Genetics

BRCA1 and BRCA2 are both important for DNA repair, in particular homologous recombination, which enables repair of double-stranded DNA breaks. BRCA1 is a large gene, spanning more than 100,000 bases of genomic DNA with 22 coding and two noncoding exons. BRCA2 is also large, consisting of 27 exons across 70 kb of genomic DNA. Both genes, by coincidence, have a large exon 11. An update of reported mutations is accessible through the Internet at http://research.nhgri.nih.gov/bic/.

Most BRCA1 mutations cause premature truncation of the peptide by frameshift or nonsense sequence changes. Large germline rearrangements also occur in BRCA1 and BRCA2.59, 60 Five percent to 10% of BRCA mutations that are missense are problematic because they are of unknown clinical significance. The proportion of these variants that are of unknown significance was as high as 10% to 23% in some series, posing counseling challenges.^61,62 The role of BRCA1 and BRCA2 in DNA damage response and homologous recombination is reviewed elsewhere.⁶³

Founder BRCA mutations have been documented in genetically isolated populations. In North American families, the most common founder mutations occur in persons of Ashkenazi Jewish origin. These mutations include a two-base-pair deletion in codon 23 of BRCA1, termed 185delAG (c.68_69delAG); another BRCA1 mutation, 5382insC (c.5266dupC); and the 6174delT (c.5946delT) mutation in BRCA2.63–66 About 1 in 40 Ashkenazi Jews harbor one of the common BRCA1 or BRCA2 mutations,^55,56,65 a relatively high carrier frequency for an inherited cancer predisposition syndrome. Other mutations in BRCA1 and BRCA2 occur in the Ashkenazim; 16 of 737 Ashkenazi Jews who were tested in a clinic-based ascertainment had a nonfounder mutation (2%).⁴³ In another study of Ashkenazi individuals with a personal history of breast or ovarian cancer who had previously been shown not to have a founder mutation, 3 of 70 (4.3%) had a deleterious nonfounder mutation.⁶⁷ Founder mutations in populations other than the Ashkenazim have also been observed.^70–70

BRCA1-linked tumors are associated with a basal-like subtype and higher mitotic indices.⁷¹ They were of higher grade, were more frequently estrogen and progesterone receptor negative,^72,73 and demonstrated a basal-like phenotype.⁷⁴ They displayed a more “aggressive” phenotype, including a higher proportion of cells in S phase, and other indices.^73,75–78 The prognostic significance of BRCA mutations is still being defined.

Epithelial ovarian carcinoma can be delineated into five distinct histologic subtypes: high-grade serous, clear cell, endometrioid, mucinous, and low-grade serous with differing manifestations, prognoses, molecular profiles, and immunohistochemistry profiles.81–81 The high-grade serous subtype comprises the majority of cases of ovarian cancer.⁸⁰ Mutations in BRCA1 and BRCA2 show a strong association with the high-grade serous carcinoma of ovary/fallopian tube or peritoneal origin, such that germline testing for BRCA1 and BRCA2 together can have up to a 22.6% to 25% percent detection rate in this histologic subtype.^82–85 Furthermore, massively parallel sequencing of 360 subjects with ovarian, fallopian tube, or peritoneal cancer for 21 tumor suppressor genes revealed germline loss-of-function mutations in 24%: 18% in BRCA1 or BRCA2 and, additionally, 6% in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53.²⁸

Clinical Management

Three elements of breast surveillance that are recommended to BRCA heterozygotes are self-examination, clinician examination, and imaging. The evidence base underlying these recommendations has been reviewed,23,86 and updated guidelines are available on the Web.⁸⁷

Increasingly, breast cancer screening including mammography and magnetic resonance imaging (MRI) together have been shown to have greatest sensitivity.⁸⁸ For women who are at the highest hereditary risk for breast cancer, whose breasts are difficult to examine or who have had biopsies showing atypia, it might be appropriate to discuss the option of removing the healthy breasts as a preventive measure (i.e., prophylactic mastectomy). Retrospective studies and reviews document the well-established risk-reducing role of surgery in high-risk patients.^91–91 Prospective and combined consortium studies have also shown the efficacy of this approach.^{34,92, 93}

Because of their antiestrogen properties, tamoxifen, raloxifene, and a newer class of synthetic estrogen receptor modulators emerged as hormonal chemopreventive agents that have been shown to decrease breast cancer rates in persons who are at increased risk.⁹⁴ The safety of these drugs in premenopausal women remains to be established. Two studies on the impact of tamoxifen on subsequent breast cancer risk in BRCA1 and BRCA2 mutation carriers have shown conflicting conclusions,^95,96 although only one of these studies was sufficiently powered to reach significant results. Tamoxifen was confirmed to decrease contralateral breast cancer risk in a follow-up of one of these studies of BRCA mutation carriers.⁹⁷

Small trials have demonstrated the ability of ultrasound with Doppler and CA125 to find early-stage ovarian cancers in BRCA mutation carriers.98,99 However, the efficacy of this approach has not been proven in large, prospective studies. Therefore prophylactic removal of the ovaries and fallopian tubes is recommended to women with strong family histories of ovarian cancer, in families linked to BRCA1 or BRCA2, or to women who are considering hysterectomy in the setting of a germline mutation associated with Lynch syndrome. Studies examining specimens from prophylactic salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers implicate the fimbriated part of the fallopian tube as harboring precursor lesions to high-grade serous epithelial ovarian cancer.^100–103 Thus prophylactic salpingo-oophorectomy is recommended because such surgeries may not only decrease the incidence of subsequent breast and ovarian cancer but also find occult early-stage pelvic neoplasms,^102,104,105 decreasing mortality.¹⁰⁶ These studies have also confirmed that serous surface carcinoma, also called papillary serous carcinoma, can still occur after prophylactic oophorectomy,^107,108 leading most authors to use the term risk-reducing salpingo-oophorectomy.

Combination oral contraceptives that contain estrogen and high-dose progestin result in a time-dependent, protective effect against ovarian cancer in some but not all studies of BRCA mutation carriers.111–111 There remains the concern of a small increased risk of breast cancer due to oral contraceptives in this group, particularly in persons with BRCA1 mutations.¹¹²

Germline BRCA1 and BRCA2 mutation-associated tumors have defective DNA repair mechanisms because of the loss of function of the remaining normal copy of the gene. This inability of the tumor to repair its DNA effectively can be exploited by therapies that disrupt alternative DNA repair pathways, such that the tumor cell accumulates so much DNA damage that it can no longer survive.113,114 Inhibitors of the base excision repair enzyme Poly(adenosine diphosphate-ribose) polymerase utilize this principle of synthetic lethality and are currently in clinical trials.¹¹⁵

These drugs may also have a role in cancers associated with germline mutations in BRCA2, including cancer of the pancreas (relative risk [RR] 4.1, 95% confidence interval [CI] 1.9-7.8), prostate (RR 6.3, 95% CI 4.3-9.0), and uveal melanoma (RR 99.4, 95% CI 11.1-359.8).¹¹⁶

Genetics

The CS-linked PTEN was mapped to 10q22-23.¹²⁴ Bannayan-Riley-Ruvalcaba syndrome, characterized by macrocephaly, intestinal polyps, lipomas, and pigmented penile macules, is also caused by germline mutations in PTEN.¹²⁵

PTEN acts as a tumor suppressor by mediating cell cycle arrest, apoptosis, or both.¹²⁶ Full sequencing and deletion/duplication analysis are available clinically, and promoter analysis is available on a research basis. Heterozygous germline mutations in PTEN cause most cases of CS. Nonsense, missense, and frameshift mutations that are predicted to disrupt normal PTEN function have been identified in some families,¹²⁴ including mutations that disrupt the protein tyrosine/dual-specificity phosphatase domain. Initially it was shown that PTEN mutations can be detected in about 80% of patients with CS.¹²⁵ More recently the mutation detection rate in persons meeting CS criteria was found to be 34%, raising the possibility that current aspects of testing criteria are too broad.¹²⁷

Risk Management Recommendations

Persons with known germline PTEN mutations should undergo appropriate cancer screening.87,128 In view of recent work outlining cancer risks in persons with CS, some investigators have suggested that National Comprehensive Cancer Network management guidelines be modified to include renal cancer screening using biannual renal imaging from age 40 years or 5 years earlier than the earliest kidney cancer diagnosis in the family, and endometrial sampling in adulthood or 5 years earlier than the earliest endometrial cancer diagnosis in the family.¹²³ Female patients with CS should have breast self-examination training and education starting at age 18 years. Beginning at age 25 years, clinical breast examinations should be performed every 6 to 12 months, and annual mammography and MRI screening should start at age 30 years or 5 years before the earliest age of breast cancer diagnosis in the family.¹²³ Men should perform monthly breast self-examination. Female patients should receive endometrial cancer screening beginning around age 30 years or 5 years before the earliest age of endometrial cancer diagnosis in the family.¹²³ Persons with CS should undergo biannual colonoscopy from age 40 years.¹²³ Both men and women should have a comprehensive annual physical examination starting at diagnosis with screening for skin and thyroid lesions, including a baseline and annual thyroid ultrasound and dermatologic examination.¹²³

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