Research News

Gene mutation may increase risk of breast cancer by up to nine times

BMJ 2014; 349 doi: (Published 11 August 2014) Cite this as: BMJ 2014;349:g5090
  1. Michael McCarthy
  1. 1Seattle

A mutation in a gene that plays a key role in the proper functioning of the so called “breast cancer genes” BRCA1 and BRCA2 increases the risk of developing breast cancer by nine times in younger women and by five times in older women, a new study has found.1

In the study, researchers analysed the risk of breast cancer in women and men from families who had germline loss-of-function mutations in a gene called PALB2 (partner and localiser of BRCA2). Loss-of-function mutations in both alleles of PALB2—which is also known as FANCN—cause Fanconi’s anaemia, and monoallelic loss-of-function mutations have been shown to be associated with an increased risk of breast and pancreatic cancer.

The PALB2 gene codes for a protein that plays a variety of roles, such as permitting BRCA2 to localise in the nucleus and providing a molecular scaffold for the BRCA1-PALB2-BRCA2 complex.

The study appeared in the New England Journal of Medicine. Marc Tischkowitz, an associate professor of medical genetics at the University of Cambridge in the United Kingdom, was the paper’s senior author.

To better estimate the risk of breast cancer due to loss-of-function mutations in PALB2 alone, the researchers identified 362 members of 154 families that had at least one member with a history of breast cancer who had a loss-of-function mutation in PALB2 but had tested negative for deleterious BRCA1 and BRCA2 mutations.

The 154 families, identified from 14 cooperating medical centres, included 311 members with PALB2 mutations, of whom 229 had breast cancer, and 51 men with PALB2 mutations, of whom seven had breast cancer.

A statistical analysis found that the risk of breast cancer for PALB2 mutation carriers increased by a factor of 9.47 (95% confidence interval (7.16 to 12.57)), compared with the general population.

The estimated cumulative risk of breast cancer among female mutation carriers was 14% (9 to 20) by 50 years of age and 35% (26 to 46) by 70 years of age, the researchers reported.

Relative risk was highest among women aged 20 to 24, at 9.01 (5.70 to 14.16), and was lowest in the oldest age group, women aged 75-79, at 4.56 (3.48 to 5.95).

A family history of breast cancer significantly affected risk, suggesting that other genetic or environmental factors that cluster in families can modify the effect of PALB2 mutations. The absolute risk by age 70 was 33% (25 to 44) for female mutation carriers with no family history of breast cancer, but it was 58% (50 to 66) among those with two or more first degree relatives with breast cancer.

“On the basis of our estimates of risk[,] 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,” the researchers concluded.


Cite this as: BMJ 2014;349:g5090


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