When a child is diagnosed with cancer, one of the first questions the parents ask is “Will my other children get cancer?” A new study from Huntsman Cancer Institute(HCI) at the University of Utah, a member of the National Comprehesive Network(NCCN), suggests the answer to that question depends on whether a family history of cancer exists. The research results were published online on June 12, 2013 in theInternational Journal of Cancerand will appear in the November 15 print issue of the journal.[1]

The study, led by Joshua Schiffman, MD, medical director of HCI’sHigh Risk Pediatric Cancer Clinic and a pediatric hematologist/oncologist in in the Department of Pediatrics at the University of Utah, examined the family medical history of 4,482 children diagnosed with cancer over a 43-year period to determine the cancer risk in their relatives.

Cancers associated with Li-Fraumeni Syndrome (LFS) seemed to be driving the increased risk to relatives in families with a history of cancer…

The research team found that when children were diagnosed with any kind of cancer at age 18 or younger, the risk to their parents, siblings, or children for childhood cancer doubled compared to families with no childhood cancer patients. If the cancer diagnosis came when the child was age 4 or less, the risk to close relatives for childhood cancer increased almost four times.

“No one had previously studied the question, so we simply told parents there was no evidence of increased risk to the other children,” said Schiffman. “Now we can give an evidence-based answer?the risk depends on your family history of cancer.”

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Risk of cancer in in relatives of patient
This is the first study that uses the Utah Population Database (UPDB) to broadly examine the risk of all types of cancer in relatives of children with cancer. This unique resource at the University of Utah links genealogies and cancer registry data from Utah to medical records and vital records, including Utah death certificates.

“Because our data came from the UPDB, the assessment of family history in our study does not rely on self- or family-reported medical history,” said lead author Karen Curtin, Ph.D., a genetic epidemiologist and UPDB assistant director. “Self-reporting of family medical history depends on an individual’s memory, while our data comes from the statewide Utah Cancer Registry that records nearly all cancer cases, which reduces possible errors in reporting family cancers.”

Li-Fraumeni Syndrome
The team also assessed known inherited genetic syndromes in adult relatives of pediatric cancer patients. They found cancers associated with Li-Fraumeni Syndrome (LFS) seemed to be driving the increased risk to relatives in families with a history of cancer.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias. LFS-related cancers often occur in childhood or young adulthood and survivors have an increased risk for multiple primary cancers.

LFS is diagnosed in individuals meeting established clinical criteria or in those who have a germline mutation in TP53 regardless of family cancer history. At least 70% of individuals diagnosed clinically have an identifiable germline mutation in TP53, the only gene so far identified in which mutations are definitively associated with LFS.

Hereditary cancer
“Not all children’s cancers are hereditary,” Schiffman explaind. “But the numbers in this study suggest that the proportion of hereditary childhood cancers may be significantly higher than the 5-10% generally cited in adult hereditary cancers, and likely even more than 20%.”

“LFS is one of the most devastating cancer syndromes,” Schiffman noted. “It causes a variety of cancers in both children and adults. For people with LFS, the lifetime risk of getting cancer is 80% to 90%, but with increased and early screening for tumors, there’s early indication of a very high survival rate, perhaps even approaching 100%. In a previous study, LFS patients who did not receive early screening only had a 20% survival rate.”

LFS is inherited in anautosomal dominantmanner. [a] Classic LFS is defined by presence of all of the following criteria:

  • A proband with a sarcoma diagnosed before age 45 years;
  • A first-degree relative, including a parent or sibling, with any cancer before age 45 years;
  • A first- or second-degree relative, including agrandparent, uncle, aunt, nephew, niece, half-sibling,with any cancer before age 45 years or a sarcoma at any age.

In addition to these criteria,the diagnosis of LFS should also be suspected in individualswho meets the Chompret criteria [2] forTP53testing,women who has a personal history of early-onset breast cancer and do not have an identifiableBRCA1orBRCA2mutation, individuals who have a personal history – regardless of family history – of adrenocortical carcinoma (ACC),and individuals who have a personal history of choroid plexus carcinoma (CPC) regardless offamily history.

New recommendation and genetic counseling
Although childhood cancer rarely occurs in the population, based on their findings, the authors recommended collection of three generations of family medical history for all newly diagnosed pediatric cancer patients and referral of families with a history of early-onset cancers in children or adults for genetic counseling. In addition, parents of children diagnosed with cancer before age five with a family history of cancer should be advised of the potential for increased risk to other children in the family.

“We want to encourage the taking of a family history as part of routine care. With all cancers, but perhaps especially with childhood cancers, so many other questions seem so urgent, a family history may not seem to be the most pressing issue,” said co-author Wendy Kohlmann, director of HCI’s Genetic Counseling Program. “When families are referred into genetic counseling, we can provide them with more information about the risks and actions they can take.”

“For families with previously unidentified LFS, following these recommendations could actually save the lives of multiple family members if at risk individuals are identified and early cancer surveillance programs implemented,” Schiffman said.

The data analyzed in this study indicated that outcomes for pediatric cancer patients are worse in families with a history of cancer. Schiffman said that further studies are planned to learn the clinical implications of this observation.

For more information:
[a] Anautosomal dominantmanneris a trait or disorder in which the phenotype is expressed in those who have inherited only one copy of a particular gene mutation (heterozygotes). It specifically refers to a gene on one of the 22 pairs of autosomes (non-sex chromosomes).

[1] Curtin K, Smith KR, Fraser A, Pimentel R, Kohlmann W, Schiffman JD. Famili
al risk of childhood cancer and tumors in the li-fraumeni spectrum in the utah population database: Implications for genetic evaluation in pediatric practice. Int J Cancer.2013 May 10. doi: 10.1002/ijc.28266. [Epub ahead of print][PubMed]
[2]Chompret A, Abel A, Stoppa-Lyonnet D, Brugieres L, Pages S, Feunteun J, Bonaiti-Pellie C. Sensitivity and predictive value of criteria for p53 germline mutation screening.J Med Genet.2001;38:43?7.[Full article] [PubMed]

Photo:Joshua Schiffman, MD (left)is working in his lab. Photo Courtesy: Huntsman Cancer Institute,2000 Circle of Hope,Salt Lake City, UT 84112.

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