Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations.

BACKGROUND: The SDHD gene encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme and tumor suppressor, succinate dehydrogenase. Mutations in this gene show a remarkable pattern of parent-of-origin related tumorigenesis, with almost all SDHD-related cases of head and neck paragangliomas and pheochromocytomas attributable to paternally-transmitted mutations. METHODS: Here we explore the underlying molecular basis of three cases of paraganglioma or pheochromocytoma that came to our attention due to apparent maternal transmission of an SDHD mutation. We used DNA analysis of family members to establish the mode of inheritance of each mutation. Genetic and immunohistochemical studies of available tumors were then carried out to confirm SDHD-related tumorigenesis. RESULTS: We found convincing genetic and immunohistochemical evidence for the maternally-related occurrence of a case of pheochromocytoma, and suggestive evidence in a case of jugular paraganglioma. The third case appears to be a phenocopy, a sporadic paraganglioma in an SDHD mutation carrier with no immunohistochemical or DNA evidence to support a causal link between the mutation and the tumor. Microsatellite analysis in the tumor of patient 1 provided evidence for somatic recombination and loss of the paternal region of chromosome 11 including SDHD and the maternal chromosome including the centromere and the p arm. CONCLUSIONS: Transmission of SDHD mutations via the maternal line can, in rare cases, result in tumorigenesis. Despite this finding, the overwhelming majority of carriers of maternally-transmitted mutations will remain tumor-free throughout life.

Two TP53 germline mutations in a classical Li-Fraumeni syndrome family.

Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited cancer predisposition syndrome characterized by a combination of tumors including sarcoma, breast cancer, brain tumors, adrenocortical carcinoma and leukemia. Germline mutations in the tumor suppressor gene TP53 are associated with LFS. We present a family with LFS in which initially a novel germline TP53 intron 5 splice site mutation was found. A second germline TP53 mutation, the exon 7 Asn235Ser (704A-->G) mutation, was detected in this family through pre-symptomatic DNA testing. This latter mutation has been reported repeatedly in the literature as a pathogenic mutation involved in LFS. We provide evidence for pathogenicity of the novel intron 5 splice site mutation, whereas this evidence is lacking for the exon 7 Asn235Ser (704A-->G) mutation. Our findings emphasize the importance of performing additional tests in case of germline sequence variants with uncertain functional effects.

Long term follow-up of HNPCC gene mutation carriers: compliance with screening and satisfaction with counseling and screening procedures.

Hereditary non polyposis colorectal cancer (HNPCC) is a hereditary predisposition to colorectal and endometrial cancer, caused by mutations of the mismatch repair (MMR) genes MSH2, MLH1 and MSH6. Regular colonoscopy reduces the incidence of colorectal cancer in mutation carriers dramatically. The aim of this study was to evaluate the use of colonoscopy by proven HNPCC mutation carriers. We also evaluated the satisfaction with the counseling and screening procedures at the long term. A questionnaire survey was performed among 94 proven MMR gene mutation carriers. Data were analyzed using univariate and multivariate analysis. The average time of follow-up was 3,5 years (range 0.5-8.5 years). The response rate was 74%. The proportion of unaffected mutation carriers under colonoscopic screening increased from 31 to 88% upon genetic testing, and for gynecological screening from 17 to 69%. However, more than half of the responders experienced colonoscopy as unpleasant or painful. About 97% felt well informed during counseling, and 88% felt sufficiently supported. Ten percent of the responders reported a high cancer worry that was significantly (P = 0.007) associated with a high perceived cancer risk. Six responders (9%) regretted being tested. Remarkably, of 4 of these 6 a close relative died recently of cancer. Problems with obtaining a disability or life insurance or mortgage were experienced by 4 out 10 healthy carriers opting for these services. In conclusion, genetic testing for HNPCC considerably improves compliance for screening, which will result in a reduction of HNPCC-related cancer morbidity and mortality in mutation carriers. Most HNPCC gene mutation carriers cope well with their cancer susceptibility on the long term.

Long-term psychological impact of carrying a BRCA1/2 mutation and prophylactic surgery: a 5-year follow-up study.

PURPOSE: To explore long-term psychosocial consequences of carrying a BRCA1/2 mutation and to identify possible risk factors for long-term psychological distress. PATIENTS AND METHODS: Five years after genetic test disclosure, 65 female participants (23 carriers, 42 noncarriers) of our psychological follow-up study completed a questionnaire and 51 participants were interviewed. We assessed general and hereditary cancer-related distress, risk perception, openness to discuss the test result with relatives, body image and sexual functioning. RESULTS: Carriers did not differ from noncarriers on several distress measures and both groups showed a significant increase in anxiety and depression from 1 to 5 years follow-up. Carriers having undergone prophylactic surgery (21 of 23 carriers) had a less favorable body image than noncarriers and 70% reported changes in the sexual relationship. A major psychological benefit of prophylactic surgery was a reduction in the fear of developing cancer. Predictors of long-term distress were hereditary cancer-related distress at blood sampling, having young children, and having lost a relative to breast/ovarian cancer. Long-term distress was also associated with less open communication about the test result within the family, changes in relationships with relatives, doubting about the validity of the test result, and higher risk perception. CONCLUSION: Our findings support the emerging consensus that genetic predisposition testing for BRCA1/2 does not pose major mental health risks, but our findings also show that the impact of prophylactic surgery on aspects such as body image and sexuality should not be underestimated, and that some women are at risk for high distress, and as a result, need more attentive care.