Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.

Linkage analysis was performed on a large pedigree with an autosomal dominant platelet disorder and a striking propensity in affected family members to develop hematologic malignancy, predominantly acute myelogenous leukemia. We report the linkage of the autosomal dominant platelet disorder to markers on chromosome 21q22. Four genetic markers completely cosegregate with the trait and yield maximum logarithm of difference scores ranging from 4.9 to 10.5 (theta = .001). Two flanking markers, D21S1265 and D21S167, define a critical region for the disease locus of 15.2 centimorgan. Further analysis of this locus may identify a gene product that affects platelet production and function and contributes to the molecular evolution of hematologic malignancy.

No abstract

#1100 BACKGROUND: The use of Direct-to-Consumer Marketing(DTC) for cancer genetic testing may result in more patients seeking genetic counseling and risk assessment who may not otherwise have been referred to a High Risk Clinic. In the Fall of 2007 a DTC marketing campaign was launched in the Eastern United States regarding genetic testing for Hereditary Breast and Ovarian Cancer Susceptibility syndrome (HBOCS). Our objective was to assess the impact this campaign process has had on the type of patient seen in our High-Risk Clinic. METHODS: Patients seen for initial consultation between November of 2007 and April of 2008 were queried regarding exposure to advertisements regarding HBOC gene testing and whether it had been a motivating factor in the referral. Demographic and family history data was collected and pre-test probabilities calculated using the BRCAPRO (v.5) and Myriad models for those citing exposure to advertisement. Categorical data was compared using Fisher's Exact Test for those citing the marketing campaign as a motivating factor versus those who did not. RESULTS: Ninety patients were counseled regarding hereditary breast and ovarian cancer risk and were queried about their exposure to the marketing campaign. Fifty-seven (63.3%) reported exposure to advertisements with 17 (29.8%) citing it as a motivating factor for the referral. The average age of patients was 48 years and differed little between the groups (48.6 vs. 49.2). Those citing marketing influence were slightly more likely to be married (64.7% vs. 60.0%) or have children (82.4% vs.75.0%) P=.73. A personal cancer diagnosis was slightly more common in those influenced by the campaign (47.1% vs. 40.0%) P=.77. Influenced patients more often presented without additional cancer family history then non-influenced patients (18.8% vs. 5%) P=.13. In 44 patients (77.2%) genetic testing was preformed either directly or in a family member with 29.5% of those tested reporting marketing influence. BRCA deleterious mutations were identified in 8 patients (8.9%) with only 2 out of the 6 exposed reporting marketing influence. The average pre-test probability for the influenced and non-influenced groups as calculated by the BRCAPRO and Myriad Models were (8.0% vs. 14.76%) and (10.86% vs. 16.87%), respectively. CONCLUSION: Though not statistically significant, the data revealed interesting outcome trends. Over half of patients seen for consultation reported exposure to DTC marketing for BRCA gene testing. The majority of patients did not cite this as a motivating factor in seeking referral and this group differed little demographically from those who were influenced. The campaign appeared to influence those without cancer family history which resulted in a lower pre-test probability for this group. This trend raises concern that the advertisements may be unnecessarily influencing low-risk women to pursue cancer genetic testing, highlighting the need for continued educational interventions on both the level of the public and community practitioners. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1100.

No abstract

Germline cancer genetic testing is a critical part of patient care influencing cancer risk reduction, prevention and now treatment decision-making. Single syndrome and mutation testing has been available for twenty years, however massively parallel sequencing technology has made multigene panel tests more readily available and at lower costs. Currently, it remains unclear if there is benefit related to panel testing in cancer families and patients already harboring a pathogenic mutation. We report 5 families found to harbor additional pathogenic mutations identified with multigene panel testing. One Ashkenazi family was found to harbor both a founder and non-founder BRCA mutation in a single lineage. Four additional families were found to harbor a second mutation in either a novel breast/ovary cancer gene or in a gene related to an established cancer syndrome. All patients were either initially BRCA2 or PALB2 positive and were subsequently found to have a second mutation in either CHEK2, RAD51D, ATM, MUTYH or PMS2. In 2 cases, the secondary mutation either increased frequency and/or decreased start age of colonoscopy screening. Interestingly, 2 of the additional mutations were first reported as variants of uncertain significance later reclassified as likely pathogenic. In all cases the traditional approach of single site/syndrome analysis for predictive testing would have failed to identify the second pathogenic mutation resulting in an underestimate of cancer risk in negative family members. Notably, the majority of secondary mutations were present within the same lineage as the known familial mutation. In 3 of 5 cases, the finding of a second mutation in already identified mutation carriers led to additional changes in medical management. As multigene panel testing becomes more accessible in both cost and provider acceptance, this case series illustrates the need to strongly consider use of multigene panel testing for relatives undergoing testing for known familial mutations regardless of family history, and ultimately indicating a role for re-testing established mutation carriers. Citation Format: Scalia Wilbur J, Laprise J, Beaston M, Legare RD. Multiple mutations in a single lineage: is it time for a shift in predictive testing? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-16.

INTRODUCTION: As the use of multi-gene breast cancer panel testing increases the phenotype of the included genes continues to evolve. PALB2 and NBN have a well characterized association with breast cancer and are included on many breast cancer gene panels. Germline PALB2 and NBN mutations have been identified in a small percentage of ovarian carcinoma cases with one study reporting a non-significant twofold increase in carriers of the PALB2 mutations amongst ovarian cancer patients (P= 0.4). Similar to BRCA1 and BRCA2 both genes are members of the Fanconi Anemia pathway therefore a potential increased risk for both breast and ovarian cancer could be anticipated. However at present overall the current literature on the association with ovarian cancer is sparse. Here we present the cases of three hereditary breast and ovarian cancer families found to carry pathogenic mutations within the PALB2 and NBN genes. In all three families the proband was diagnosed with ovarian or fallopian tube cancer and carries a pathogenic PALB2 or NBN mutation. Our PALB2 family carries the well-known French Canadian founder mutation, c.2323C>T, and includes the proband who was diagnosed with a stage II-C, grade 3, fallopian tube carcinoma at age 58, her heterozygote sister with ovary cancer at 68 and her mother with ovary cancer at 43 who was not able to be tested. This PALB2 proband has 5 sisters, 7 brothers and 41 nieces and nephews with only one sister diagnosed with breast cancer at 69 who also is PALB2 positive and a maternal grandmother with breast cancer at 48 who was unable to be tested. The NBN Slavic founder mutation, c.657_661del, was discovered in a 66 year old woman with stage IV, high-grade serous ovarian cancer having a mother with breast cancer at 91 and a maternal aunt with ovary cancer at 59 who have not yet been tested. Lastly, our patient from Laos with a diagnosis of a stage II-C endometrioid adenocarcinoma of the ovary diagnosed at 38 years old was found to carry the deleterious NBN mutation, c.1550dupA. She is not aware of any cancer family history and reports a large family including five brothers, four sisters and multiple aunts and uncles on both side of the family. CONCLUSION: These case studies suggest a link between PALB2 and NBN, two known breast cancer susceptibility genes, and hereditary ovarian cancer risk. These observations suggest that further data are needed to accurately evaluate ovarian cancer risk within novel hereditary breast cancer genes now commonly tested as part of multiplex panel analysis. Citation Format: Nassikas N, Wilbur JS, Laprise JK, Legare RD. Novel hereditary breast cancer gene mutations: Should there be greater concern regarding ovarian cancer risk?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-06-03.

Background: Molecular profiling has identified different subtypes of invasive carcinoma. The basal-like tumors represent a subgroup that is known for aggressive behavior. The NCCN guidelines recommend genetic testing for patients with triple negative breast cancer as over 80% of breast cancers in BRCA1 mutation carriers are triple negative tumors, and 70% of those fulfill criteria for basal-like tumors. Ductal carcinoma in-situ (DCIS) is thought to represent a non-obligate precursor to invasive breast cancer. Little is known about basal-like precursor lesions and their association with germline BRCA mutations. The aims of this study were to characterize the immunohistochemical phenotype of BRCA associated DCIS and evaluate the clinical importance of such lesions. Material and Methods: We identified 32 cases of DCIS from 28 women with a known BRCA1/2 mutation, from our genetics database. Tumor samples were reviewed to identify areas of DCIS for staining. Five micron sections were stained on the Dako Autostainer with antibodies to estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptor (EGFR), and CK 5/6. Results: 44% of the DCIS tumors were from BRCA1 mutation carriers and 56% from BRCA2 mutation carriers. 53% of the samples were triple negative (staining negative for ER, PR, HER-2) and 69% of the triple negative tumors were basal-like tumors (staining positive for either EGFR or CK5/6). The basal-like DCIS specimens were all high grade, and they all came from BRCA1 positive patients. 71% of BRCA1 positive DCIS had basal-like features. Conclusions: DCIS in BRCA1 mutation carriers shows basal-like features that are in line with historical control for invasive carcinomas in the same group, suggesting that DCIS is a precursor lesion for BRCA1 positive cancer. Although further investigation is needed, our data suggest that patients with basal-like DCIS should be offered genetic testing. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-18-03.