Doctors in this Field
A pioneering clinic at UCLA Mattel Children’s Hospital is making a significant impact on the lives of children and their families with rare genetic conditions that predispose them to cancer, as well as those diagnosed with pediatric cancers that are potentially related to a rare genetic syndrome.
The UCLA Pediatric Cancer Predisposition Clinic was established in 2012, at a time when powerful new genetic testing technologies were first being implemented clinically at UCLA. This so-called next-generation DNA sequencing enabled, for the first time, comprehensive testing of all of the protein-coding regions of the genome to diagnose rare conditions and identify genetic predispositions.
“At the time, little was known about the utility of genetic testing in children with genetic syndromes that could predispose them to early cancers,” says Julian A. Martinez, MD, PhD, a clinical geneticist and the center’s co-director. “We believed it had potential value in that it would enable surveillance of patients with these predispositions to detect and treat the tumors early, as well as facilitating targeted treatments in patients already diagnosed with cancer based on the genetic cause identified.”
That initial vision has borne out, Dr. Martinez notes, and the clinic’s approach to patients with cancer-predisposing genetic conditions or cancers resulting from genetic syndromes has become the international standard for how such patients should be evaluated and managed. The clinic’s value has only grown with the continued advances in DNA sequencing technologies and the development of new treatments that target the specific genetic mutations underlying an individual patient’s cancer.
The UCLA Pediatric Cancer Predisposition Clinic remains one of the few multidisciplinary efforts of its kind, notes Vivian Y. Chang, MD, MS, a pediatric hematologist-oncologist and co-director of the clinic. The clinic brings together oncologists, geneticists, genetic counselors and social workers to provide diagnostic genetic testing and counseling, as well as personalized screening protocols as needed. All cases are discussed at a weekly genomic board meeting that includes bioinformatics specialists and pathologists as well as clinicians.
Most of the clinic’s patients fall into one of two categories. The first are those who have already been diagnosed with a genetic syndrome associated with a high risk for developing a cancer. “My role as the oncologist is to educate these patients about their cancer risk and develop personalized cancer screening plans,” Dr. Chang explains. “We know that if we catch these cancers early, it offers the best prognosis and the best treatment options.”
Dr. Chang has been a leader in developing surveillance guidelines for patients with underlying genetic syndromes that predispose to cancer risk, as part of an expert panel convened by the American Association for Cancer Research. “With these genetic diagnoses that are this rare, it’s important to share data across centers,” she notes. “By doing so, we have developed evidence-based guidelines so that these patients can be treated in a standardized way.”
The second major population of patients seen at the clinic are children — and in some cases, adults — who have already been diagnosed with a cancer, but certain features of their presentation or family history suggest an underlying genetic cause. Often, Dr. Martinez notes, these patients have gone through what is commonly referred to as a diagnostic journey, presenting with multiple medical conditions that have eluded a unifying diagnosis. “With our state-of-the-art genetic testing, we can put an end to the diagnostic journey so that these families are no longer making their way through the medical system, trying to find answers,” Dr. Martinez says. “We are able to provide a medical home for these patients and a roadmap for what to expect, in addition to better-informed treatment.”
Ending the diagnostic journey brings multiple benefits, Dr. Martinez notes. For families, there is great psychological benefit to finding closure after a long, emotionally trying odyssey in search of an explanation for their child’s symptoms. That journey can include expensive and ultimately fruitless testing, at significant cost to both the families and the healthcare system. In some cases, the definitive diagnosis points to a condition that could affect other family members, who can then benefit from being tested and, if they test positive, being treated or more frequently screened, as appropriate.
Dr. Martinez says that roughly 10 percent of the pediatric cancer patients referred to the clinic have been found to have a well-documented genetic syndrome, and his team has described new syndromes along the way. Other centers that have followed the UCLA clinic’s approach have found, similarly, that about 10 percent of their pediatric cancer patients will have a known genetic disorder that can benefit from surveillance and personalized care.
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We see individuals and families affected by, or at risk for, the following conditions and for many other inherited genetic conditions that increase the risk for tumors and cancers:
Hereditary breast and ovarian cancer syndrome is an inherited condition that increases the risk of developing breast cancer and ovarian cancer. In addition, some families with HBOC have higher rates of pancreatic cancer, prostate cancer, melanoma, and other cancers. HBOC is associated with inherited harmful changes in the BRCA1 and BRCA2 genes, as well as several other genes including ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C, and RAD51D.
Lynch Syndrome is an inherited condition that is associated with an increased risk for several types of cancers. These include cancers of the colon, uterus, ovary, stomach, small intestine, urinary tract/bladder/kidney, bile duct, pancreas, sebaceous gland, and brain cancer (usually glioblastoma). Lynch Syndrome is linked to inherited harmful changes in the MLH1, MSH2, MSH6, PMS2 and EPCAM genes. Lynch syndrome is sometimes called hereditary nonpolyposis colorectal cancer syndrome (HNPCC).
Familial adenomatous polyposis is an inherited condition in which individuals may develop hundreds to thousands of precancerous growths in the colon, called adenomatous polyps. They also have a higher risk for cancers, including stomach, small bowel, pancreas, bile duct, liver, thyroid, and brain (usually medulloblastoma). Some people with FAP have benign growths called desmoid tumors and a benign eye condition called congenital hyperpigmentation of the retinal pigment epithelium (CHRPE). FAP is due to inherited harmful changes in the APC gene.
MUTYH-associated polyposis is an inherited condition in which individuals may develop a few, or hundreds to thousands of precancerous growths in the colon, called adenomatous polyps. People with MAP are also at an increased risk to have colon, small bowel, and thyroid cancer, and possibly other cancers. MUTYH-associated polyposis is caused by inheriting two copies of the MUTYH with harmful changes, one from each parent.
Li-Fraumeni syndrome is a rare condition that is associated with an increased risk for many kinds of cancer such as early onset breast cancer, soft tissue cancers, bone cancer, brain tumors, cancer of the adrenal gland, and leukemias. LFS is caused by inherited harmful changes in the TP53 gene.
Peutz-Jeghers syndrome is an inherited condition that is associated with an increased risk for benign tumors and cancers of the colon, stomach, pancreas, breast, and ovary. Individuals with PJS are also at increased risk for hamartomaous gastrointestinal polyps that can cause a condition called intussusception that can require surgery. Peutz-Jeghers syndrome is caused by inherited harmful changes in the STK11 gene.
Hereditary paraganglioma-pheochromocytoma syndrome is an inherited condition in which individuals develop benign tumors of the paraganglia, specialized cells of the nervous system. Hereditary paraganglioma-pheochromocytoma syndrome can be caused by inherited harmful changes in several genes including SDHA, SDHAF2, SDHB, SDHC, and SDHD.
Hereditary diffuse gastric cancer is an inherited condition in which individuals are at an increased risk of developing diffuse gastric cancer and lobular breast cancer. Diffuse gastric cancer is a type of cancer that forms in the stomach causing thickening of the wall of the stomach (linitis plastica) that does not form a distinct mass. Hereditary diffuse gastric cancer is linked to inherited harmful changes in the CDH1 gene.
Von Hippel-Lindau Disease is an inherited disorder that is characterized by the abnormal growth of blood vessels. Individuals with VHL have an increased risk of developing kidney cancer and tumors in the adrenal gland called pheochromocytomas. Von Hippel-Lindau Disease is associated with inherited harmful changes in the VHL gene.
Multiple Endocrine Neoplasia syndromes are a group of hereditary conditions that are associated with increased risk for tumors in hormone producing glands. Type 1 can involve tumors of the parathyroid or pituitary gland as well as neuroendocrine tumors of the pancreas. Type 2 causes a form of thyroid cancer called medullary thyroid carcinoma. Inherited harmful changes in the MEN1, RET, and other genes can cause multiple endocrine neoplasia.
Hereditary leiomyomatosis and renal cell cancer is an inherited condition associated with increased risk for benign skin tumors, benign tumors in the uterus, and kidney cancers. Hereditary leiomyomatosis is associated with inherited harmful changes in the FH gene.
Birt-Hogg-Dubé syndrome is a hereditary condition associated with benign skin tumors, lung cysts and an increased risk of both benign kidney tumors and kidney cancer. Birt-Hogg-Dubé is associated with inherited harmful changes in the FLCN gene.
FAMMM is considered when two or three close relatives have been diagnosed with melanoma and pancreatic cancer or a family member has been diagnosed with melanoma multiple times. Some affected individuals have 50 or more moles. FAMMM is due to inherited harmful changes in the CDKN2A gene. Familial melanoma can be linked in some families to inherited harmful changes in other genes, including CDK4 and BAP1.