Familial Malignant Hematological Disorders: A Systematic Assessment in 216 Consecutive Patients with Acute Leukaemia.

Abstract Purpose Our objective was to describe the biological characteristics of acute leukemia (AL) patients with or without a familial form of malignant hematological disorders. Population The study population included all newly diagnosed cases of AL treated in the departments of hematology of Institut Paoli-Calmettes between January 2002 and December 2004. We identified 291 eligible patients, of which 216 (74.2%) provided consent to participate in the study and filled a short questionnaire collecting demographic, personal and familial medical data. A face to face interview was arranged for 185 patients (85.7%) and a pedigree compiled for each family and reviewed by 2 familial cancer consultants. Results Among the 185 patients with full data on personal and familial history of cancer, 34 (18.4%) had a strong familial history of cancer of which 16 (8.6%) presented a familial form of malignant hematological disorders (at least another case of hematological malignancy in the 1, 2 or 3 degree relatives). Seven families had at least 2 first degree family members with leukemia and 2 families had 5 relatives (1st, 2nd or 3rd degree) diagnosed with leukaemia. Most index cases were diagnosed with AML in both groups (88.1%). Among familial forms, 7 AML (50%) were classified as FAB M1 or M2. No M3, M6 or M7 were identified. White blood cell count was higher than 30 G/l in 37.5% of familial form as compared to 23.5% in sporadic cases (NS). The mean circulating blast percentage was higher in familial forms (66.6% (SD= 35.5)) than in sporadic cases (36.7% (SD=32.1)) (p=0.001). None of the familial forms were consecutive to pre-existing myelodysplasic or myeloproliferative syndrome. Among familial cases with AML, 43% had normal cytogenetics (vs 36% in sporadic cases); none had a complex karyotype; one presented with a t(3;15)(p26;q11) as a mosaic, a translocation not previously reported. Complete remission (CR) rates after 1st induction and Overall Survival (OS) were similar in both groups (CR in both groups: 61.5% (n=112); OS: median: 16 months (95%CI = 10.2 – 21.8) in familial forms vs 23.9 months (18.8 – 28.9)). Conclusion According to our data, among the 15 900 new cases of AL diagnosed every year in the US, 1 370 may correspond to familial forms. This warrants awareness of clinicians who should systematically assess family cancer history. Familial AL tends to present as a proliferative form, with no prior hematologic malignancies and normal cytogenetics. This is consistent with pathogenesis pathways described in other familial cancer syndrome.

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The importance to update the guidelines for the use of genetic testing in noncancer patients in Brazil

Revista de Saúde Pública ◽

10.1590/s0034-8910.2015049005988 ◽

2015 ◽

Vol 49 (0) ◽

Cited By ~ 1

Author(s):

Tirzah Braz Petta Lajus

Keyword(s):

Genetic Testing ◽

Private Health Insurance ◽

Breast Lesion ◽

Private Insurance ◽

Technical Note ◽

Cancer Syndrome ◽

History Of ◽

National Regulatory Agency ◽

Generation Sequencing ◽

History Of Cancer

The Brazilian National Regulatory Agency for Private Health Insurance and Plans has recently published a technical note defining the criteria for the coverage of genetic testing to diagnose hereditary cancer. In this study we show the case of a patient with a breast lesion and an extensive history of cancer referred to a private service of genetic counseling. The patient met both criteria for hereditary breast and colorectal cancer syndrome screening. Her private insurance denied coverage for genetic testing because she lacks current or previous cancer diagnosis. After she appealed by lawsuit, the court was favorable and the test was performed using next-generation sequencing. A deletion of MLH1 exon 8 was found. We highlight the importance to offer genetic testing using multigene analysis for noncancer patients.

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Hereditary Nonpolyposis Colorectal Cancer Syndrome in a Patient With Urothelial Carcinoma of the Upper Urothelial Tract

Archives of Pathology & Laboratory Medicine ◽

10.5858/2003-127-e60-hnccsi ◽

2003 ◽

Vol 127 (2) ◽

pp. e60-e63

Author(s):

Arndt Hartmann ◽

John C. Cheville ◽

Wolfgang Dietmaier ◽

Ferdinand Hofstädter ◽

Lawrence J. Burgart ◽

...

Keyword(s):

Colorectal Cancer ◽

Urinary Tract ◽

Urothelial Carcinoma ◽

Hereditary Nonpolyposis Colorectal Cancer ◽

Upper Urinary Tract ◽

Cancer Syndrome ◽

Tract Cancer ◽

Hereditary Nonpolyposis ◽

History Of ◽

History Of Cancer

Abstract Urothelial carcinoma of the upper urinary tract is relatively uncommon but may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability or loss of the respective protein by immunostaining. No well-established screening test is available for urothelial carcinomas of the upper urinary tract, and little is known of the clinical impact of screening for HNPCC in patients with upper urinary tract cancer. We describe herein a patient with a urothelial carcinoma of the ureter and a strongly positive history of cancer, who was subsequently found to have HNPCC. Our findings reinforce the importance of obtaining a comprehensive history of cancer in patients with urothelial carcinoma of the renal pelvis and ureter. Subsequent identification of individuals with HNPCC enables the patient and at-risk relatives to benefit from targeted surveillance and management programs.

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Cancer Risks for Relatives of Children with Cancer

Journal of Cancer Epidemiology ◽

10.1155/2014/806076 ◽

2014 ◽

Vol 2014 ◽

pp. 1-4 ◽

Cited By ~ 6

Author(s):

John A. Heath ◽

Elizabeth Smibert ◽

Elizabeth M. Algar ◽

Gillian S. Dite ◽

John L. Hopper

Keyword(s):

Childhood Cancer ◽

Familial Cancer ◽

Incidence Rates ◽

Cancer Syndrome ◽

Degree Relative ◽

Cancer History ◽

First Degree Relatives ◽

History Of ◽

Familial Cancer Syndromes ◽

Gender Specific

We determined the extent and distribution of cancers in relatives of 379 children newly diagnosed with cancer. Family history was collected from 1,337 first-degree and 3,399 second-degree relatives and incidence compared with national age- and gender-specific rates. Overall, 14 children (3.7%) had a relative with a history of childhood cancer and 26 children (6.9%) had a first-degree relative with a history of cancer, with only one of these having an identifiable familial cancer syndrome. There was a higher than expected incidence of childhood cancer among first-degree relatives (parents and siblings) (standardized incidence ratio (SIR) 1.43; 95% CI 0.54–5.08). There was also a higher than expected incidence of adult cancers among first-degree relatives (SIR 1.45; 95% CI 0.93–2.21), particularly in females (SIR 1.82; 95% CI 1.26–3.39). The increased family cancer history in first-degree females was largely attributable to an effect in mothers (SIR 1.78; 95% CI 1.27–3.33). The gender-specific association was reflected in higher than expected incidence rates of breast cancer in both mothers (SIR 1.92; 95% CI 0.72–6.83) and aunts (SIR 1.64; 95% CI 0.98–2.94). These findings support the hypothesis that previously undetected familial cancer syndromes contribute to childhood cancer.

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Pathogenic Variant Profile of Hereditary Cancer Syndromes in a Vietnamese Cohort

Frontiers in Oncology ◽

10.3389/fonc.2021.789659 ◽

2022 ◽

Vol 11 ◽

Author(s):

Van Thuan Tran ◽

Sao Trung Nguyen ◽

Xuan Dung Pham ◽

Thanh Hai Phan ◽

Van Chu Nguyen ◽

...

Keyword(s):

Ovarian Cancer ◽

Genetic Testing ◽

Hereditary Cancer ◽

Carrier Frequency ◽

Hereditary Cancer Syndromes ◽

Cancer Syndrome ◽

Pathogenic Variants ◽

History Of ◽

Cancer Syndromes ◽

History Of Cancer

BackgroundHereditary cancer syndromes (HCS) are responsible for 5-10% of cancer cases. Genetic testing to identify pathogenic variants associated with cancer predisposition has not been routinely available in Vietnam. Consequently, the prevalence and genetic landscape of HCS remain unknown.Methods1165 Vietnamese individuals enrolled in genetic testing at our laboratory in 2020. We performed analysis of germline mutations in 17 high- and moderate- penetrance genes associated with HCS by next generation sequencing.ResultsA total of 41 pathogenic variants in 11 genes were detected in 3.2% individuals. The carrier frequency was 4.2% in people with family or personal history of cancer and 2.6% in those without history. The percentage of mutation carriers for hereditary colorectal cancer syndromes was 1.3% and for hereditary breast and ovarian cancer syndrome was 1.6%. BRCA1 and BRCA2 mutations were the most prevalent with the positive rate of 1.3% in the general cohort and 5.1% in breast or ovarian cancer patients. Most of BRCA1 mutations located at the BRCA C-terminus domains and the top recurrent mutation was NM_007294.3:c.5251C>T (p.Arg1751Ter). One novel variant NM_000038.6(APC):c.6665C>A (p.Pro2222His) was found in a breast cancer patient with a strong family history of cancer. A case study of hereditary cancer syndrome was illustrated to highlight the importance of genetic testing.ConclusionThis is the first largest analysis of carrier frequency and mutation spectrum of HCS in Vietnam. The findings demonstrate the clinical significance of multigene panel testing to identify carriers and their at-risk relatives for better cancer surveillance and management strategies.

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Detection of R337H, a germline mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening programme in southern Brazil

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.21029 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 21029-21029

Author(s):

E. I. Palmero ◽

M. Caleffi ◽

M. I. Waddington Achatz ◽

G. Martel-Planche ◽

V. Marcel ◽

...

Keyword(s):

Breast Cancer ◽

Germline Mutation ◽

Screening Programme ◽

Familial Cancer ◽

Pcr Amplification ◽

Population Based ◽

Mammographic Screening ◽

Clinical Criteria ◽

History Of ◽

History Of Cancer

21029 Background: A specific germline mutation at codon 337 in TP53 (R337H) has been detected in a number of unrelated subjects with familial cancer risk in South Brazil, suggesting that this mutation may be relatively common in this population. Methods: To assess the TP53 R337H prevalence in a group of asymptomatic individuals unselected for family history of cancer, we studied 750 women aged 40–69 ys participating in a mammographic screening programme in Porto Alegre, Brazil`s southernmost capital. DNA was extracted from peripheral blood using standard procedures and PCR-amplified to generate a 238-base product encompassing TP53 exon 10, which was analyzed by RFLP using the restriction enzyme HhaI. The mutant, uncleaved allele was identified in agarose gels and positive RFLP findings were further confirmed by an independent PCR amplification and bi-directional, automated sequencing. Results and Discussion: The R337H mutant was detected in two of the 750 participants (0.15%), suggesting a much higher prevalence for this than for other TP53 germline mutations causing the LFS/LFL syndromes in the general population. Interestingly, these two subjects reported a familial history of cancer, and were found to be 2nd degree relatives. Three additional family members were also positive: one woman affected with breast cancer at the age of 36 years and two asymptomatic 62- and 80-year-old women. The presence of four R337H-positive cancer- unaffected individuals in this family, two of them well above the age of 50, indicates that this is a low-penetrance allele. In addition, the pedigree does not fulfill any of the currently recognized clinical criteria for the diagnosis of LFS/LFLS syndrome. This is the first study to report detection of a germline TP53 mutation in a population-based screening programme. Conclusions: The TP53 R337H mutant appears to be relatively common and may occur in families that do not fulfill the known clinical criteria for LFS/LFLS, the family described here contains asymptomatic carriers suggesting partial penetrance. No significant financial relationships to disclose.

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Familial history of cancer and childhood acute leukemia: a French population-based case–control study

European Journal of Cancer Prevention ◽

10.1097/01.cej.0000243849.82232.cb ◽

2007 ◽

Vol 16 (5) ◽

pp. 466-470 ◽

Cited By ~ 15

Author(s):

Mahaut Ripert ◽

Florence Menegaux ◽

Yves Perel ◽

Françoise Méchinaud ◽

Emmanuel Plouvier ◽

...

Keyword(s):

Acute Leukemia ◽

Case Control Study ◽

Population Based ◽

Case Control ◽

French Population ◽

Familial History ◽

History Of ◽

Childhood Acute Leukemia ◽

Control Study ◽

History Of Cancer

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High Prevalence of Hereditary Cancer Syndromes in Adolescents and Young Adults With Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2015.61.4503 ◽

2015 ◽

Vol 33 (31) ◽

pp. 3544-3549 ◽

Cited By ~ 86

Author(s):

Maureen E. Mork ◽

Y. Nancy You ◽

Jun Ying ◽

Sarah A. Bannon ◽

Patrick M. Lynch ◽

...

Keyword(s):

Colorectal Cancer ◽

Genetic Counseling ◽

Family History ◽

Hereditary Cancer ◽

Hereditary Cancer Syndrome ◽

Hereditary Cancer Syndromes ◽

Cancer Syndrome ◽

History Of ◽

Cancer Syndromes ◽

History Of Cancer

Purpose Established guidelines recommend evaluation for hereditary cancer syndromes in patients younger than 50 years diagnosed with colorectal cancer (CRC). This group has been well described in the literature; however, patients diagnosed as adolescents and young adults are not well represented in CRC studies. Here, we define the clinical profile, including the extent of hereditary cancer syndromes and family history of cancer, in patients diagnosed with CRC at age 35 or younger. Patients and Methods We reviewed patients who underwent genetic counseling at our institution during 5 years (2009 to 2013). Data were collected regarding demographics, clinicopathologic information, tumor and genetic testing, and family history. Patients with an identified hereditary cancer syndrome were compared with those without a syndrome. Results Of the 193 patients with evaluable data, 35% had an identifiable hereditary cancer syndrome, including 23 with Lynch syndrome, 22 with mutation-negative Lynch syndrome, 16 with familial adenomatous polyposis, two with constitutional mismatch repair deficiency, two with biallelic MUTYH mutations, and one with Li-Fraumeni syndrome. Patients without a hereditary syndrome more frequently presented with metastatic disease, whereas patients with a syndrome were more likely to present at earlier stages and to have a family history of cancer. Nevertheless, a substantial proportion of the hereditary syndromes (19%) were diagnosed in individuals with no family history of the disease. Conclusion We conclude that patients diagnosed with CRC at age 35 years or younger should receive genetic counseling regardless of their family history and phenotype.

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Is uterine serous carcinoma a part of hereditary breast cancer syndrome?

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.5587 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 5587-5587

Author(s):

Saeed Rafii ◽

Philip Dawson ◽

Sarah Williams ◽

Jennifer S. Pascoe ◽

James E. Nevin ◽

...

Keyword(s):

Breast Cancer ◽

Hormone Receptor ◽

Personal History ◽

Tamoxifen Treatment ◽

Serous Carcinoma ◽

Cancer Syndrome ◽

Younger Age ◽

History Of ◽

Uterine Serous Carcinoma ◽

History Of Cancer

5587 Background: Whilst the association between breast cancer and uterine serous carcinoma (USC) is attributed to tamoxifen treatment, few studies have reported that this increased risk is independent of tamoxifen. Methods: To further investigate the relationship between breast cancer and USC, we retrospectively studied 216 patients from 5 hospital trusts in Birmingham, UK who were diagnosed with USC between 1993 and 2012. We collected personal history of cancer in these cases before or after USC diagnosis. In addition FIGO staging, clinical and survival data were collected from our local cancer registry and patients’ clinical records. Results: In this case series, 56 patients (25.9%) had personal history of at least one cancer before and 18 patients (8.3%) had history of at least one cancer after the diagnosis of USC. Within the group of patients with the history of cancer before the USC, 38 patients (68%, 17.5% of all cases) had personal history of breast cancer prior to the development of USC, higher than the UK expected age standardised relative incidence of breast cancer (350 in 100,000, CRUK 2006-2008). Although 27/38 cases (71%) had endocrine treatment for their primary breast cancer, 11/38 patients (29%) did not have any tamoxifen treatment due to hormone receptor negative breast cancer. Additionally the median age of breast cancer diagnosis for the hormone receptor negative group was significantly lower than those patients who had hormonal treatment for their breast cancer (56 vs. 64 years, p :0.036) compatible with the younger age at diagnosis expected of the familial (BRCA mutated) or triple negative breast cancer. Of 18 patients with a second cancer after diagnosis of USC, 6 patients (33%) were diagnosed with breast/ovarian cancer. This group also had no treatment with tamoxifen. Conclusions: Lack of exposure to tamoxifen and younger age at diagnosis in this subgroup suggest that other factors such as a common underlying genetic predisposition may be responsible for the development of both malignancies. We propose that at least a subgroup of USC may be a part of hereditary breast cancer syndrome. This may have implications in prevention (prophylactic hysterectomy) or trials of targeted treatments (PARP inhibitors) for a subgroup of USC patients.

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