Michal Sagi

Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations

Background: The risks for cancers other than breast (BC) or ovarian (OC) cancer in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers were elevated in studies of carrier families. However, case–control studies did not confirm this observation. Objective: To compare the risks for other cancers in BRCA1/2 mutation carriers and non-carriers, all affected with BC and/or OC. Both groups share risk modifiers of BC/OC, which enabled assessment of the role of BRCA1/2 mutations. Methods: 1098 Ashkenazi Jewish women affected with BC and/or OC were ascertained during 1995–2003; molecular testing revealed 229 BRCA1 and 100 BRCA2 carriers and 769 non-carriers. COX proportional hazard models were used to evaluate the risk of other cancers. Analyses were conducted including all other cancers or only those diagnosed after BC/OC diagnosis. Results: The HRs for any other cancer were 2.6 (95% CI 1.7 to 4.2, p<0.001) and 1.8 (95% CI 0.95 to 3.6, pu200a=u200a0.07) in BRCA1 and BRCA2 carriers, respectively. The corresponding colon cancer HRs were 3.9 (95% CI 1.3 to 12.1, pu200a=u200a0.02) and 2.3 (95% CI 0.5 to 11.3, pu200a=u200a0.3) in BRCA1 and BRCA2 carriers. The HR for lymphoma was 11.9 (95% CI 3.1 to 46.2, pu200a=u200a0.001) in BRCA2 carriers. Risk estimates for other cancers after the onset of BC/OC were similar. Conclusion: A 2.5-fold increase in any other cancer and a fourfold risk of colon cancer were found among BRCA1 carriers. The corresponding HRs in BRCA2 carriers were non-significant, except for the markedly elevated risk of lymphoma. These results suggest a role for BRCA1/2 mutations in colorectal cancer risk in a subgroup of BC/OC-affected carriers.

Complete remission, in BRCA2 mutation carrier with metastatic pancreatic adenocarcinoma, treated with cisplatin based therapy.

Carriers of a germline mutation in the BRCA genes, in particular BRCA2, have an increased risk of developing pancreatic adenocarcinoma when compared with the general population. While the addition of cisplatin to gemcitabine did not produce survival benefit compared to single-agent gemcitabine in prospective trials it is postulated that the addition of DNA cross-linking agent such as cisplatin to standard gemcitabine chemotherapy should be considered in known BRCA mutation carriers. We report a case of pancreatic adenocarcinoma arising in a 60-year-old carrier of a rare BRCA2 (1153insertionT) germline mutation. The patient received gemcitabine without any response and actually progression of the disease had occurred. Therefore cisplatin was added in combination with gemcitabine. A dramatic complete response to therapy was encountered with no evidence of disease in both CT scans and markers (CA19-9). In conclusion, in patients with known BRCA mutation associated pancreatic adenocarcinoma, the addition of a DNA cross-linking agent such as cisplatin should be considered. Physicians should consider BRCA mutation testing when the diagnosis of pancreatic cancer is established, especially when the patient belongs to an ethnic group where founder mutations exist, and/or there is strong personal or family history of cancer. This may be applied also to other metastatic tumors diagnosed in BRCA1/2 carriers.

The R245X Mutation of PCDH15 in Ashkenazi Jewish Children Diagnosed with Nonsyndromic Hearing Loss Foreshadows Retinitis Pigmentosa

Usher syndrome is a frequent cause of the combination of deafness and blindness due to retinitis pigmentosa (RP). Five genes are known to underlie different forms of Usher syndrome type I (USH1). In the Ashkenazi Jewish population, the R245X mutation of the PCDH15 gene may be the most common cause of USH1 (Ben-Yosef T, Ness SL, Madeo AC, Bar-Lev A, Wolfman JH, Ahmed ZM, Desnick RK, Willner JP, Avraham KB, Ostrer H, Oddoux C, Griffith AJ, Friedman TB N Engl J Med 348: 1664–1670, 2003). To estimate what percentage of Ashkenazi Jewish children born with profound hearing loss will develop RP due to R245X, we examined the prevalence of the R245X PCDH15 mutation and its carrier rate among Ashkenazi Jews in Israel. Among probands diagnosed with nonsyndromic hearing loss not due to mutations of connexin 26 (GJB2) and/or connexin 30 (GJB6), and below the age of 10, 2 of 20 (10%) were homozygous for the R245X mutation. Among older nonsyndromic deaf individuals, no homozygotes were detected, although one individual was heterozygous for R245X. The carrier rate of the R245X mutation among the normal hearing Ashkenazi population in Israel was estimated at 1%. Ashkenazi Jewish children with profound prelingual hearing loss should be evaluated for the R245X PCDH15 mutation and undergo ophthalmologic evaluation to determine whether they will develop RP. Rehabilitation can then begin before loss of vision. Early use of cochlear implants in such cases may rescue these individuals from a dual neurosensory deficit.

Cystic fibrosis mutations delta F508 and G542X in Jewish patients.

We have screened our CF patients for mutations in exons 10 and 11 of the CFTR gene. Two mutations, delta F508 and G542X, have been found in 66 Jewish CF patients. The average frequency of the delta F508 mutation in the Jewish population is 33.8%. The G542X mutation accounts for 13% of the Ashkenazi CF mutations and has been found in three out of seven chromosomes of Jewish patients from Turkey (probably descended from Ashkenazi immigrants). The G542X mutation was not found in any of the other non-Ashkenazi patients. All the G542X bearing chromosomes have the same haplotype. Based on these observations it is concluded that the G542X mutation was introduced into the Jewish people after the split into Ashkenazi and non-Ashkenazi.

Sporadic breast cancer among relatives of BRCA mutation carriers.

To the Editor: The development of breast cancer is a multistep process with many factors contributing to malignant transformation. Even among carriers of BRCA mutations, not all subjects will develop breast cancer,1 and environmental and hormonal factors may determine whether cancer will develop.2– 4 Family members who are not carriers may be exposed to the same environmental factors, which may impact on the development of sporadic cancer as well. Breast cancer associated with a BRCA mutation often develops at a young age and is more often bilateral than sporadic breast cancer.5,6 Sporadic cancer among relatives of BRCA mutation carriers has not been well studied. Relatives of BRCA mutation carriers who are not found to be carriers themselves are generally counseled that their risk of developing breast cancer is no different than that of a woman without a family history of the disease. However, with breast cancer being one of the most common cancers in much of the Western world, the risk of developing breast cancer without carrying a genetic mutation is still substantial. We searched our clinical oncogenetics database of 1061 Ashkenazi Jewish female patients with breast cancer who were tested for all three Ashkenazi BRCA1 and BRCA2 founder mutations (165delAG, 5382insC, and 6174delT). A complete family history was available for all patients, and genetic counseling and testing were routinely recommended for all first-degree relatives of patients found to be carriers. We sought families in November/December 2005 Vol. 7 No. 9 l e t t e r s t o t h e e d i t o r