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Noelle Johnson, 42, was diagnosed with her first cancer – a soft tissue sarcoma under her right arm – in 1999, when she was 21 years old. In 2013, his doctors discovered six different cancers within. In the years that followed, surgeons discovered and removed many masses considered "premalignant" from its ovary, uterus, leg, arm and chest wall, in order to get them out before they do not become cancerous.
Each tumor was distinct, that is to say that none resulted from the spread of one of the others. For Johnson, diagnosing many primitive tumors at an unusually young age was both frightening and disconcerting. "It was crazy," recalls Johnson, who lives in Windsor, Col., where she runs a daycare at her home. "My world started to turn. It was a huge red flag. "
Many people assume that when cancer occurs after an earlier tumor, it is a metastasis of the first. But this is not always the case. Multiple primary cancers can occur alone and researchers in recent years have begun to understand some of the reasons.
"Cancer therapies have improved dramatically in the modern era, resulting in a growing population of cancer survivors – more than 15 million," said Stephen J. Chanock, director of the Division of Epidemiology and Cancer Genetics at the National Cancer Institute. Cancer Institute (NCI). "As these people live longer, some of them develop a second cancer, tumors unrelated to their initial cancer. Several factors are probably involved and we always learn about their causes. "
Experts believe that many of these additional primary tumors result from pre-initial cancer treatments that often occur in childhood. Radiation therapy and chemotherapy, while managing to eliminate the first disease, also cause DNA damage. This may prompt new cancers to develop later, including lymphomas, leukemias and breast, thyroid or soft tissue cancers.
Random infections
Other factors likely to promote the emergence of new tumors include probably environmental exposures, such as smoking or alcohol use, hormonal influences, viral infections – especially HIV – and genetics, which seems to be a major player. In addition, experts believe that a combination of these factors is involved. "New evidence suggests that common hereditary factors associated with treatment may affect the risk of developing a second cancer," says Chanock.
Finally, there is also the element of chance – some one must be the first – that is, a spontaneous gene mutation that is transmitted at the beginning of the chain.
Johnson asked why she was susceptible to so many cancers. Six years ago, she finally discovered: genes.
In 2013, after undergoing a double mastectomy – and before the discovery of the last masses – genetic tests showed that she had Li-Fraumeni syndrome (LFS), a hereditary familial predisposition to a wide range of cancers. specific and often rare, especially among children and young people. adults. These often include breast cancer, osteosarcoma – a form of bone cancer – and soft tissue cancers, brain tumors, leukemias, and a cancer called adrenocortical carcinoma that affects the outer layer of the glands adrenals, according to the National Institutes of Health. A parent with the mutation is enough to transmit it.
LFS involves hereditary mutations of the TP53 gene (and sometimes – but less often – the CHEK2 gene), a tumor suppressor gene that, undamaged, controls the spread of cancer cells. When mutations occur, cells can divide, proliferate, and form tumors. According to NIH, other genetic and environmental factors probably increase the risk of cancer in people with TP53 mutations. The Cancer Institute has an ongoing study to learn more about the syndrome.
It is unclear how many people carry these mutations, although the Li-Fraumeni Syndrome Association reports that more than 1,000 multigenerational families are affected. Researchers believe this estimate is conservative.
"Historically, we think that EFT is very rare," says Kim Nichols, who heads the cancer predisposition group of the St. Jude Children's Research Hospital in Memphis. "The medical literature says between 400 and 500 reported cases, but I really believe that there are more. Not everyone has been diagnosed because it is not on the radar screens of most oncologists. For me, it's very obvious, but in the real world, where oncologists treat many cancers, they do not always think about it. "
Hereditary factors
The failure of many doctors to take a family history is one of the reasons they are underreported, she adds. Cancers among closely related family members – especially at a young age – are an important clue. For example, Johnson's mother, who died at age 50, had leiomyosarcoma, an aggressive cancer of smooth muscle tissue. "Doctors often do not think about the possibility of an underlying genetic predisposition," says Nichols.
She and others point out that other genetic variants can lead to multiple tumors, including BRCA1 and BRCA2, which are known to cause breast and ovarian cancer in women, but are also linked to tumors. malignancies such as cancer of the pancreas and prostate, melanoma – in men – and breast cancer in humans. In addition, variants of the DICER1 gene may predispose individuals to many types of tumors, both malignant and benign.
Retinoblastoma, a cancer of the retinal tissues that usually affects children under 5, may be hereditary or sporadic, but survivors with Rb1 gene mutations may later develop sarcomas, melanomas, and brain cancers. of the nasal cavity. Radiation therapy used to treat retinoblastoma seems to increase the risk, suggesting a possible interaction.
In addition, researchers believe that there could be many common genetic variants involved in the development of multiple, yet unidentified tumors.
"These are not just rare variants that we should be thinking about in the case of multiple cancers, but common variants, perhaps many of them," says Lindsay Morton, a scientist in the division of the United States. epidemiology and genetics of NCI cancer.
Morton's research focuses on the second treatment-related cancers, including the interaction of genetics with the effects of previous treatment.
"It's a different way of thinking about precision medicine," she says. "Usually, people think of targeted therapy, but we say that the benefit-risk assessment of a given treatment might depend on someone's genetics. Individuals may have a genetic variant that reduces the ability of their normal cells to repair DNA damage resulting from cancer treatment, compared to another person who does not have this genetic variant. "
Nichols agrees.
"We know that when people are treated for the first cancer, many of the drugs or radiation therapy kill the cancer cells by interfering with DNA," says Nichols, a researcher in the Li-Fraumeni study of NIH and collaborator in several institutions. LFS Research Consortium. "When that happens, you can introduce a change in the DNA that can lead to cancer. The question is: how much is the treatment associated with a risk and how much does it come from an underlying genetic disease? We are learning about it now. It has not been studied in depth and must be. "
With LFS, there is no way to prevent cancers. Experts believe that the best way to cope is to detect and treat them quickly.
Joshua Schiffman, Professor of Pediatric Hematology / Oncology at the Huntsman Cancer Institute at the University of Utah and Medical Director of the Family Cancer Assessment Clinic, has been studying EPA for over 10 years. He was involved after treating a 4-year-old child with leukemia, who had already suffered from a brain tumor. By examining the family history, Schiffman found that the child's father and uncle had died from glioblastoma, an aggressive brain cancer.
"We knew there had to be something," says Schiffman. "We tested it, along with its siblings, and found out that it was a family with LFS."
He studies the genetics of EPA by studying elephants, which rarely develop cancer. Elephants have 40 copies of the TP53 gene, compared to humans, who have only two. "We are trying to understand the molecular basis of the functioning of the elephant TP53 and its difference with human TP53," says Schiffman.
Whole body MRI use
Meanwhile, Schiffman believes in using an entire body MRI to detect tumors early, and has collaborated on several studies that suggest that the approach works. The first, in 2011, led by David Malkin of Sick Kids Hospital in Toronto, followed a small group of EPA patients for five years. Some opted for screening, others did not. After five years, those who chose imaging were still alive, compared with only 20% who refused.
The protocol, called the Toronto Protocol, is recommended by the National Comprehensive Cancer Network. But imaging is expensive – Schiffman estimates it would cost between $ 3,000 and $ 10,000 – and many insurance companies will not cover it. A recent study that he wrote demonstrates that it is cost-effective compared to cancer treatment discovered later. "We know that hundreds of patients can get cancer, but they can not afford to be scanned," he says.
Johnson's family – she has four sons, two of whom are EPA positive – is part of the NIH study. She expects other cancers to develop, "but we are working to detect them earlier and eliminate them," she says.
In the meantime, she says that she is trying to keep anxiety in the background.
"Time is a gift, not a guarantee," she says. "I firmly believe that our days are numbered. But our quality of life is always under our control. "
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