Publications by authors named "Henry T Lynch"

271 Publications

Variation in cancer risk among families with genetic susceptibility.

Genet Epidemiol 2021 03 8;45(2):209-221. Epub 2020 Oct 8.

Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Germline mutations in many genes have been shown to increase the risk of developing cancer. This risk can vary across families who carry mutations in the same gene due to differences in the specific variants, gene-gene interactions, other susceptibility mutations, environmental factors, and behavioral factors. We develop an analytic tool to explore this heterogeneity using family history data. We propose to evaluate the ratio between the number of observed cancer cases in a family and the number of expected cases under a model where risk is assumed to be the same across families. We perform this analysis for both carriers and noncarriers in each family, using carrier probabilities when carrier statuses are unknown, and visualize the results. We first illustrate the approach in simulated data and then apply it to data on colorectal cancer risk in families carrying mutations in Lynch syndrome genes from Creighton University's Hereditary Cancer Center. We show that colorectal cancer risk in carriers can vary widely across families, and that this variation is not matched by a corresponding variation in the noncarriers from the same families. This suggests that the sources of variation in these families are to be found predominantly in variants harbored in the mutated MMR genes considered, or in variants interacting with them.
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http://dx.doi.org/10.1002/gepi.22366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902332PMC
March 2021

Preferences for breast cancer prevention among women with a or mutation.

Hered Cancer Clin Pract 2020 29;18:20. Epub 2020 Sep 29.

AbbVie Inc, Dublin, Ireland.

Background: Women with a or mutation have high lifetime risks of developing breast and ovarian cancer. The decision to embark on risk reduction strategies is a difficult and personal one. We surveyed an international group of women with mutations and measured choices and sequence of breast cancer risk reduction strategies.

Methods: Women with a mutation and no previous cancer diagnosis were recruited from the US, Canada, the UK, Australia, and from a national advocacy group. Using an online survey, we asked about cancer-risk reduction preferences including for one of two hypothetical medicines, randomly assigned, and women's recommendations for a hypothetical woman (Susan, either a 25- or 36-year-old). Sunburst diagrams were generated to illustrate hierarchy of choices.

Results: Among 598 respondents, mean age was 40.9 years (range 25-55 years). Timing of the survey was 4.8 years (mean) after learning their positive test result and 33% had risk-reducing bilateral salpingo-oophorectomy (RRBSO) and bilateral mastectomy (RRBM), while 19% had RRBSO only and 16% had RRBM only. Although 30% said they would take a hypothetical medicine, 6% reported taking a medicine resembling tamoxifen. Respondents were 1.5 times more likely to select a hypothetical medicine for risk reduction when Susan was 25 than when Susan was 36. Women assigned to 36-year-old Susan were more likely to choose a medicine if they had a family member diagnosed with breast cancer and personal experience taking tamoxifen.

Conclusions: Women revealed a willingness to undergo surgeries to achieve largest reduction in breast cancer risk, although this would not be recommended for a younger woman in her 20s. The goal of achieving the highest degree of cancer risk reduction is the primary driver for women with or mutations in selecting an intervention and a sequence of interventions, regardless of whether it is non-surgical or surgical.
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http://dx.doi.org/10.1186/s13053-020-00152-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526374PMC
September 2020

Predictors of long-term cancer-related distress among female BRCA1 and BRCA2 mutation carriers without a cancer diagnosis: an international analysis.

Br J Cancer 2020 07 12;123(2):268-274. Epub 2020 May 12.

Center for Observational Research, Amgen Inc., South San Francisco, CA, USA.

Background: Women with a BRCA1 or BRCA2 mutation have high lifetime risks of developing breast and ovarian cancers. We sought to estimate the prevalence of cancer-related distress and to identify predictors of distress in an international sample of unaffected women with a BRCA mutation.

Methods: Women with a BRCA1/2 mutation and no previous cancer diagnosis were recruited from the United States, Canada, the United Kingdom, Australia and from a national advocacy group. Using an online survey, we asked about cancer risk reduction options and screening, and we measured cancer-related distress using the Impact of Event Scale.

Results: Among 576 respondents, mean age was 40.8 years (SD = 8.1). On average 4.9 years after a positive test result, 16.3% of women reported moderate-to-severe cancer-related distress. Women who had undergone risk-reducing breast and ovarian surgery were less likely to have (moderate or severe) cancer-related distress compared to other women (22.0% versus 11.4%, P value = 0.007). Women recruited from the advocacy group were more likely to have cancer-related distress than other women (21.6% versus 5.3%, P value = 0.002).

Conclusions: Approximately 16% of women with a BRCA1 or BRCA2 mutation experience distress levels comparable to those of women after a cancer diagnosis. Distress was lower for women who had risk-reducing surgery.
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http://dx.doi.org/10.1038/s41416-020-0861-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374749PMC
July 2020

Does preventive oophorectomy increase the risk of depression in BRCA mutation carriers?

Menopause 2020 02;27(2):156-161

Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.

Objective: BRCA mutation carriers are advised to undergo bilateral salpingo-oophorectomy to prevent ovarian cancer. The abrupt hormonal withdrawal associated with early surgical menopause has been shown to increase the risk of depression and anxiety among women in the general population. The impact in women with a BRCA1 or BRCA2 mutation is not known.

Methods: We undertook a matched prospective study of BRCA mutation carriers to evaluate the impact of oophorectomy on self-reported initiation of antidepressant use. We identified women with no personal history of cancer or depression and prospectively evaluated the frequency of self-reported medication use after surgery. Each exposed participant (oophorectomy) was randomly matched to a control participant (no oophorectomy) according to year of birth (within 3 years), BRCA mutation type (BRCA1 or BRCA2), and country of residence (Canada, United States, Poland). A total of 506 matched sets were included. We estimated the odds ratio (OR) and 95% confidence intervals (CIs) of antidepressant use (ever/never) following preventive oophorectomy in the entire study population and stratified by age at oophorectomy and by use of hormone therapy.

Results: Oophorectomy was not associated with more frequent antidepressant use among BRCA mutation carriers (OR = 0.46; 95% CI 0.22-0.96). We observed reductions in the odds of antidepressant medication use among women who underwent oophorectomy before the age of 50 years (OR = 0.33; 95% CI 0.14-0.78) and among those who initiated hormone therapy use after oophorectomy (OR = 0.35; 95% CI 0.14-0.90). Findings were similar when the analysis was based on self-reported depression (rather than antidepressant use).

Conclusions: Although based on a small number of women, these findings suggest that oophorectomy does not increase psychological distress among women at an elevated risk of ovarian cancer.
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http://dx.doi.org/10.1097/GME.0000000000001437DOI Listing
February 2020

Methylated plasma test for colorectal cancer detection may be applicable to Lynch syndrome.

BMJ Open Gastroenterol 2019 28;6(1):e000299. Epub 2019 May 28.

Hereditary Cancer Center, Creighton University, Omaha, Nebraska, USA.

Objective: The plasma-based methylated (mSEPT9) is a colorectal cancer (CRC) screening test for adults aged 50-75 years who are at average risk for CRC and have refused colonoscopy or faecal-based screening tests. The applicability of mSEPT9 for high-risk persons with Lynch syndrome (LS), the most common hereditary CRC condition, has not been assessed. This study sought preliminary evidence for the utility of mSEPT9 for CRC detection in LS.

Design: Firstly, SEPT9 methylation was measured in LS-associated CRC, advanced adenoma, and subject-matched normal colorectal mucosa tissues by pyrosequencing. Secondly, to detect mSEPT9 as circulating tumor DNA, the plasma-based mSEPT9 test was retrospectively evaluated in LS subjects using the Epi proColon 2.0 CE assay adapted for 1mL plasma using the "1/1 algorithm". LS case groups included 20 peri-surgical cases with acolonoscopy-based diagnosis of CRC (stages I-IV), 13 post-surgical metastatic CRC, and 17 pre-diagnosis cases. The control group comprised 31 cancer-free LS subjects.

Results: Differential hypermethylation was found in 97.3% (36/37) of primary CRC and 90.0% (18/20) of advanced adenomas, showing LS-associated neoplasia frequently produce the mSEPT9 biomarker. Sensitivity of plasma mSEPT9 to detect CRC was 70.0% (95% CI, 48%-88%)in cases with a colonoscopy-based CRC diagnosis and 92.3% (95% CI, 64%-100%) inpost-surgical metastatic cases. In pre-diagnosis cases, plasma mSEPT9 was detected within two months prior to colonoscopy-based CRC diagnosis in 3/5 cases. Specificity in controls was 100% (95% CI 89%-100%).

Conclusion: These preliminary findings suggest mSEPT9 may demonstrate similar diagnostic performance characteristics in LS as in the average-risk population, warranting a well-powered prospective case-control study.
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http://dx.doi.org/10.1136/bmjgast-2019-000299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6577308PMC
May 2019

The benefits of a model of interval comprehensive assessments (MICA) in hereditary cancer Syndromes: Hereditary diffuse gastric cancer (HDGC) as an example.

Cancer Genet 2019 04 25;233-234:43-47. Epub 2019 Mar 25.

Creighton University, Internal Medicine Department, 7500 Mercy Road, Omaha, NE 68124, United States. Electronic address:

A high percentage of individuals at risk for hereditary cancer syndromes are unaware of their risk. This is especially detrimental in syndromes such as hereditary diffuse gastric cancer due to a CDH1 germline mutation, for which lifesaving prevention is possible. Surveillance for diffuse gastric cancer in the syndrome is limited, hence the recommendation for prophylactic total gastrectomy for mutation carriers. Genetic counseling and testing is crucial in suspected families but initial contact could be limited, leading to the importance of an interval comprehensive review every 5-8 years to identify and screen additional high-risk individuals. Our contact with a hereditary diffuse gastric cancer family in Jordan in 2011 led to a number of family members receiving education and genetic counseling. Our model of interval comprehensive assessment (MICA) was constructed and implemented by conducting family information service, video call and emails to the high-risk individuals 7 years after initial contact. Using an updated family pedigree we reached out to an additional thirteen high-risk members in six different countries and provided them with genetic education, counseling, and testing. Six members agreed to CDH1 testing (46%). Four tested positive (66%) and one member (25%) underwent prophylactic total gastrectomy.
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http://dx.doi.org/10.1016/j.cancergen.2019.03.005DOI Listing
April 2019

International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation.

Br J Cancer 2019 07 11;121(1):15-21. Epub 2019 Apr 11.

Women's College Research Institute, Toronto, ON, Canada.

Background: Women with a BRCA1 or BRCA2 mutation face high risks of breast and ovarian cancer. In the current study, we report on uptake of cancer screening and risk-reduction options in a cohort of BRCA mutation carriers from ten countries over two time periods (1995 to 2008 and 2009 to 2017).

Methods: Eligible subjects were identified from an international database of female BRCA mutation carriers and included women from 59 centres from ten countries. Subjects completed a questionnaire at the time of genetic testing, which included past use of cancer prevention options and screening tests. Biennial follow-up questionnaires were administered.

Results: Six-thousand two-hundred and twenty-three women were followed for a mean of 7.5 years. The mean age at last follow-up was 52.1 years (27-96 years) and 42.3% of the women had a prior diagnosis of breast cancer. In all, 27.8% had a prophylactic bilateral mastectomy and  64.7% had a BSO. Screening with breast MRI increased from 70% before 2009 to 81% at or after 2009. There were significant differences in uptake of all options by country.

Conclusion: For women who received genetic testing more recently, uptake of prophylactic mastectomy and breast MRI is significantly higher than those who received genetic testing more than 10 years ago. However, uptake of both BSO and breast MRI is not optimal, and interventions to increase uptake are needed.
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http://dx.doi.org/10.1038/s41416-019-0446-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738089PMC
July 2019

Analysis of the Gene in FAMMM Syndrome Families Reveals Early Age of Onset for Additional Syndromic Cancers.

Cancer Res 2019 06 9;79(11):2992-3000. Epub 2019 Apr 9.

Hereditary Cancer Center, Creighton University, Omaha, Nebraska.

Familial atypical multiple mole melanoma (FAMMM) syndrome is a hereditary cancer syndrome that results from mutations in several genes, including the gene. In addition to melanoma, certain other malignancies such as pancreatic cancer are known to occur more frequently in family members who carry the mutation. However, as these families have been followed over time, additional cancers have been observed in both carriers and noncarriers. We sought to determine whether these additional cancers occur at higher frequencies in carriers than noncarriers. We performed survival analyses using 10 FAMMM syndrome families ( = 1,085 individuals) as well as a mixed effects Cox regression, with age at last visit to the clinic or age at cancer diagnosis as our time variable. This analysis was done separately for the known FAMMM-related cancers and "other" cancer groups. The survival curves showed a significant age effect with carriers having a younger age at cancer onset than noncarriers for FAMMM-related cancers (as expected) as well as for newly associated cancers. The Cox regression reflected what was seen in the survival curves, with all models being highly significant ( = 7.15E-20 and = 5.00E-13 for the FAMMM-related and other cancers, respectively). These analyses support the hypothesis that mutation carriers in FAMMM syndrome families have increased risk for early onset of several cancer types beyond the known cancers. Therefore, these individuals should be screened for additional cancers, and mutation screening should be extended to more than first-degree relatives of an index carrier patient. SIGNIFICANCE: This study shows that carriers of mutations in the gene in FAMMM syndrome are at increased risk for early onset of several cancer types beyond the known cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1580DOI Listing
June 2019

Oophorectomy and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers.

Breast Cancer Res Treat 2019 Jun 12;175(2):443-449. Epub 2019 Feb 12.

Women's College Research Institute, Women's College Hospital, 76 Grenville St., 6th Floor, Toronto, ON, M5S 1B2, Canada.

Purpose: Following a diagnosis of breast cancer, BRCA mutation carriers face an increased risk of developing a second (contralateral) cancer in the unaffected breast. It is important to identify predictors of contralateral cancer in order to make informed decisions about bilateral mastectomy. The impact of bilateral salpingo-oophorectomy (i.e., oophorectomy) on the risk of developing contralateral breast cancer is unclear. Thus, we conducted a prospective study of the relationship between oophorectomy and the risk of contralateral breast cancer in 1781 BRCA1 and 503 BRCA2 mutation carriers with breast cancer.

Methods: Women were followed from the date of diagnosis of their first breast cancer until the date of diagnosis of a contralateral breast cancer, bilateral mastectomy, date of death, or date of last follow-up. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of contralateral breast cancer associated with oophorectomy. Oophorectomy was included as a time-dependent covariate. We performed a left-censored analysis for those women who reported a primary breast cancer prior to study entry (i.e., from completion of baseline questionnaire).

Results: After an average of 9.8 years of follow-up, there were 179 (7.8%) contralateral breast cancers diagnosed. Oophorectomy was not associated with the risk of developing a second breast cancer (HR 0.92; 95% CI 0.68-1.25). The relationship did not vary by BRCA mutation type or by age at diagnosis of the first breast cancer. There was some evidence for a decreased risk of contralateral breast cancer among women with an ER-positive primary breast cancer, but this was based on a small number of events (n = 240).

Conclusion: Overall, our findings suggest that oophorectomy has little impact on the risk of contralateral breast cancer.
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http://dx.doi.org/10.1007/s10549-019-05162-7DOI Listing
June 2019

Oestrogen receptor status and survival in women with BRCA2-associated breast cancer.

Br J Cancer 2019 02 6;120(4):398-403. Epub 2019 Feb 6.

Women's College Research Institute, Toronto, ON, Canada.

Background: To evaluate the predictors of mortality, including ER status, in women with a BRCA2 mutation and breast cancer.

Methods: Eligible participants were identified from within two longitudinal cohorts. These patients were selected because they were diagnosed with breast cancer between 1975 and 2015 and carried a BRCA2 mutation. Data were abstracted from the medical record and pathology report. We analysed the effects of ER status and other variables on breast cancer specific survival using a Cox proportional hazards model.

Results: Three hundred ninety women with breast cancer and a BRCA2 mutation were included in the analysis. The mean follow-up time was 12.3 years (range 1-39 years) and 89 subjects died (22.8%). In the multivariate analysis, women with ER-positive tumours were more likely to die than women with ER-negative tumours (HR 2.08, 95% CI 0.99-4.36, p = 0.05), and this was of borderline significance. For the 233 women with ER-positive tumours the 20-year survival rate was 62.2%, compared to 83.7% for 58 women with ER-negative tumours (p = 0.03).

Conclusions: The majority of women with a BRCA2 mutation present with ER-positive breast cancer, and for these women, prognosis may be worse than for BRCA2 carriers with ER-negative breast cancer.
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http://dx.doi.org/10.1038/s41416-019-0376-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462020PMC
February 2019

Age-specific ovarian cancer risks among women with a BRCA1 or BRCA2 mutation.

Gynecol Oncol 2018 07 21;150(1):85-91. Epub 2018 May 21.

Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. Electronic address:

Objectives: For women at high risk of developing ovarian cancer, it is important to provide an accurate recommendation for the optimal age for preventive surgery in order to maximize the preventative effect while delaying symptoms associated with early surgical menopause. The goal of the current study was to estimate age-specific incidence rates of ovarian cancer among women with a BRCA1 or BRCA2 mutation.

Methods: From our international registry, we identified 5689 women with no previous diagnosis of ovarian or fallopian tube cancer or preventive oophorectomy. Women were followed from the date of completion of the baseline questionnaire until either a diagnosis of ovarian or fallopian tube cancer, prophylactic oophorectomy, death or last follow-up. The annual and cumulative incidence rates of ovarian cancer were estimated.

Results: Over a mean follow-up period of 4.7 years (ranges 0-22.6), 195 incident ovarian or fallopian tube cancers were diagnosed (169 [86%] ovarian cancers, 22 [11%] fallopian tube cancers and four [2%] cancers that involved both the ovaries and fallopian tubes). Of these, 45 (23%) cancers were diagnosed at preventive surgery (occult cancers). The cumulative risk of ovarian cancer to age 80 was 49% for BRCA1 and 21% for BRCA2 mutation carriers. The mean age at diagnosis was 51.3 years (ranges 33-84) among women with a BRCA1 mutation and 61.4 years (ranges 44-80) among women with a BRCA2 mutation.

Conclusion: Based on a cumulative risk of 0.55% to age 35 for BRCA1 mutation carriers and of 0.56% to age 45 for BRCA2 mutation carriers, we recommend bilateral salpingo-oophorectomy before age 40, but ideally by age 35, for women with a BRCA1 mutation and by age 45 for those with a BRCA2 mutation to maximize prevention and to minimize adverse effects.
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http://dx.doi.org/10.1016/j.ygyno.2018.05.011DOI Listing
July 2018

Age at first full-term birth and breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Breast Cancer Res Treat 2018 Sep 17;171(2):421-426. Epub 2018 May 17.

Women's College Research Institute, Women's College Hospital, 76 Grenville St., 6th Floor, Toronto, ON, M5S 1B2, Canada.

Purpose: In the general population, an early age at first full-term birth confers protection against the risk of developing breast cancer. The relationship between age at first birth and breast cancer risk is not clear for women with a mutation in the BRCA1 or BRCA2 gene. Thus, we undertook a case-control study of women with a BRCA1 or BRCA2 mutation to study the effects of age at first full-term birth matched for other reproductive factors.

Methods: Information about reproductive factors, including age at first birth as well as medical history, was collected from a routinely administered research questionnaire. There were 2,295 matched pairs of women with a BRCA1 or BRCA2 mutation included in the final analysis.

Results: There was no significant difference in the mean age at first full-term birth among the BRCA1 (24.9 vs. 25.2; P = 0.10) or BRCA2 mutation carriers (26.5 vs. 26.6 years; P = 0.80). Findings were similar in the analysis limited to cases who were diagnosed with breast cancer prior to age 45.

Conclusion: This matched analysis of a large number of BRCA mutation carriers suggests that age at first birth has little influence on BRCA1 or BRCA2 breast cancer risk.
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http://dx.doi.org/10.1007/s10549-018-4822-yDOI Listing
September 2018

Hormone Replacement Therapy After Oophorectomy and Breast Cancer Risk Among BRCA1 Mutation Carriers.

JAMA Oncol 2018 08;4(8):1059-1065

Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.

Importance: Prophylactic bilateral salpingo-oophorectomy is recommended for BRCA1 mutation carriers to prevent ovarian cancer. Whether or not hormone replacement therapy (HRT) initiated after oophorectomy is associated with an increased risk of breast cancer has not been evaluated in a prospective study.

Objective: To determine the association between HRT use and BRCA1-associated breast cancer.

Design, Setting, And Participants: A prospective, longitudinal cohort study of BRCA1 and BRCA2 mutation carriers from 80 participating centers in 17 countries was conducted between 1995 and 2017 with a mean follow-up of 7.6 years. Participants had sought genetic testing for a BRCA1 or BRCA2 mutation because of a personal or family history of breast and/or ovarian cancer. Carriers of BRCA1 mutation with no personal medical history of cancer who underwent bilateral oophorectomy following enrollment were eligible for the cohort study.

Exposures: A follow-up questionnaire was administered every 2 years to obtain detailed information on HRT use. A left-truncated Cox proportional hazard analysis was used to estimate the hazard ratios (HRs) and 95% CIs associated with the initiation of HRT use postoophorectomy.

Main Outcomes And Measures: Incident breast cancer.

Results: A total of 872 BRCA1 mutation carriers with a mean postoophorectomy follow-up period of 7.6 years (range, 0.4-22.1) were included in this study. Mean (SD) age of participants was 43.4 (8.5) years. Among these, 92 (10.6%) incident breast cancers were diagnosed. Overall, HRT use after oophorectomy was not associated with an increased risk of breast cancer. The HR was 0.97 (95% CI, 0.62-1.52; P = .89) for ever use of any type of HRT vs no use; however, the effects of estrogen alone and combination hormonal therapy were different. After 10 years of follow-up, the cumulative incidence of breast cancer among women who used estrogen-alone HRT was 12% compared with 22% among women who used estrogen plus progesterone HRT (absolute difference, 10%; log rank P = .04).

Conclusions And Relevance: These findings suggest that use of estrogen after oophorectomy does not increase the risk of breast cancer among women with a BRCA1 mutation and should reassure BRCA1 mutation carriers considering preventive surgery that HRT is safe. The possible adverse effect of progesterone-containing HRT warrants further study.
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http://dx.doi.org/10.1001/jamaoncol.2018.0211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143051PMC
August 2018

Germline Lysine-Specific Demethylase 1 () Mutations Confer Susceptibility to Multiple Myeloma.

Cancer Res 2018 05 20;78(10):2747-2759. Epub 2018 Mar 20.

University of Chicago, Chicago, Illinois.

Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation. KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955848PMC
May 2018

Prospective evaluation of body size and breast cancer risk among BRCA1 and BRCA2 mutation carriers.

Int J Epidemiol 2018 Jun;47(3):987-997

Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.

Background: Although evidence suggests that larger body size in early life confers lifelong protection from developing breast cancer, few studies have investigated the relationship between body size and breast cancer risk among BRCA mutation carriers. Therefore, we conducted a prospective evaluation of body size and the risk of breast cancer among BRCA mutation carriers.

Methods: Current height and body mass index (BMI) at age 18 were determined from baseline questionnaires. Current BMI and weight change since age 18 were calculated from updated biennial follow-up questionnaires. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI).

Results: Among 3734 BRCA mutation carriers, there were 338 incident breast cancers over a mean follow-up of 5.5 years. There was no association between height, current BMI or weight change and breast cancer risk. Women with BMI at age 18 ≥22.1 kg/m2 had a decreased risk of developing post-menopausal breast cancer compared with women with a BMI at age 18 between 18.8 and 20.3 kg/m2 (HR 0.49; 95% CI 0.30-0.82; P = 0.006). BMI at age 18 was not associated with risk of pre-menopausal breast cancer.

Conclusions: There was no observed association between height, current BMI and weight change and risk of breast cancer. The inverse relationship between greater BMI at age 18 and post-menopausal breast cancer further supports a role of early rather than current or adulthood exposures for BRCA-associated breast cancer development. Future studies with longer follow-up and additional measures of adiposity are necessary to confirm these findings.
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http://dx.doi.org/10.1093/ije/dyy039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005062PMC
June 2018

Physical activity during adolescence and young adulthood and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

Breast Cancer Res Treat 2018 Jun 5;169(3):561-571. Epub 2018 Feb 5.

Women's College Research Institute, Women's College Hospital, 76 Grenville St., 6th Floor, Toronto, ON, M5S 1B2, Canada.

Background: Physical activity is inversely associated with the risk of breast cancer among women in the general population. It is not clear whether or not physical activity is associated with the risk of BRCA-associated breast cancer.

Methods: We conducted a case-control study of 443 matched pairs of BRCA mutation carriers to evaluate the association between physical activity and breast cancer risk. Moderate and vigorous physical activities at ages 12-13, ages 14-17, ages 18-22, ages 23-29 and ages 30-34 were determined using the Nurses' Health Study II Physical Activity Questionnaire. We estimated mean metabolic equivalent task hours/week for moderate, vigorous and total physical activities overall (ages 12-34), during adolescence (ages 12-17) and during early adulthood (ages 18-34). Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for total, moderate and strenuous recreational physical activities and breast cancer risk, by menopausal status.

Results: Overall, there was no significant association between total physical activity and subsequent breast cancer risk (OR = 1.01, 95% CI 0.69-1.47; P-trend = 0.72). Moderate physical activity between ages 12-17 was associated with a 38% decreased risk of premenopausal breast cancer (OR = 0.62; 95% CI 0.40-0.96; P-trend = 0.01). We found no association between exercise and breast cancer diagnosed after menopause.

Conclusions: These findings suggest that early-life physical activity is associated with a reduced risk of premenopausal breast cancer among BRCA mutation carriers.

Impact: Future prospective analyses, complemented by mechanistic evidence, are warranted in this high-risk population.
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http://dx.doi.org/10.1007/s10549-018-4694-1DOI Listing
June 2018

The association between smoking and cancer incidence in BRCA1 and BRCA2 mutation carriers.

Int J Cancer 2018 06 25;142(11):2263-2272. Epub 2018 Jan 25.

Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada.

Tobacco smoke is an established carcinogen, but the association between tobacco smoking and cancer risk in BRCA mutation carriers is not clear. The aim of this study was to evaluate prospectively the association between tobacco smoking and cancer incidence in a cohort of BRCA1 and BRCA2 mutation carriers. The study population consisted of unaffected BRCA mutation carriers. Information on lifestyle including smoking histories, reproductive factors, and past medical histories was obtained through questionnaires. Incident cancers were updated biennially via follow-up questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using time-dependent Cox regression models. There were 700 incident cancers diagnosed over 26,711 person-years of follow-up. The most frequent cancers seen in BRCA mutation carriers were breast (n = 428; 61%) and ovarian (n = 109; 15%) cancer. Compared to nonsmokers, (ever) smoking was associated with a modest increased risk of all cancers combined (HR = 1.17; 95%CI 1.01-1.37). Women in the highest group of total pack-years (4.3-9.8) had an increased risk of developing any cancer (HR = 1.27; 95%CI 1.04-1.56), breast cancer (HR = 1.33, 95%CI 1.02-1.75), and ovarian cancer (HR = 1.68; 95%CI 1.06-2.67) compared to never smokers. The associations between tobacco smoking and cancer did not differ by BRCA mutation type or by age at diagnosis. This prospective study suggests that tobacco smoking is associated with a modest increase in the risks of breast and ovarian cancer among women with BRCA1 or BRCA2 mutation.
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http://dx.doi.org/10.1002/ijc.31257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020833PMC
June 2018

Efficacy of proximal colectomy for surgical management of right-sided first colorectal cancer in Lynch Syndrome mutation carriers.

Am J Surg 2018 07 8;216(1):99-105. Epub 2017 Nov 8.

Division of Clinical Research and Evaluative Sciences, Creighton University, School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA.

Background: This study analyzes the occurrence of colorectal cancer (CRC) in Lynch syndrome (LS) mutation carriers, interval until diagnosis of metachronous CRC, and survival after proximal colectomy (PC) compared with total (TC) and subtotal colectomy (STC) for right-sided first CRC in LS mutation carriers.

Methods: Sixty-four LS mutation carriers with right-sided first CRC treated with PC or TC + STC were confirmed by clinical records. Bivariate analyses were examined for significance and life tables were generated for risk of metachronous CRC and survival estimates following surgery.

Results: One of 16 (6.3%) mutation carriers treated with TC + STC developed subsequent CRC compared with 13/48 (27%) treated by PC. There was no significant difference in survival estimates between PC compared with TC + STC through 25 years after surgery.

Conclusion: Risk of subsequent CRC and survival estimates following PC and TC + STC should be considered in surgical management of right-sided first CRC in LS mutation carriers.
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http://dx.doi.org/10.1016/j.amjsurg.2017.11.003DOI Listing
July 2018

Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge.

Fam Cancer 2018 07;17(3):403-414

Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, 333 Cassell Drive, Suite 1200, Baltimore, MD, 21224, USA.

Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. It is caused by germline mutations in the mismatch repair genes. Both its phenotype and genotype show marked heterogeneity. This review gives a historical overview of the syndrome, its heterogeneity, its genomic landscape, and its implications for complex diagnosis, genetic counseling and putative implications for immunotherapy.
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http://dx.doi.org/10.1007/s10689-017-0053-3DOI Listing
July 2018

Curcumin: An age-old anti-inflammatory and anti-neoplastic agent.

J Tradit Complement Med 2017 Jul 9;7(3):339-346. Epub 2016 Sep 9.

Creighton University, Department of Preventive Medicine, Omaha, NE 68178, United States.

Curcumin is a natural anti-inflammatory agent that has been used for treating medical conditions for many years. Several experimental and pharmacologic trials have demonstrated its efficacy in the role as an anti-inflammatory agent. Curcumin has been shown to be effective in treating chronic conditions like rheumatoid arthritis, inflammatory bowel disease, Alzheimer's and common malignancies like colon, stomach, lung, breast, and skin cancers. As treatments in medicine become more and more complex, the answer may be something simpler. This is a review article written with the objective to systematically analyze the wealth of information regarding the medical use of curcumin, the "curry spice", and to understand the existent gaps which have prevented its widespread application in the medical community.
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http://dx.doi.org/10.1016/j.jtcme.2016.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506636PMC
July 2017

Preferences for breast cancer risk reduction among BRCA1/BRCA2 mutation carriers: a discrete-choice experiment.

Breast Cancer Res Treat 2017 Sep 17;165(2):433-444. Epub 2017 Jun 17.

Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.

Purpose: Unaffected women who carry BRCA1 or BRCA2 mutations face difficult choices about reducing their breast cancer risk. Understanding their treatment preferences could help us improve patient counseling and inform drug trials. The objective was to explore preferences for various risk-reducing options among women with germline BRCA1/2 mutations using a discrete-choice experiment survey and to compare expressed preferences with actual behaviors.

Methods: A discrete-choice experiment survey was designed wherein women choose between hypothetical treatments to reduce breast cancer risk. The hypothetical treatments were characterized by the extent of breast cancer risk reduction, treatment duration, impact on fertility, hormone levels, risk of uterine cancer, and ease and mode of administration. Data were analyzed using a random-parameters logit model. Women were also asked to express their preference between surgical and chemoprevention options and to report on their actual risk-reduction actions. Women aged 25-55 years with germline BRCA1/2 mutations who were unaffected with breast or ovarian cancer were recruited through research registries at five clinics and a patient advocacy group.

Results: Between January 2015 and March 2016, 622 women completed the survey. Breast cancer risk reduction was the most important consideration expressed, followed by maintaining fertility. Among the subset of women who wished to have children in future, the ability to maintain fertility was the most important factor, followed by the extent of risk reduction. Many more women said they would take a chemoprevention drug than had actually taken chemoprevention.

Conclusions: Women with BRCA1/2 mutations indicated strong preferences for breast cancer risk reduction and maintaining fertility. The expressed desire to have a safe chemoprevention drug available to them was not met by current chemoprevention options.
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http://dx.doi.org/10.1007/s10549-017-4332-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543193PMC
September 2017

Major hereditary gastrointestinal cancer syndromes: a narrative review.

J Gastrointestin Liver Dis 2017 Jun;26(2):157-163

Creighton University Medical Center, Omaha, NE, USA.

Gastrointestinal cancer is one of the major causes of death worldwide. Hereditary gastrointestinal cancer syndromes constitute about 5-10% of all cancers. About 20-25% of undiagnosed cases have a possible hereditary component, which is not yet established. In the last few decades, the advance in genomics has led to the discovery of multiple cancer predisposition genes in gastrointestinal cancer. Physicians should be aware of these syndromes to identify high-risk patients and offer genetic testing to prevent cancer death. In this review, we describe clinical manifestations, genetic testing and its challenges, diagnosis and management of the major hereditary gastrointestinal cancer syndromes.
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http://dx.doi.org/10.15403/jgld.2014.1121.262.majDOI Listing
June 2017

Commentary on Almassalha et al., "The Greater Genomic Landscape: The Heterogeneous Evolution of Cancer".

Cancer Res 2016 10 16;76(19):5602-5604. Epub 2016 Sep 16.

Department of Dermatology, Keck USC School of Medicine and the Hoag-USC Advanced Skin Cancer Program, Los Angeles, California.

In this issue of Cancer Research, Almassalha and colleagues have proposed a new concept of the development of malignancy, that of the greater genomic landscape. They propose a stressor-related exploration of intracellular genomic sites as a response mechanism. This process can express sites with beneficial or deleterious effects, among them those that promote cell proliferation. They point out that their conception is broader, although certainly inclusive, of the process of gene induction. The authors view the physical process of chromatin reorganization as central to the exploration of the genomic landscape. Accordingly, they advocate the development of agents to limit chromatin structural modification as a chemotherapeutic approach in cancer. We found their theory relevant to understand the phenotypic heterogeneity of malignancy, particularly in familial cancer syndromes. For example, the familial atypical multiple mole melanoma (FAMMM) syndrome, related to a gene mutation, is characterized by a diversity of melanocytic lesions, only some of which become malignant melanoma. This new conceptualization can do much to increase understanding of the diversity of malignancy in families with hereditary cancer. Cancer Res; 76(19); 5602-4. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2319DOI Listing
October 2016

Therapeutic and Preventive Implications of Moonshot in Hereditary Cancer Syndromes.

JAMA Oncol 2017 05;3(5):592-593

Department of Preventive Medicine, Creighton University, Omaha, Nebraska.

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http://dx.doi.org/10.1001/jamaoncol.2016.3046DOI Listing
May 2017

Bilateral Oophorectomy and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

J Natl Cancer Inst 2017 01 6;109(1). Epub 2016 Sep 6.

Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada.

Background: Whether oophorectomy reduces breast cancer risk among BRCA mutation carriers is a matter of debate. We undertook a prospective analysis of bilateral oophorectomy and breast cancer risk in BRCA mutation carriers.

Methods: Subjects had no history of cancer, had both breasts intact, and had information on oophorectomy status (n = 3722). Women were followed until breast cancer diagnosis, prophylactic bilateral mastectomy, or death. A Cox regression model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with oophorectomy (coded as a time-dependent variable). All statistical tests were two-sided.

Results: Over a mean follow-up of 5.6 years, 350 new breast cancers were diagnosed. Among women with a BRCA1 or BRCA2 mutation, oophorectomy was not associated with breast cancer risk compared with women who did not undergo an oophorectomy. The age-adjusted hazard ratio associated with oophorectomy was 0.96 (95% CI = 0.73 to 1.26, P = 76) for BRCA1 and was 0.65 (95% CI = 0.37 to 1.16, P = 14) for BRCA2 mutation carriers. In stratified analyses, the effect of oophorectomy was statistically significant for breast cancer in BRCA2 mutation carriers diagnosed prior to age 50 years (age-adjusted HR = 0.18, 95% CI = 0.05 to 0.63, P = 007). Oophorectomy was not associated with risk of breast cancer prior to age 50 years among BRCA1 mutation carriers (age-adjusted HR = 0.79, 95% CI = 0.55 to 1.13, P = 51).

Conclusions: Findings from this large prospective study support a role of oophorectomy for the prevention of premenopausal breast cancer in BRCA2, but not BRCA1 mutation carriers. These findings warrant further evaluation.
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http://dx.doi.org/10.1093/jnci/djw177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284253PMC
January 2017

Introduction to special issue of Familial Cancer.

Fam Cancer 2016 07;15(3):357-8

, Omaha, NE, USA.

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http://dx.doi.org/10.1007/s10689-016-9909-1DOI Listing
July 2016

Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.

Am J Hum Genet 2016 06 12;98(6):1082-1091. Epub 2016 May 12.

Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins. In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities. Wild-type embryonic ductus arteriosus (DA) exhibited high levels of PRDM6, which rapidly declined postnatally as the number of VSMCs necessary for ductus contraction increased. This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA. Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908195PMC
June 2016

Family Chronicles of Missed Opportunities.

JAMA Oncol 2016 May;2(5):573-574

Department of Preventive Medicine, Creighton's Hereditary Cancer Center, Omaha, Nebraska.

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http://dx.doi.org/10.1001/jamaoncol.2016.0110DOI Listing
May 2016
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