Family history of cancer predicts endometrial cancer risk independently of Lynch Syndrome: Implications for genetic counselling.

OBJECTIVE: To determine endometrial cancer (EC) risk according to family cancer history, including assessment by degree of relatedness, type of and age at cancer diagnosis of relatives. METHODS: Self-reported family cancer history was available for 1353 EC patients and 628 controls. Logistic regression was used to quantify the association between EC and cancer diagnosis in ≥1 first or second degree relative, and to assess whether level of risk differed by degree of relationship and/or relative's age at diagnosis. Risk was also evaluated for family history of up to three cancers from known familial syndromes (Lynch, Cowden, hereditary breast and ovarian cancer) overall, by histological subtype and, for a subset of 678 patients, by EC tumor mismatch repair (MMR) gene expression. RESULTS: Report of EC in ≥1 first- or second-degree relative was associated with significantly increased risk of EC (P=3.8×10-7), independent of lifestyle risk factors. There was a trend in increasing EC risk with closer relatedness and younger age at EC diagnosis in relatives (PTrend=4.43×10-6), and with increasing numbers of Lynch cancers in relatives (PTrend≤0.0001). EC risk associated with family history did not differ by proband tumor MMR status, or histological subtype. Reported EC in first- or second-degree relatives remained associated with EC risk after conservative correction for potential misreported family history (OR 2.0; 95% CI, 1.24-3.37, P=0.004). CONCLUSION: The strongest predictor of EC risk was closer relatedness and younger EC diagnosis age in ≥1 relative. Associations remained significant irrespective of proband MMR status, and after excluding MMR pathogenic variant carriers, indicating that Lynch syndrome genes do not fully explain familial EC risk.

Are videoconferenced consultations as effective as face-to-face consultations for hereditary breast and ovarian cancer genetic counseling?

PURPOSE: Videoconferencing is increasingly used to deliver family cancer services for hereditary breast and ovarian cancer to outreach areas. This study compared the effectiveness and acceptability of genetic counseling for hereditary breast and ovarian cancer through videoconferencing (hereafter referred to as "telegenetics"). METHODS: One hundred six women seen by telegenetics and 89 women seen face-to-face completed self-administered questionnaires before, and 1 month after, genetic counseling. Telegenetics consultations involved a genetic clinician via telegenetics in addition to a local genetic counselor present with the patient. RESULTS: No significant differences were found between telegenetics and face-to-face genetic counseling in terms of knowledge gained (P = 0.55), satisfaction with the genetic counseling service (P = 0.76), cancer-specific anxiety (P = 0.13), generalized anxiety (P = 0.42), depression (P = 0.96), perceived empathy of the genetic clinician (P = 0.13), and perceived empathy of the genetic counselor (P = 0.12). Telegenetics performed significantly better than face-to-face counseling in meeting patients' expectations (P = 0.009) and promoting perceived personal control (P = 0.031). CONCLUSION: Telegenetics seems to be an acceptable and effective method of delivering genetic counseling services for hereditary breast and ovarian cancer to underserved areas.

Screening behavior in women at increased familial risk for breast cancer.

This multicenter study examined the adherence of high-risk women to screening recommendations for breast and ovarian cancer following consultation at a familial cancer clinic (FCC). Self-report questionnaires assessing recall of screening advice, tests undertaken, risk perception, anxiety (Impact of Events Scale) and demographics were mailed to 396 consecutive eligible women who had attended one of six FCCs a median of 3.6 years prior. Family history, genetic test results and screening recommendations were abstracted from medical records. 182/266 (68.4%) women responded with 130 lost to follow-up. The proportions of women undertaking at least the recommended frequency of screening tests were: breast self examination (BSE) 50.4%, clinical breast examination (CBE) 66.0%, mammography 82.2%, transvaginal ultrasound (TVUS) 70.0%, CA125 84.0%. Factors associated with adherence to screening were: higher anxiety for BSE and CBE, being BRCA1/2 positive for CBE, older age, method of arrangement and having at least one affected first degree relative for mammography. Factors significantly associated with over-adherence were higher scores for anxiety for BSE and CBE and younger age (< 40 years) for TVUS. Between 41.3% (BSE) and 57.6% (CBE) of women incorrectly recalled their screening recommendations. A substantial minority of high-risk women do not adhere to screening advice. Strategies to improve the accuracy of recall of recommendations and the uptake of recommended screening are required.

Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing.

PURPOSE: Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations. PATIENTS AND METHODS: Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS). RESULTS: Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered. CONCLUSION: Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.

How can we best detect hereditary non-polyposis colorectal cancer?

New tumour testing methods can improve the accuracy of diagnosis.

Germ-line mutations in BRCA1 or BRCA2 in the normal breast are associated with altered expression of estrogen-responsive proteins and the predominance of progesterone receptor A.

The breast cancer susceptibility genes BRCA1 and BRCA2 are responsible for a large proportion of familial breast and ovarian cancer, yet little is known of how disruptions in the functions of the proteins these genes encode increased cancer risk preferentially in hormone-dependent tissue. There is no information on whether a germ-line mutation in BRCA1 or BRCA2 causes disruptions in hormone-signaling pathways in the normal breast. In this study markers of hormone responsiveness were measured in prophylactically removed normal breast tissue (n = 31) in women bearing a germ-line pathogenic mutation in one of the BRCA genes. The estrogen receptor (ER) and proteins associated with ER action in hormone-sensitive tissues, namely, PS2 and the progesterone receptor (PR), were detected immunohistochemically. ER expression was not different in BRCA mutation carriers than in noncarriers, but there was a reduction in PS2 expression. PR expression was also reduced, and there was a striking lack of expression of the PRB isoform, which resulted in cases with PRA-only expression in BRCA1 and BRCA2 mutation carriers. The alterations in PS2 and PR expression were similar in the BRCA1 and BRCA2 carriers, demonstrating that although these proteins are structurally and functionally distinct, there is overlap in their interaction with hormone-signaling pathways. This study provides evidence for altered cell function arising from loss of function of one BRCA allele in the normal breast, leading to PS2 loss, preferential PRB loss, and expression of PRA alone. In breast cancer development, PRA overexpression becomes evident in premalignant lesions and is associated with features of poor prognosis in invasive disease and altered cell function in vitro. The results of this study suggest that heterozygosity for a germ-line mutation in BRCA1 or BRCA2 results in development of PRA predominance. This is likely to lead to changes in progesterone signaling in hormone-dependent tissues, which may be a factor in the increased risk of cancer in these tissues in women with germ-line BRCA1 or BRCA2 mutations.