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PALB2 mutation associated with increased risk for breast cancer
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Women who harbored loss-of-function mutations in the PALB2 gene were five to nine times more likely to develop breast cancer than women of the same age who did not harbor the mutation, according to study results.
Female mutation carriers had an estimated 14% (95% CI, 9-20) cumulative risk for breast cancer by age 50 years and an estimated 35% (95% CI, 26-46) cumulative risk by age 70 years compared with women in the general population, results showed.
Antonis C. Antoniou, PhD, of the department of public health and primary care at the University of Cambridge in the United Kingdom, and colleagues evaluated data from 154 families comprised of 311 women and 51 men with PALB2 mutations. Researchers identified 48 varieties of PALB2 truncation, splice or deletion mutations in the cohort.
Overall, 229 of the women and seven of the men with PALB2 mutations had breast cancer.
A single-gene model indicated PALB2 mutation carriers had a 9.47 (95% CI, 7.16-12.57) relative risk for breast cancer compared with the general population of the UK between 1993 and 1997.
Researchers calculated a relative risk of 8.3 (95% CI, 0.77-88.56) for men with a PALB2 mutation compared with men in the general population.
Women who harbored a PALB2 mutation demonstrated an increased risk for breast cancer compared with the general population according to age. The risk for breast cancer was eight to nine times higher among those aged younger than 40 years, six to eight times higher among those aged 40 to 60 years, and five times higher among those aged older than 60 years.
The risk for breast cancer with a PALB2 mutation was significantly associated with birth cohort (P˂.001). Women born before 1940 had the lowest risk (RR=1; 95% CI, 0.59-1.69), whereas those born in 1960 or later had the greatest risk (RR=6.29; 95% CI, 2.81-14.1)
The risk for breast cancer with a PALB2 mutation also was associated with familial factors (P=.04). Women who harbored a PALB2 mutation but had no family history of breast cancer demonstrated a 33% (95% CI, 25-44) absolute risk by age 70 years, whereas those with a PALB2 mutation plus two or more first-degree relatives demonstrated a 58% (95% CI, 50-66) absolute risk by age 50 years.
“On the basis of our risk estimates, women with loss-of-function mutations in PALB2 should be studied to determine whether enhanced surveillance for breast cancer, in line with that offered to women with mutations in BRCA2, can influence outcomes,” Antoniou and colleagues wrote. “Because of the widespread availability of multigene panels and whole-exome sequencing, screening for inherited loss-of function mutations in PALB2 has begun to enter clinical practice. As families with PALB2 mutations are identified, it will be valuable to collect family history and other data for future analysis in order to refine estimates of cancer risks for PALB2 mutation carriers.”
Disclosure: The researchers report being listed on patents for breast and ovarian cancer susceptibility genes licensed to Myriad Genetics.
Perspective
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Adam M. Brufsky, MD, PhD, FACP
Typically, screening for BRCA1 and BRCA2 in women with a family history of breast cancer yields mutations of clinical significance in a bit less than 50% of women, or about 5% to 10% of all women with breast cancer. Clearly, there are genes or collections of genes that are unknown that likely account for this risk, or about another 10% of all breast cancers. Recent developments in basic science and DNA sequencing now allow for rapid screening of other genes. One such gene is PALB2, which can account for perhaps 1% of breast cancer risk. This publication in The New England Journal of Medicine suggests that mutations in PALB2 result in an increased risk of breast cancer over a lifetime, perhaps a bit less than BRCA1 or BRCA2. Patients with strong family histories of breast cancer who test negative for BRCA1 or BRCA2 should consider being screened for PALB2.
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