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Annals of Surgical Oncology 14(9):24282429 DOI: 10.1245/s10434-007-9379-7
Editorial
Heterogenic Loss of BRCA in Breast Cancer: The Two-Hit Hypothesis Takes a Hit
Funda Meric-Bernstam, MD
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1400 Holcombe Boulevard, P.O. Box 301402, Houston, Texas 77030, USA
Most hereditary cancers have been linked to mutations in tumor suppressor genes. The rst tumor suppressor to be cloned was the retinoblastoma gene, RB1. Retinoblastoma occurs in both hereditary and nonhereditary forms. In the hereditary form, most children with an affected parent develop bilateral retinoblastoma; however, some develop unilateral retinoblastoma, and others are not affected themselves, but have an affected child. These ndings led to the theory that a single mutation is not sufcient for tumorigenesis. Alfred Knudson hypothesized that hereditary retinoblastoma involves two mutations, one in the germ line, whereas nonhereditary retinoblastoma is due to two somatic mutations, a hypothesis known as Knudsons two-hit hypothesis.1
BRCA1 and BRCA2 are thought to be classical tumor suppressor genes for which the two-hit hypothesis holds true. Individuals who are predis-posed to BRCA-associated hereditary breast and ovarian syndrome carry a particular deleterious germ-line mutation in the BRCA1 or BRCA2 gene in every cell. Then, a second hit is thought to be required in the wild-type BRCA allele for the development of BRCA-associated cancer.
In this issue of Annals of Surgical Oncology, King and colleagues evaluate whether loss of the wild-type allele is indeed obligatory for breast and ovarian cancer progression in BRCA1 and BRCA2 heterozygotes by assessing loss of heterozygosity (LOH) in
14 BRCA1-linked and 12 BRCA2-linked breast cancers, 10 prophylactic mastectomy samples, and 12 BRCA-linked ovarian cancers. The authors compared the LOH found in normal breast...