Katherine M. Tucker

Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study

PURPOSE To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population. PATIENTS AND METHODS We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers. RESULTS Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97). CONCLUSION We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.

Psychological impact of genetic testing in women from high-risk breast cancer families

Psychological adjustment in 90 women (30 carriers and 60 non-carriers) who had undergone genetic testing for mutations in BRCA1 and BRCA2 breast/ovarian cancer susceptibility genes was compared with that of 53 women who were not offered genetic testing. Women were assessed prior to genetic testing and 7-10 days, 4 and 12 months after carrier status disclosure using self-administered questionnaires. Compared with women not offered testing, mutation carriers had significantly higher breast cancer distress 7-10 days (t=2.80, P=0.005) and 12 months (t=2.01, P=0.045) post-notification. Non-carriers showed a significant decrease in state anxiety 7-10 days post-notification (t=2.27, P=0.024) and in depression 4 months post-notification (t=2.26, P=0.024), compared with women not offered testing. These data show that non-carriers derive psychological benefits from genetic testing. Women testing positive may anticipate a sustained increase in breast cancer distress following disclosure, although no other adverse psychological outcomes were observed in this group.

Renal Tumors Associated With Germline Sdhb Mutation Show Distinctive Morphology

Germline succinate dehydrogenase B (SDHB) mutation causes pheochromocytoma/paraganglioma syndrome type 4 (PGL4). PGL4 is characterized by pheochromocytoma and paraganglioma, type 2 (SDHB negative) gastrointestinal stromal tumors and renal tumors, which are usually classified as carcinoma. We report 4 kindreds with 5 PGL4-associated renal tumors. Four of the tumors occurred before the age of 30 years, 4 were in the left kidney, 3 were in female patients, and 4 demonstrated consistent but previously unrecognized morphology. The tumors were composed of cuboidal cells with bubbly eosinophilic cytoplasm and indistinct cell borders. Many of the cells displayed distinctive cytoplasmic inclusions, which were vacuolated or contained eosinophilic fluid-like material. The cells were arranged in solid nests or in tubules surrounding central spaces. The tumors were well circumscribed or lobulated and frequently showed cystic change. Benign tubules or glomeruli were often entrapped at the edges of the tumors. The fifth tumor lacked these features but displayed sarcomatoid dedifferentiation. Immunohistochemistry for SDHB was completely negative in all 4 available tumors. Death from metastatic disease occurred in the patient with dedifferentiated tumor 1 year after diagnosis, whereas the other 4 tumors were cured by local excision alone (mean follow-up, 11 y; range, 2 to 30 y). We conclude that morphology supported by negative immunohistochemistry for SDHB can be used to identify kindreds with germline SDHB mutations (PGL4 syndrome) presenting with this unique type of renal tumor. These renal tumors appear to have a good prognosis after complete excision unless there is sarcomatoid dedifferentiation.

Somatic mutations of KIT in familial testicular germ cell tumours

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.

Risks of Colorectal and Other Cancers After Endometrial Cancer for Women With Lynch Syndrome

BACKGROUND Lynch syndrome is an autosomal dominantly inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Previous studies have shown that MMR gene mutation carriers are at increased risk of colorectal, endometrial, and several other cancers following an initial diagnosis of colorectal cancer. We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations. METHODS We obtained data from the Colon Cancer Family Registry for a cohort of 127 women who had a diagnosis of endometrial cancer and who carried a mutation in one of four MMR genes (30 carried a mutation in MLH1, 72 in MSH2, 22 in MSH6, and 3 in PMS2). We used the Kaplan-Meier method to estimate 10- and 20-year cumulative risks for each cancer. We estimated the age-, country-, and calendar period-specific standardized incidence ratios (SIRs) for each cancer, compared with the general population. RESULTS Following endometrial cancer, women carrying MMR gene mutations had the following 20-year risks of other cancer cancers: colorectal cancer (48%, 95% confidence interval [CI] = 35% to 62%); cancer of the kidney, renal pelvis, or ureter (11%, 95% CI = 3% to 20%); urinary bladder cancer (9%, 95% CI = 2% to 17%); and breast cancer (11%, 95% CI = 4% to 19%). Compared with the general population, these women were at statistically significantly elevated risks of colorectal cancer (SIR = 39.9, 95% CI = 27.2 to 58.3), cancer of the kidney, renal pelvis, or ureter (SIR = 28.3, 95% CI = 11.9 to 48.6), urinary bladder cancer (SIR = 24.3, 95% CI = 8.56 to 42.9), and breast cancer (SIR = 2.51, 95% CI = 1.17 to 4.14). CONCLUSIONS Women with Lynch syndrome who are diagnosed with endometrial cancer have increased risks of several cancers, including breast cancer.

Renal Tumors and Hereditary Pheochromocytoma-Paraganglioma Syndrome Type 4

This letter indicates that immunohistochemical analysis to detect succinic dehydrogenase subunit B (SDHB) protein can screen renal tumors for underlying SDHB germline mutations at a fraction of the time and cost of formal genetic testing.

Psychological impact of prophylactic oophorectomy in women at increased risk for ovarian cancer

Women with a family history consistent with a hereditary breast/ovarian cancer syndrome are at significantly increased risk for ovarian cancer. Prophylactic oophorectomy is an option for high‐risk women. This study explores the psychosexual impact of prophylactic oophorectomy. A qualitative methodology was selected as most appropriate as no previous research has examined this issue. In‐depth interviews were conducted with fourteen women, between 4 months and 7 years after prophylactic oophorectomy. Of these, six were pre‐ and eight were postmenopausal at the time of oophorectomy. Even though individual differences were observed, a majority view was expressed on several issues. All but one participant reported being satisfied with their decision to undergo oophorectomy. Women emphasised that the procedure had decreased their anxiety about developing ovarian cancer. Postmenopausal women reported no negative impact on their libido. Amongst premenopausal women all but one commenced hormone replacement therapy (HRT) following surgery and, in these women, HRT appeared to mitigate the sexual impact of the procedure. Premenopausal women reported unmet information needs both before and after the procedure, including the effects of surgical menopause and the link between HRT and breast cancer. This exploratory study suggests that prophylactic oophorectomy is a psychologically acceptable risk reduction strategy in high‐risk women. Copyright

Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer

We studied 2332 individuals with monoallelic mutations in MUTYH among 9504 relatives of 264 colorectal cancer (CRC) cases with a MUTYH mutation. We estimated CRC risks through 70 years of age of 7.2% for male carriers of monoallelic mutations (95% confidence interval [CI], 4.6%-11.3%) and 5.6% for female carriers of monoallelic mutations (95% CI, 3.6%-8.8%), irrespective of family history. For monoallelic MUTYH mutation carriers with a first-degree relative with CRC diagnosed by 50 years of age who does not have the MUTYH mutation, risks of CRC were 12.5% for men (95% CI, 8.6%-17.7%) and 10% for women (95% CI, 6.7%-14.4%). Risks of CRC for carriers of monoallelic mutations in MUTYH with a first-degree relative with CRC are sufficiently high to warrant more intensive screening than for the general population.

Attitudes to Prophylactic Surgery and Chemoprevention in Australian Women at Increased Risk for Breast Cancer

BACKGROUND Because of the uncertain efficacy of breast cancer screening in women at increased risk of developing breast cancer, bilateral prophylactic oophorectomy and mastectomy are considered management options for high-risk women. Data on the attitudes to prophylactic strategies of high-risk women who have not attended specialist clinics are needed to ascertain the need for patient education and provide the basis for planning of support services. METHODS Three hundred seventy-one women unaffected by cancer and with unknown mutation status from families with a dominantly inherited susceptibility to breast cancer, recruited through a large Australian population-based, epidemiological study, were assessed using a mailed self-administered questionnaire with validated measures of psychological outcome. RESULTS Sixteen percent of women reported considering prophylactic mastectomy, and 1% had already had the procedure. Among women with a family history of breast/ovarian cancer, 33% had considered and 5% had already had a prophylactic oophorectomy. Twenty-three percent of women reported considering taking tamoxifen if it were shown to prevent breast cancer. Consideration of prophylactic oophorectomy (OR = 1.51 for a 10% change in perceived risk, 95% CI 1.14-1.99, p = 0.0045) and tamoxifen (OR = 1.14 for a 10% change in perceived risk, 95% CI 1.002-1.30, p = 0.047) were positively associated with perceived cancer risk. CONCLUSIONS Attitudes to prophylactic surgery and psychological distress levels in high-risk women participating in an epidemiological study appear to be comparable to those of women attending familial cancer clinics and indicate that women attending high-risk clinics may be representative of the larger population of women at increased risk.

Psychological adjustment of women at increased risk of developing hereditary breast cancer

This study aims to describe psychological adjustment in a sample of Australian women at increased risk for hereditary breast cancer and to assess the sociodemographic, personality and appraisal factors which contribute to psychological distress. Psychological adjustment of 355 unaffected women at increased risk of developing hereditary breast cancer who approached familial cancer clinics for advice about their breast cancer risk was assessed in a cross-sectional design, using validated measures of psychological distress. Eight per cent of women showed presence of a significant stress response in relation to being at risk of developing breast cancer. In multiple regression, state anxiety and breast cancer anxiety were both highly correlated with overestimating ones breast cancer risk and having experienced a breast cancer-related event in the family in the past year. State anxiety was strongly associated with a tendency to monitor for threatening information ( t = 3.41, p = 0.001), and breast cancer anxiety was correlated with having had a relative die from breast cancer ( t = 1.49, p = 0.006). Results suggest that women who have experienced a recent breast cancerrelated event in the family and those who have exaggerated risk perceptions are most likely to have high levels of psychological distress. Thus women are likely to benefit from supportive counselling and attempts at correcting inflated risk perceptions. A small group of women was identified who showed a significant stress response to being at risk of developing breast cancer. For these women clear pathways of referral for psychological or psychiatric assistance need to be accessible.