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Study of Affected Families Finds PALB2 Mutations Increase Breast Cancer Risk Significantly

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Originally published August 11.

NEW YORK (GenomeWeb) — Research by an international team led by University of Cambridge scientists has found that mutations in the gene PALB2 confer almost as great a risk of developing breast cancer as mutations in BRCA1 and BRCA2, the genes most commonly implicated in familial forms of the disease.

Published in the New England Journal of Medicine last week, the study calculated the lifetime risk of breast cancer conferred by the presence of mutations in the gene PALB2 by examining a group of 154 families in which such mutations were passed down. The study also outlined how risk varies based on a patient's family history.

According to the results, women with PALB2 mutations have about a 14 percent chance of developing breast cancer by age 50 and a 35 percent chance by age 70. Lifetime risk is even higher — 58 percent — for women with two or more family members who have developed cancer. Overall, the research revealed that PALB2 risk runs a close third to the two BRCA mutations, falling just behind, and even overlapping slightly, the lowest end of the risk spectrum for BRCA1 and BRCA2.

As multi-gene sequencing panels covering larger numbers of genes have found use as screening tools for hereditary cancers, knowledge of how some of the more infrequent events they detect — like PALB2 mutations — actually influence lifetime risk has not kept up, according to the study authors.

Mutations in PALB2, which encodes a protein that interacts with both BRCA2 and BRCA1, appear to occur in about 2.4 percent of families with inherited breast cancers, based on the group's study. This relative infrequency has limited the reliability of previous estimates of how such mutations influence cancer risk, Marc Tischkowitz, the study's senior author and a member of the department of medical genetics at Cambridge, told PGx Reporter.

What this has meant is that as tests have entered the market that detect the presence of a PALB2 mutations, clinicians have lacked evidence with which to explain to patients what the presence of such mutations actually means in terms of a woman's chance of developing cancer over her lifetime.

"Until about two years ago BRCA1 and BRCA2 were the only genes tested for," Tischkowitz said. "There has since been an explosion … and now you have commercial and public laboratories testing for 10 or 20 genes that are supposedly linked to hereditary cancer but the evidence for many of them is weak so if you find a mutation it's often unclear what the clinical implications are."

Tischowitz and his co-authors set out with their effort to try to recruit a large-enough cohort of PALB2 mutation-carrying families to calculate a reliable estimate of how much these mutations increase cancer risk.

For the study, researchers at 14 participating centers tracked down families who had at least one family member with breast cancer that was negative for BRCA1 and BRCA2, but positive for a loss-of-function mutation in PALB2.

After excluding some families for statistical reasons, the group narrowed down to a cohort of 154 families representing 362 individuals with PALB2 mutations. Of these, 311 were women, and 229 of them had breast cancer. The cohort also included 51 PALB2-mutated men, of whom seven had breast cancer.

Using different risk models, the researchers looked to see what pattern of risk would best fit the data from these families. They found that the model that best fit accounted for differences in risk based not only on the presence of a PALB2 mutation, but also on differences in family history.

Under this scheme, the researchers calculated women's cumulative risk of developing cancer to be about 14 percent by age 50 and 35 percent by age 70. If a woman had two or more relatives with breast cancer, her risk by age 70 rose to 58 percent.

In comparison, women with BRCA1 mutations have between a 50 percent and 70 percent chance of developing breast cancer by age 70, while those with BRCA2 mutations have a 40 percent to 60 percent chance of doing so.

The team also found that relative risk of ovarian cancer among PALB2 mutation carriers was about 2.31, and the relative risk of breast cancer for males in the cohort was about eight compared with male breast cancer incidence in the general population. However, Tischkowitz said, these findings were not statistically significant.

According to the authors, the results suggest that the risk conferred by PALB2 mutations meets the threshold set by professional guidelines as high enough to merit use in a clinical setting.

While PALB2 has found its way into some commercial and public laboratories' hereditary cancer screening tests, it is not mandated in assessing women with a family history of breast cancer in the same way as BRCA1 and BRCA2.

"Previous studies have been based on small numbers and their risk estimates have varied, some higher and some lower. With this study we came out about in the middle," Tischkowitz said.

"We showed that the upper end of the risk for this overlaps with the lower end for BRCA1 and 2, which indicates that it's high enough to be used in a clinical setting," he added

As more and more women and men are tested for PALB2, which Tischkowitz said is likely with the advent of broader sequencing-based hereditary cancer tests, an even more accurate picture of how PALB2 impacts breast cancer risk should emerge.

Tischkowitz said a larger sample set may also help confirm some of the hints the group found of what the gene might mean in terms of men's breast cancer risk and women's risk of ovarian cancer.

"With BRCA1 and BRCA2, those estimates are derived from sample sets of thousands of patients," he said. "This is the best we have at the moment for PALB2 … It's an ongoing process, but because this gene is now on many panels … I think from here on in, hopefully we will be able to collect larger datasets."

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