of 39 women living in Vancouver, New York, and Japan. The team specifically looked at a form of endometriosis called deep-infiltrating endometriosis. Results showed that most of the samples had either one or multiple gene mutations. These findings are especially unnerving as endometritis is estimated to affect around one in 10 women.

The team report that because these lesions caused by endometriosis feed on estrogen, progestin-only pills or surgical removal of the lesions are recommended as treatment.

According to the Medicine Net, endometriosis occurs when cells on the outside of the uterus, called endometrial cells, begin to grow abnormally. The exact cause of the condition is not clear, although the condition is fairly more common in women who experience infertility. Some women have no symptoms, but for those who do, common symptoms may include pelvic pain during menstruation, intercouse, or during a bowel movement or urination. Infertility may also be a symptom of the condition.

Whats more endometriosis is not limited to the female reproductive tract, and can also occur in the liver, brain, lung, and in old surgical scars, Medicine Net reported.

Though worrying, the results are important as they may help researchers better understand how to treat this condition.

These mutations are a first step in understanding the breadth of symptoms and outcomes that affect every patient differently, added Anglesio. Finally, we have a roadmap to find the right treatments.

Not only does the condition increase a womans risk of experiencing infertility, increases a womans risk of other pregnancy problems such as miscarriage and ectopic pregnancy ].

Source: Anglesio MS, Papadopoulos N, Ayhan A, et al. Cancer-Associated Mutations in Endometriosis without Cancer. The New England Journal of Medicine. 2017

See Also:

Endometrial Cancer Symptoms: What To Know About Female Reproductive Cancer After Journalist Gwen Ifills Death

Endometriosis Awareness Month: What Are The Symptoms Of This Commonly Misdiagnosed Womens Health Condition

Go here to read the rest:
Some Endometriosis Lesions In Women Linked To Cancer-Causing Gene Mutations - Medical Daily

Rare feline genetic disorders identified through whole genome sequencing Science Daily In another study representing the first time precision medicine has been applied to feline health, Lyons and her team used whole genome sequencing and the 99 Lives consortium to identify a lysosomal disorder in a 36-week-old silver tabby kitten that ... and more »

Continue reading here:
Rare feline genetic disorders identified through whole genome sequencing - Science Daily

Our next group of correspondents stood out due to their vocations: In one way or another, their chosen careers brought them into the subculture of scientific thinking. These readers tended to be more favorably disposed to gene editing than others.

Take this reader, a semi-retired school psychologist and a lover of science whose daughter plans to become a clinical geneticist:

I agree with the premise of your article [that prophylactic gene editing could soon be mandatory] and am not frightened by it at all. Scientific advances have not, cannot, and should not be stopped. Since the first civilizations science has been dragging religion and society reluctantly along into a more technologically advanced future. What we gain from this seems always to be more than what we have lost.

A medical student who hopes one day to do gene editing was likewise eager for a future where it is used to cure diseaseand even to direct the way that humans evolve:

Modern medicine, in its current form, is basically the answer to the question: What is the best way to treat diseases whose cures cannot and will not ever be found? Treating someone with cystic fibrosis, for instance, is an admirable thing to do, but its also an exercise in futility: That patient will undoubtedly die prematurely. Anything besides excising the mutant gene and replacing it with a normal copy is treading water and delaying the inevitable (though, obviously, the patients must still be treated).

In modern societies, infectious diseases and trauma are more or less under control (relative to developing countries and bygone eras). Curing genetic diseases (cancer loosely being included in this category) are currently a dead end. So, logically, addressing this head-on is the only next step.

I view gene therapy and editing as the way of the future, not only of medicine but also of humanity in general. It will start as the means for cures of currently incurable diseases. Eventually, it will be a means by which we can continue to evolve ourselves as a species. If 3.5 billion years of evolution churned our species out through the natural selection of random mutations, how much better can we do with logic and molecular precision? In my opinion, anything that can widely (and, potentially, permanently) change mankind and society for the better should be done.

I wish I shared the correspondents confidence that logic and molecular precision will serve humanity better in this realm than the decentralized systems of dating and mating have done so far. Reflecting on the decisions that literally every bygone generation might have made if able to edit genes, I fear that our choices will prove as imprudent in hindsightand thats not even accounting for unintended consequences.

The next reader is working to earn his Masters degree in Biochemistry:

It is not unreasonable to imagine that in the near future gene editing will be a safe and effective means of preventing genetic diseases. It is also not unreasonable to imagine that in the case of many diseases, such as sickle-cell anemia or cystic fibrosis, which are caused by small mutations in a single gene coding for a functionally important protein, gene editing would be likely to prevent the disease without affecting the child in any other way. For these diseases, once it is demonstrated that gene editing works the way that it is supposed to, I think parents should be punished for failing to employ gene editing. I think that if it had been demonstrated that gene editing was safe, effective, and selective, refusal to use this technique to prevent disease would essentially amount to fear and mistrust of the scientific and medical communities. I really dont think thats a valid reason to allow another person to be afflicted by a preventable disease.

However, I draw a distinction here between expecting parents to make edits that will definitely prevent a debilitating disease, and expecting edits that reduce the risk of a disease that the child may or may not have ended up getting. I certainly wouldnt be opposed to parents editing genes to reduce the chance of cancer, but I wouldnt really expect it. There are a number of behaviors that we know reduce cancer risk which we dont really expect parents to push on their kids. For example, parents could probably reduce cancer risk in their children by some small fraction by giving them grape juice every day or something like that. I dont really expect parents to do that. If you cant blame parents for not giving their kids grape juice you really cant blame them for not editing the kids genome.

At the same time, he adds, we can really only justify using gene editing for medical purposes:

We are a long way from understanding our biology well enough to be able to make genome modifications to enhance intelligence or beauty or athleticism without risking horrible unforeseen side effects. But even if we did have the ability to do that, I still dont think it would be justified because I dont think we can tie these traits to an increased sense of happiness or fulfillment.

I am short and scrawny, and Im perfectly happy with that. I know plenty of people who are perfectly content with being as dumb as rocks. I know plenty of smart people who are miserable. So, Ill grant that I am basing my opinion here on a biased personal experience, but I really dont think that we can say that it really is in the best interests of the child to alter superficial traits.

When discussing a childs future, people often talk as if the parents preference is the most important thing. But parents dont own their children. Parents are stewards of their children. I think that making designer babies would be an example of parents making self-serving decisions, rather than making decisions in the best interests of the child. I dont think that is justifiable.

The next correspondent is a biochemistry grad student who works in a research group that specializes in genome-editing technology, and cautions against its near-term limits:

If gene therapy with Cas9 were at some future time as cheap, easy, and safe as an antibiotic treatment, then yes, I would support punishments for parents who forewent a cure for their children. In some cases, a genetic disorder is very similar to other macro-level disorders, e.g. genes can be broken in the same sense that a wrist is broken. While wrists can come in many healthy shapes and sizes and colors, broken in two is not one of them; likewise, while genetic diversity is important and natural and cant always be cleanly mapped to disease, some genetic mutations are incontrovertibly damaging and lead to illness and suffering. Refusing a simple medical treatment for a disorder with a clear singular genetic root cause (of which there are fewer than one might think) would be as unethical as refusing to set a broken wrist.

But I dont think gene therapy will be as cheap, easy, or safe as antibiotics in our lifetimerather, my opinion is that gene therapy will be expensive, invasive, and risky (at least relative to an antibiotic pill) for the foreseeable future. I dont expect gene therapy to become routine in the same way that oral therapies are, and so choosing not to subject your child to gene editing cannot be chalked up to negligence. (A contemporary example: Sovaldi is a drug that essentially cures Hepatitis C, but it costs $200,000 and there are other treatmentscould you imagine a parent being prosecuted for refusing to pay for Sovaldi?)

Why am I so down on gene therapy?

First of all, regarding cost, the clamor surrounding the Cas9 patent dispute should give you an idea of how profitable the players in this field expect gene therapy to be. Gene therapy will always be more expensive than an oral antibiotic because the treatment requires many more steps (each of which is far costlier), is much lower throughput, and will require specialized care and oversight. For similar reasons, it will not be nearly as convenient for patients as filling a prescription. And as Ive written elsewhere, our current early-generation gene-therapy tools and limited understanding of the link between genetics and disease means that gene therapy carries unprecedented safety risks. (For example, no currently approved therapy could cause permanent heritable genetic changes.)

These risks shouldnt disqualify gene therapy as a possible future treatment, but they could certainly give the most informed and adventurous patient pause. In short, I believe technical limitations and cost and safety concerns will delay the debate over mandatory gene editing for decades at least. More pressing to discuss are the multitude of other ways that gene editing and GMOs affect modern life and medicine.

Read more:
Should Parents Who Refuse to Edit Their Babies' Genes Be Punished? - The Atlantic

May 10, 2017 Endometriosis in the peritoneal tissue (left) forming a scar. Under microscopy, it is composed of glands and surrounding stroma with chronic inflammation and fibrosis. Credit: le-Ming Shih

Using gene sequencing tools, scientists from Johns Hopkins Medicine and the University of British Columbia have found a set of genetic mutations in samples from 24 women with benign endometriosis, a painful disorder marked by the growth of uterine tissue outside of the womb. The findings, described in the May 11 issue of the New England Journal of Medicine, may eventually help scientists develop molecular tests to distinguish between aggressive and clinically "indolent," or non-aggressive, types of endometriosis.

"Our discovery of these mutations is a first step in developing a genetics-based system for classifying endometriosis so that clinicians can sort out which forms of the disorder may need more aggressive treatment and which may not," says Ie-Ming Shih, M.D., Ph.D., the Richard W. TeLinde Distinguished Professor in the Department of Gynecology & Obstetrics at the Johns Hopkins University School of Medicine and co-director of the Breast and Ovarian Cancer Program at the Johns Hopkins Kimmel Cancer Center.

Endometriosis occurs when tissue lining the uterus forms and grows outside of the organ, most often into the abdomen. The disease occurs in up to 10 percent of women before menopause and half of those with abdominal pain and infertility problems. In the 1920s, Johns Hopkins graduate and trained gynecologist John Sampson first coined the term "endometriosis" and proposed the idea that endometriosis resulted when normal endometrial tissue spilled out through the fallopian tubes into the abdominal cavity during menstruation.

The new study, Shih says, challenges that view. The presence of the unusual set of mutations they found in their tissue samples, he says, suggests that while the origins of endometriosis are rooted in normal endometrial cells, acquired mutations changed their fate.

For reasons the researchers say are not yet clear, the mutations they identified have some links to genetic mutations found in some forms of cancer. They emphasize that although abnormal tissue growth in endometriosis often spreads throughout the abdominal cavity, the tissue rarely becomes cancerous except in a few cases when ovaries are involved.

For the study, Shih and his colleagues sequencedor figured out the genetic alphabeta part of the genome known as the exome, which contains all of the genes that can be expressed and make proteins. Specifically, they sequenced the exome of both normal tissue and endometriosis tissue removed during laparoscopic biopsies on 24 women, some with more than one abnormal endometrial growth. All had deep infiltrating endometriosis, the type that typically causes pain and infertility.

Seven of the 24 women were from Japan; the rest were patients at Lenox Hill Hospital-Northwell Health in New York City. The use of samples from Japanese women was selected because endometriosis before menopause occurs more often in Asian women (13-18 percent) than in Caucasian women (6-10 percent), Shih says.

The scientists looked for mutations, or abnormal changes in the DNA, and filtered out normal variations in genes that commonly occur among humans. Of the 24 women, 19 had one or more mutations in their endometriosis tissue that were not present in their normal tissue.

The type and number of mutations varied per endometriosis lesion and between each of the women. The most common mutations, occurring in five of the women, occurred in genes including ARID1A, PIK3CA, KRAS and PPP2R1A, all known for controlling cell growth, cell invasion and DNA damage repair.

Mutations in these genes have been associated with one of the deadliest types of ovarian cancer, called clear cell carcinoma. Nickolas Papadopoulos, Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, led the team that completed the first sequencing of the clear cell ovarian cancer genome in 2010.

"We were surprised to find cancer-linked genes in these benign endometriosis samples because these lesions do not typically become cancer," says Papadopoulos, whose Ludwig Center laboratories performed the sequencing. "We don't yet understand why these mutations occur in these tissues, but one possibility is that they could be giving the cells an advantage for growth and spread."

In an additional group of endometriosis samples biopsied from 15 women at the University of British Columbia, the scientists looked specifically for mutations in the KRAS gene, whose expression signals proteins that spur cell growth and replication. They found KRAS mutations in five of the 15 patients.

The scientists make clear that their sequencing studies may have missed mutations in some of the samples. Their data do not at this point reveal the aggressiveness of the lesions.

However, Shih says, he and his team are working on additional studies to determine if the mutations correlate with patients' outcomes. He says a molecular test that sorts lesions as more or less aggressive has the potential to help doctors and patients decide how to treat and monitor the progression and control of the disease. "We may also be able to develop new treatments for endometriosis that use agents that block a gene-related pathway specific to a person's disease," says Shih.

Women with endometriosis are typically prescribed anti-hormonal treatments that block estrogen to shrink lesions. When the disease occurs in the ovaries and forms a large cyst, which increases the risk of developing ovarian cancer, the lesion is usually surgically removed.

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Gene sequencing study reveals unusual mutations in endometriosis - Medical Xpress

Researchers from the University of Texas Health Science Center in San Antonio have found a way to cure type 1 diabetes in mice. It is hoped that the novel technique - which boosts insulin secretion in the pancreas - will reach human clinical trials in the next 3 years.

Study co-author Dr. Bruno Doiron, Ph.D., of the Division of Diabetes, and colleagues recently reported their findings in the journal Current Pharmaceutical Biotechnology.

Type 1 diabetes is estimated to affect around 1.25 million children and adults in the United States. Onset of the condition is most common in childhood, but it can arise at any age.

In type 1 diabetes, the immune system destroys the insulin-producing beta cells of the pancreas. Insulin is the hormone that regulates blood glucose levels. As a result, blood glucose levels become too high.

There is currently no cure for type 1 diabetes; the condition is managed through diet and insulin therapy. However, in recent years, researchers have investigated replacing beta cells as a means of eradicating type 1 diabetes once and for all.

Dr. Doiron and colleagues have taken a different approach with their new study. The team reveals how they used a method called gene transfer to coax other pancreatic cells into producing insulin.

Using this technique, the researchers have managed to cure type 1 diabetes in mice, bringing us one step closer to curing the condition in humans.

The gene transfer technique - called Cellular Networking, Integration and Processing - involves introducing specific genes into the pancreas using a virus as a vector.

The team notes that beta cells are rejected in patients with type 1 diabetes. With the gene transfer method, the newly introduced genes encourage non-beta cells to produce insulin, without any side effects.

"The pancreas has many other cell types besides beta cells, and our approach is to alter these cells so that they start to secrete insulin, but only in response to glucose [sugar]," says study co-author Dr. Ralph DeFronzo, chief of the Division of Diabetes. "This is basically just like beta cells."

Upon testing their technique on mouse models of type 1 diabetes, the researchers found that they were able to induce long-term insulin secretion and blood glucose regulation, with no adverse side effects.

"It worked perfectly. We cured mice for 1 year without any side effects. That's never been seen. But it's a mouse model, so caution is needed. We want to bring this to large animals that are closer to humans in physiology of the endocrine system."

Dr. Bruno Doiron, Ph.D.

Importantly, the researchers point out that the gene transfer therapy only releases insulin in response to blood sugar, so it has the potential to transform current treatments for type 1 diabetes.

"A major problem we have in the field of type 1 diabetes is hypoglycemia (low blood sugar)," says Dr. Doiron. "The gene transfer we propose is remarkable because the altered cells match the characteristics of beta cells. Insulin is only released in response to glucose."

Not only could the novel strategy yield a cure for type 1 diabetes, but the researchers say that it may also eliminate the need for insulin therapy in patients with type 2 diabetes, which arises when the body is unable to use insulin effectively.

It will cost around $5 million to test their technique in large animal models, but the researchers are confident that this can be achieved. They hope to reach human clinical trials within the next 3 years.

Learn how maternal omega-3 intake may influence the risk of type 1 diabetes in infants.

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Type 1 diabetes cured in mice using gene therapy - Medical News Today

May 11, 2017 by Molly Peterson Findings from Leslie Lyons study could help feline preservationists implement breeding strategies in captivity for rare and endangered species such as the African black-footed cat. Credit: Cleveland Zoo

Whole genome sequencing (WGS), which is the process of determining an organism's complete DNA sequence, can be used to identify DNA anomalies that cause disease. Identifying disease-causing DNA abnormalities allows clinicians to better predict an effective course of treatment for the patient. Now, in a series of recent studies, scientists at the University of Missouri are using whole genome sequencing through the 99 Lives Cat Genome Sequencing Consortium to identify genetic variants that cause rare diseases, such as progressive retinal atrophy and Niemann-Pick type 1, a fatal disorder in domestic cats. Findings from the study could help feline preservationists implement breeding strategies in captivity for rare and endangered species such as the African black-footed cat.

The 99 Lives project was established at Mizzou by Leslie Lyons, the Gilbreath-McLorn Endowed Professor of Comparative Medicine in the College of Veterinary Medicine, to improve health care for cats through research. The database has genetically sequenced more than 50 felines and includes DNA from cats with and without known genetic health problems. The goal of the database is to identify DNA that causes genetic disorders and have a better understanding of how to treat diseases.

In the first study, Lyons and her team used the 99 Lives consortium to identify a genetic mutation that causes blindness in the African black-footed cat, an endangered species often found in U.S. zoos. The team sequenced three cats two unaffected parents and an affected offspring to determine if the mutation was inherited or spontaneous. The genetic mutation identified was located the IQCB1 gene and is associated with progressive retinal atrophy, an inherited degenerative retinal disorder that leads to blindness. The affected cat had two copies of the genetic mutation, indicating that it was an inherited disorder.

"African black-footed cats are closely related to domestic cats, so it was a good opportunity to use the 99 Lives database," Lyons said. "When sequencing DNA, we are looking for the high priority variants, or genetic mutations that result in disease. Variants in the IQCB1 gene are known to cause retinal degeneration in humans. We evaluated each gene of the African black-footed cat, one at a time, to look for the genetic mutation that is associated with vision loss."

In another study representing the first time precision medicine has been applied to feline health, Lyons and her team used whole genome sequencing and the 99 Lives consortium to identify a lysosomal disorder in a 36-week-old silver tabby kitten that was referred to the MU Veterinary Health Center. The kitten was found to have two copies of a mutation in the NPC1 gene, which causes Niemman-Pick type 1, a fatal disorder. The NCP1 gene identified is not a known variant in humans; it is a rare mutation to the feline population.

"Genetics of the patient is a critical aspect of an individual's health care for some diseases," Lyons said. "Continued collaboration with geneticists and veterinarians could lead to the rapid discovery of undiagnosed genetic conditions in cats. The goal of genetic testing is to identify disease early, so that effective and proactive treatment can be administered to patients."

Identification of both the IQCB1 gene in the African black-footed cat and the NCP1 in the silver tabby will help to diagnose other cats and allow them to receive appropriate treatment. Using results of the black-footed cat study, zookeepers will be implementing species survival plans to help manage the cats in captivity in North America.

Explore further: Linking human genome sequences to health data will change clinical medicine, says expert

More information: Annie Oh et al. Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes), Scientific Reports (2017). DOI: 10.1038/srep43918

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