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Women with inherited loss-of-function mutations in the PALB2 gene were more than nine times as likely to develop breast cancer, compared with the general population, according to a large multicenter study reported Aug. 6 in the New England Journal of Medicine.
The study showed that women with germline loss-of-function PALB2 mutations had a 14% cumulative risk of breast cancer by age 50 years and a 35% risk by age 70, said Antonis C. Antoniou, Ph.D., of the University of Cambridge, England, and his associates.
"On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2," the researchers said.
Germline PALB2 mutations affect about 0.08% of the population and are a known risk factor for breast cancer. To better characterize lifetime risk in PALB2 mutation carriers, the researchers studied 154 families in the United Kingdom whose 362 members had inherited harmful truncating, splice, or deletion mutations in PALB2 (N. Engl. J. Med. 2014;371:497-506). The cohort included 311 women, of whom 229 had breast cancer, the researchers said.
After controlling for other familial factors, the risk of breast cancer in PALB2 mutation carriers was 9.47 times (95% confidence interval, 7.16-12.57) greater than in the United Kingdom overall between 1993 and 1997, the investigators reported.
Risk correlated inversely with age and also was affected by family history of breast cancer, they found. Women with the mutation whose first-degree relatives were cancer free had a 33% risk of breast cancer at age 70 years (95% CI, 25%-44%), but this risk was 58% if the women had at least two first-degree relatives who developed breast cancer by age 50 years (95% CI, 50%-66%), Dr. Antoniou and his associates said.
"Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers," Dr. Antoniou and associates said. As screening for these mutations enters clinical practice, more families with the PALB2 mutation will be identified and risk estimates can be refined, they said, adding that future studies should evaluate whether the heightened breast cancer surveillance that women with BRCA2 mutations receive can affect outcomes in women who carry the PALB2 loss-of-function mutation.
The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported being listed on patents related to breast cancer susceptibility genes. The authors disclosed no other conflicts of interest.
The results point to new opportunities to pursue the "synthetic lethality of cancer therapy," said Dr. Michele Evans and Dr. Dan Longo.
In synthetic lethality, two related genes simultaneously lose function, which has a cumulative effect and spurs cell death instead of sublethal changes. "Loss of heterozygosity at the PALB2 locus is likely to result in increased sensitivity to cell death with PARP inhibition as well, given that synthetic lethality is seen with other proteins that are involved in homologous recombination," they said.
"The promise of synthetic lethality in breast-cancer treatment through genetic and pharmacologic targeting of the Fanconi’s anemia-breast cancer pathway will lead the way to the examination and exploitation of defective DNA-repair mechanisms in other cancers," they wrote.
Based on the findings, women with germline PALB2 mutations face about the same risk of breast cancer as women who carry the BRCA2 mutation, Dr. Evans and Dr. Longo said. They noted that PALB2 encodes a protein that binds and colocalizes with BRCA2 in cell nuclei, which enables tumor suppression by preventing DNA damage and promoting repair.
The analyses also indicate that risks linked to PALB2 mutations "synergize with unknown environmental, lifestyle, or additional genetic factors," which "highlights the need to use genetic information within the context of family history and lifestyle factors when assessing risk," they added.
Because the study cohort was racially homogeneous, future studies need to characterize PALB2 in other populations, they noted.
Dr. Evans and Dr. Longo are with the National Institute on Aging, Baltimore. These remarks were excerpted from their editorial accompanying Dr. Antoniou’s report (N. Engl. J. Med. 2014;371:566-8 [doi: 10.1056/NEJMe1405784]).
The results point to new opportunities to pursue the "synthetic lethality of cancer therapy," said Dr. Michele Evans and Dr. Dan Longo.
In synthetic lethality, two related genes simultaneously lose function, which has a cumulative effect and spurs cell death instead of sublethal changes. "Loss of heterozygosity at the PALB2 locus is likely to result in increased sensitivity to cell death with PARP inhibition as well, given that synthetic lethality is seen with other proteins that are involved in homologous recombination," they said.
"The promise of synthetic lethality in breast-cancer treatment through genetic and pharmacologic targeting of the Fanconi’s anemia-breast cancer pathway will lead the way to the examination and exploitation of defective DNA-repair mechanisms in other cancers," they wrote.
Based on the findings, women with germline PALB2 mutations face about the same risk of breast cancer as women who carry the BRCA2 mutation, Dr. Evans and Dr. Longo said. They noted that PALB2 encodes a protein that binds and colocalizes with BRCA2 in cell nuclei, which enables tumor suppression by preventing DNA damage and promoting repair.
The analyses also indicate that risks linked to PALB2 mutations "synergize with unknown environmental, lifestyle, or additional genetic factors," which "highlights the need to use genetic information within the context of family history and lifestyle factors when assessing risk," they added.
Because the study cohort was racially homogeneous, future studies need to characterize PALB2 in other populations, they noted.
Dr. Evans and Dr. Longo are with the National Institute on Aging, Baltimore. These remarks were excerpted from their editorial accompanying Dr. Antoniou’s report (N. Engl. J. Med. 2014;371:566-8 [doi: 10.1056/NEJMe1405784]).
The results point to new opportunities to pursue the "synthetic lethality of cancer therapy," said Dr. Michele Evans and Dr. Dan Longo.
In synthetic lethality, two related genes simultaneously lose function, which has a cumulative effect and spurs cell death instead of sublethal changes. "Loss of heterozygosity at the PALB2 locus is likely to result in increased sensitivity to cell death with PARP inhibition as well, given that synthetic lethality is seen with other proteins that are involved in homologous recombination," they said.
"The promise of synthetic lethality in breast-cancer treatment through genetic and pharmacologic targeting of the Fanconi’s anemia-breast cancer pathway will lead the way to the examination and exploitation of defective DNA-repair mechanisms in other cancers," they wrote.
Based on the findings, women with germline PALB2 mutations face about the same risk of breast cancer as women who carry the BRCA2 mutation, Dr. Evans and Dr. Longo said. They noted that PALB2 encodes a protein that binds and colocalizes with BRCA2 in cell nuclei, which enables tumor suppression by preventing DNA damage and promoting repair.
The analyses also indicate that risks linked to PALB2 mutations "synergize with unknown environmental, lifestyle, or additional genetic factors," which "highlights the need to use genetic information within the context of family history and lifestyle factors when assessing risk," they added.
Because the study cohort was racially homogeneous, future studies need to characterize PALB2 in other populations, they noted.
Dr. Evans and Dr. Longo are with the National Institute on Aging, Baltimore. These remarks were excerpted from their editorial accompanying Dr. Antoniou’s report (N. Engl. J. Med. 2014;371:566-8 [doi: 10.1056/NEJMe1405784]).
Women with inherited loss-of-function mutations in the PALB2 gene were more than nine times as likely to develop breast cancer, compared with the general population, according to a large multicenter study reported Aug. 6 in the New England Journal of Medicine.
The study showed that women with germline loss-of-function PALB2 mutations had a 14% cumulative risk of breast cancer by age 50 years and a 35% risk by age 70, said Antonis C. Antoniou, Ph.D., of the University of Cambridge, England, and his associates.
"On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2," the researchers said.
Germline PALB2 mutations affect about 0.08% of the population and are a known risk factor for breast cancer. To better characterize lifetime risk in PALB2 mutation carriers, the researchers studied 154 families in the United Kingdom whose 362 members had inherited harmful truncating, splice, or deletion mutations in PALB2 (N. Engl. J. Med. 2014;371:497-506). The cohort included 311 women, of whom 229 had breast cancer, the researchers said.
After controlling for other familial factors, the risk of breast cancer in PALB2 mutation carriers was 9.47 times (95% confidence interval, 7.16-12.57) greater than in the United Kingdom overall between 1993 and 1997, the investigators reported.
Risk correlated inversely with age and also was affected by family history of breast cancer, they found. Women with the mutation whose first-degree relatives were cancer free had a 33% risk of breast cancer at age 70 years (95% CI, 25%-44%), but this risk was 58% if the women had at least two first-degree relatives who developed breast cancer by age 50 years (95% CI, 50%-66%), Dr. Antoniou and his associates said.
"Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers," Dr. Antoniou and associates said. As screening for these mutations enters clinical practice, more families with the PALB2 mutation will be identified and risk estimates can be refined, they said, adding that future studies should evaluate whether the heightened breast cancer surveillance that women with BRCA2 mutations receive can affect outcomes in women who carry the PALB2 loss-of-function mutation.
The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported being listed on patents related to breast cancer susceptibility genes. The authors disclosed no other conflicts of interest.
Women with inherited loss-of-function mutations in the PALB2 gene were more than nine times as likely to develop breast cancer, compared with the general population, according to a large multicenter study reported Aug. 6 in the New England Journal of Medicine.
The study showed that women with germline loss-of-function PALB2 mutations had a 14% cumulative risk of breast cancer by age 50 years and a 35% risk by age 70, said Antonis C. Antoniou, Ph.D., of the University of Cambridge, England, and his associates.
"On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2," the researchers said.
Germline PALB2 mutations affect about 0.08% of the population and are a known risk factor for breast cancer. To better characterize lifetime risk in PALB2 mutation carriers, the researchers studied 154 families in the United Kingdom whose 362 members had inherited harmful truncating, splice, or deletion mutations in PALB2 (N. Engl. J. Med. 2014;371:497-506). The cohort included 311 women, of whom 229 had breast cancer, the researchers said.
After controlling for other familial factors, the risk of breast cancer in PALB2 mutation carriers was 9.47 times (95% confidence interval, 7.16-12.57) greater than in the United Kingdom overall between 1993 and 1997, the investigators reported.
Risk correlated inversely with age and also was affected by family history of breast cancer, they found. Women with the mutation whose first-degree relatives were cancer free had a 33% risk of breast cancer at age 70 years (95% CI, 25%-44%), but this risk was 58% if the women had at least two first-degree relatives who developed breast cancer by age 50 years (95% CI, 50%-66%), Dr. Antoniou and his associates said.
"Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers," Dr. Antoniou and associates said. As screening for these mutations enters clinical practice, more families with the PALB2 mutation will be identified and risk estimates can be refined, they said, adding that future studies should evaluate whether the heightened breast cancer surveillance that women with BRCA2 mutations receive can affect outcomes in women who carry the PALB2 loss-of-function mutation.
The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported being listed on patents related to breast cancer susceptibility genes. The authors disclosed no other conflicts of interest.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Inherited loss-of-function mutations in PALB2 significantly increase women’s lifetime risk of breast cancer.
Major finding: Women with inherited loss-of-function mutations in the PALB2 gene were 9.47 times more likely to develop breast cancer than the general population.
Data source: Modified segregation analysis of breast cancer risk among 154 families in the United Kingdom whose 362 members had truncating, splice, or deletion mutations in the PALB2 gene.
Disclosures: The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported having been listed on patents related to breast cancer susceptibility genes. The authors reported no other conflicts of interest.
