Sirolimus for vascular anomalies associated with PTEN hamartoma tumor syndrome.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a rare condition associated with vascular anomalies and increased tumor risk. Sirolimus, an mTOR inhibitor used for managing vascular anomalies is underexplored in PHTS. A single-institution retrospective review of children with PHTS and vascular anomalies treated with sirolimus identified seven patients. Median age at sirolimus initiation was 10 years. After a median 2.5-year follow-up, six of seven patients (86%) showed significant clinical improvement. No significant adverse effects were observed, except mild buccal ulcers and acne. This study supports sirolimus as an effective and safe treatment for vascular anomalies in a small group of children with PHTS.

Predictors of mammographic density among women with a strong family history of breast cancer.

BACKGROUND: Mammographic density is one of the strongest risk factors for breast cancer. In the general population, mammographic density can be modified by various exposures; whether this is true for women a strong family history is not known. Thus, we evaluated the association between reproductive, hormonal, and lifestyle risk factors and mammographic density among women with a strong family history of breast cancer but no BRCA1 or BRCA2 mutation. METHODS: We included 97 premenopausal and 59 postmenopausal women (age range: 27-68 years). Risk factor data was extracted from the research questionnaire closest in time to the mammogram performed nearest to enrollment. The Cumulus software was used to measure percent density, dense area, and non-dense area for each mammogram. Multivariate generalized linear models were used to evaluate the relationships between breast cancer risk factors and measures of mammographic density, adjusting for relevant covariates. RESULTS: Among premenopausal women, those who had two live births had a mean percent density of 28.8% vs. 41.6% among women who had one live birth (P=0.04). Women with a high body weight had a lower mean percent density compared to women with a low body weight among premenopausal (17.6% vs. 33.2%; P=0.0006) and postmenopausal women (8.7% vs. 14.7%; P=0.04). Among premenopausal women, those who smoked for 14 years or longer had a lower mean dense area compared to women who smoked for a shorter duration (25.3cm2 vs. 53.1cm2; P=0.002). Among postmenopausal women, former smokers had a higher mean percent density (19.5% vs. 10.8%; P=0.003) and dense area (26.9% vs. 16.4%; P=0.01) compared to never smokers. After applying the Bonferroni correction, the association between body weight and percent density among premenopausal women remained statistically significant. CONCLUSIONS: In this cohort of women with a strong family history of breast cancer, body weight was associated with mammographic density. These findings suggest that mammographic density may explain the underlying relationship between some of these risk factors and breast cancer risk, and lend support for the inclusion of mammographic density into risk prediction models.

Colorectal cancer in adolescents and young adults: Defining a growing threat.

Colorectal cancer (CRC) incidence is rising among adolescents and young adults (AYAs), with the greatest increase occurring in distal colon and rectal cancers. Reasons for this striking trend are not well understood. Genetically linked cases of CRC occur in the context of familial conditions such as Lynch Syndrome, but most AYA cases of CRC are sporadic. Unique biology is suggested, yet limited information is available regarding the molecular underpinnings of CRC in this age group. Young patients are more likely to experience delays in diagnosis and to present with advanced-stage disease; yet, prognosis by stage is comparable between younger and older adults. Treatment paradigms are based on evidence reflecting the older adult population. Given the concerning rise in CRC rates among AYAs, there is urgent need for further research into the role of screening from a younger age, biology of disease, and optimal therapies in this age group.

Serum osteoprotegerin levels and mammographic density among high-risk women.

PURPOSE: Mammographic density is a risk factor for breast cancer but the mechanism behind this association is unclear. The receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) pathway has been implicated in the development of breast cancer. Given the role of RANK signaling in mammary epithelial cell proliferation, we hypothesized this pathway may also be associated with mammographic density. Osteoprotegerin (OPG), a decoy receptor for RANKL, is known to inhibit RANK signaling. Thus, it is of interest to evaluate whether OPG levels modify breast cancer risk through mammographic density. METHODS: We quantified serum OPG levels in 57 premenopausal and 43 postmenopausal women using an enzyme-linked immunosorbent assay (ELISA). Cumulus was used to measure percent density, dense area, and non-dense area for each mammographic image. Subjects were classified into high versus low OPG levels based on the median serum OPG level in the entire cohort (115.1 pg/mL). Multivariate models were used to assess the relationship between serum OPG levels and the measures of mammographic density. RESULTS: Serum OPG levels were not associated with mammographic density among premenopausal women (P ≥ 0.42). Among postmenopausal women, those with low serum OPG levels had higher mean percent mammographic density (20.9% vs. 13.7%; P = 0.04) and mean dense area (23.4 cm2 vs. 15.2 cm2; P = 0.02) compared to those with high serum OPG levels after covariate adjustment. CONCLUSIONS: These findings suggest that low OPG levels may be associated with high mammographic density, particularly in postmenopausal women. Targeting RANK signaling may represent a plausible, non-surgical prevention option for high-risk women with high mammographic density, especially those with low circulating OPG levels.

Quality of preoperative pelvic computed tomography (CT) and magnetic resonance imaging (MRI) for rectal cancer in a region in Ontario: A retrospective population-based study.

BACKGROUND AND OBJECTIVES: Treatment decisions for rectal cancer rely on preoperative staging with CT and MRI scans. We assessed the quality of such scans in a region of Ontario. METHODS: We retrospectively collected data for patients undergoing rectal cancer surgery between July 2011 and December 2014. We measured three aspects of quality: use; comprehensiveness of reporting T-category, N-category, mesorectal fascia (MRF) status; and in non-radiated patients sensitivity and specificity of reports for relevant elements. RESULTS: A total of 559 patients underwent major rectal cancer surgery. Preoperative staging with CT and MRI was performed in 93% and 50% of patients. CT scan reports provided information on T-category, N-category, and MRF status in 41%, 92%, and 16% of cases. These same elements were reported on MRI in 88%, 93%, and 62% of cases. CT scan sensitivity and specificity was 80% and 80% for T-category, and 85% and 39% for N-category. MRI sensitivity and specificity was 75% and 81% for T-category, 79% and 37% for N-category, and 33% and 89% for MRF status. CONCLUSION: In this region of Ontario, pre-operative MRI was underutilized, CT reporting of MRF status was low, and when reported sensitivity and specificity of T- and N-category were similar for CT and MRI.

Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry.

BACKGROUND: Previous studies assessing breast cancer risk in families with Lynch syndrome (LS) have yielded conflicting results. Furthermore, conclusions are limited by small sample size and few breast cancer outcomes. This study assesses breast cancer risk in a large prospectively followed LS cohort. METHODS: Pedigrees of 325 unrelated families with LS within the Familial Gastrointestinal Cancer Registry in Canada were examined for breast cancer diagnoses. Standardised incidence ratios (SIR) and lifetime cumulative incidence calculations were used to compare the incidence of breast cancer in mutation carriers with the general population. RESULTS: Forty-one mutation carriers diagnosed with breast cancer belonging to 34 unrelated families were identified. Mean age at diagnosis was 54 years. The mutation distribution among the LS patients with breast cancer was statistically different from those without breast cancer (p=0.015), reflecting the predominance of MSH2 mutations among affected patients (74%). Eighty-eight per cent of LS families with breast cancer met Amsterdam criteria, compared with 49% of LS families without breast cancer (p=0.03). Lifetime cumulative incidence of breast cancer in female MSH2 mutation carriers in our cohort was 22% (p<0.001). The SIR for breast cancer of female MSH2 mutation carriers in our cohort was 3.11 (95% CI 1.95 to 4.71). CONCLUSIONS: An increased risk of breast cancer in MSH2 mutation carriers was demonstrated in a Canadian familial cancer registry. Women with breast cancer often had a personal and family history of multiple LS-related malignancies. These results suggest a potential role for intensified breast cancer surveillance among women with LS.

SDH-deficient renal cell carcinoma - clinical, pathologic and genetic correlates: a case report.

BACKGROUND: Succinate dehydrogenase (SDH)- deficient renal cell carcinoma (RCC) is a newly identified rare subtype of RCC, having only gained acceptance from the World Health Organization in 2016. To the best of our knowledge, there are only 55 reported cases worldwide. Here, we report a new case of SDH-deficient RCC. CASE PRESENTATION: A 49-year-old male patient was incidentally found to have a large right renal mass. He had no personal or family history of paragangliomas (PGL), pheochromocytomas (PC), or gastrointestinal stromal tumors (GIST). The neoplasm was unilateral and unifocal. He underwent an open partial nephrectomy. Detailed pathological analysis was conducted to confirm the diagnosis. Genetic testing revealed a pathogenic mutation in the SDHB gene. He has been followed for 24 months now and has remained well without any evidence of local or distant recurrence. In this report we describe our experience with this diagnosis and review the relevant clinical, pathological, and genetic features. CONCLUSIONS: Without the identification of SDHB deficiency, this patient's personal and familial predisposition to PC, PGL, GIST and metachronous RCCs may have gone undetected despite his RCC diagnosis. When faced with an eosinophilic RCC, pathologists should routinely search for vacuoles or flocculent cytoplasmic inclusions. When these are present, or in cases of difficult eosinophilic renal tumors, staining for SDHB is recommended. For tumours without adverse pathologic features (i.e. high nuclear grade, coagulative necrosis, or sarcomatoid differentiation) excision alone may be a reasonable option, with the addition of regular surveillance for PC and PGLs in those found to harbor germline SDH mutations.

Role of the status of the mesorectal fascia in the selection of patients with rectal cancer for preoperative radiation therapy: a retrospective cohort study

Background: Patients with rectal cancer in whom the mesorectal fascia is threatened by tumour are more likely than all patients with stage II/III disease to benefit from preoperative radiotherapy (RT). The objective of this study was to assess whether the status of the mesorectal fascia versus a stage II/III designation can best inform the use of preoperative RT in patients undergoing major rectal cancer resection. Methods: We reviewed the charts of consecutive patients with primary rectal cancer treated by a single surgeon at McMaster University, Hamilton, Ontario, between March 2006 and December 2012. The status of the mesorectal fascia was assessed by digital rectal examination, pelvic computed tomography and, when needed, pelvic magnetic resonance imaging (MRI). Patients whose mesorectal fascia was threatened or involved by tumour received preoperative RT. The study outcomes were rates of positive circumferential radial margin (CRM) and local tumour recurrence. Results: A total of 153 patients were included, of whom 76 (49.7%) received preoperative RT because of concerns of a compromised mesorectal fascia. The median length of follow-up was 4.5 years. The number of CRM-positive cases in the RT and no-RT groups was 16 (22%) and 1 (1%), respectively (p < 0.01), and the number of cases of local tumour recurrence was 5 (7%) and 2 (3%), respectively (p = 0.2). Rates were similar when only patients with stage II/III tumours were included. Overall, 26 patients (17.0%) received MRI. Conclusion: The status of the mesorectal fascia, not tumour stage, may best identify patients for preoperative RT.

Contexte: Plus que tous les patients présentant une maladie de stade II/III, les patients atteints d'un cancer du rectum dont le fascia mésorectal est menacé par la tumeur sont de bons candidats à la radiothérapie (RT) préopératoire. L'objectif de cette étude était d'évaluer ce qui, entre l'état du fascia mésorectal et une désignation de stade II/III, permet le mieux de confirmer le bien-fondé d'une RT préopératoire chez les patients qui doivent subir une résection majeure pour cancer du rectum. Méthodes: Nous avons passé en revue les dossiers de patients consécutifs atteints d'un cancer rectal primaire traités par un seul chirurgien à l'Université McMaster, à Hamilton, en Ontario, entre mars 2006 et décembre 2012. L'état du fascia mésorectal a été évalué par toucher rectal, tomodensitométrie pelvienne et, au besoin, imagerie par résonnance magnétique (IRM) pelvienne. Les patients dont le fascia mésorectal était menacé ou affecté par la tumeur ont reçu une RT préopératoire. Les paramètres de l'étude étaient : taux de positivité de la marge radiale circonférentielle (MRC) et récurrence de la tumeur locale. Résultats: En tout, 153 patients ont été inclus, dont 76 (49,7 %) ont reçu une RT préopératoire en raison d'une atteinte du fascia mésorectal. La durée moyenne du suivi a été de 4,5 ans. Dans les groupes soumis et non soumis à la RT, les nombres de cas MRC-positifs ont été respectivement de 16 (22 %) et de 1 (1 %), (p < 0,01), et les nombres de cas de récurrence de la tumeur locale ont été respectivement de 5 (7 %) et de 2 (3 %) (p = 0,2). Les taux étaient similaires lorsque seuls les patients présentant des tumeurs de stade II/III étaient inclus. Globalement, 26 patients (17,0 %) ont subi l'IRM. Conclusion: C'est l'état du fascia mésorectal et non le stade de la tumeur qui peut le mieux permettre d'identifier les candidats à une RT préopératoire.

Cancer phenomics: RET and PTEN as illustrative models.

Cancer phenomics, the systematic acquisition and objective documentation of host and/or somatic cancer phenotypic data at many levels, is a young field compared with other molecular-based 'omics'. Two relatively advanced phenomic paradigms are associated with phosphatase and tensin homologue (PTEN) and rearranged during transfection (RET), genes that are associated with cancer predisposition syndromes in addition to developmental disorders. The phenomic characterization of PTEN and RET underscores the importance of incorporating robust phenomics into the host 'omic' profile, and shows that the evolution of phenomics will be crucial to the advancement of personalized medicine.

Prospective study of high-risk, BRCA1/2-mutation negative women: the 'negative study'.

BACKGROUND: We previously reported that women from high-risk families who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation were four times more likely to develop breast cancer compared to women in the general population. Preventive measures and risk factors for breast cancer development in these high-risk women have not been evaluated to the same extent as BRCA1/2 positive women. Further, there is virtually no scientific evidence about best practices in their management and care. The proposed study will examine a role of genetic and non-genetic factors and develop the systems and parameters for the monitoring and surveillance necessary to help establish guidelines for the care of this high-risk population. METHODS/DESIGN: To achieve our goals, we will assemble and follow a Canadian cohort of 1,000 cancer-free women with a strong family history breast cancer (defined as two or more relatives affected by breast cancer under the age of 50, or three or more relatives diagnosed with breast cancer at any age from one side of the family and with no BRCA1/2 mutation in the family). All eligible participants will be mailed a study package including invitation to participate, consent form, a research questionnaire to collect data regarding family history, reproductive and lifestyle factors, as well as screening and surgery. Usual dietary intake will be assessed by a diet history questionnaire. Biological samples including toenail clippings, urine and blood samples will be collected. These women will be followed every two years by questionnaire to update exposure information, screening practices, surgical and chemoprevention, and disease development. DISCUSSION: Findings from this study will serve to help establish clinical guidelines for the implementation of prevention, counseling, and treatment practices for women who face an elevated risk of breast cancer due to family history, but who do not carry a BRCA1/2 mutation.

Accelerated muscle and adipose tissue loss may predict survival in pancreatic cancer patients: the relationship with diabetes and anaemia.

Weight loss leading to cachexia is associated with poor treatment response and reduced survival in pancreatic cancer patients. We aim to identify indicators that allow for early detection that will advance our understanding of cachexia and will support targeted anti-cachexia therapies. A total of fifty pancreatic cancer patients were analysed for skeletal muscle and visceral adipose tissue (VAT) changes using computed tomography (CT) scans. These changes were related to physical characteristics, secondary disease states and treatment parameters. Overall, patients lost 1.72 (SD 3.29) kg of muscle and 1.04 (SD 1.08) kg of VAT during the disease trajectory (413 (SD 213) d). After sorting patients into tertiles by rate of VAT and muscle loss, patients losing VAT at > -0.40 kg/100 d had poorer survival outcomes compared with patients with < -0.10 kg/100 d of VAT loss (P= 0.020). Patients presenting with diabetes at diagnosis demonstrated significantly more and accelerated VAT loss compared with non-diabetic patients. In contrast, patients who were anaemic at the first CT scan lost significantly more muscle tissue and at accelerated rates compared with non-anaemic patients. Accelerated rates of VAT loss are associated with reduced survival. Identifying associated features of cachexia, such as diabetes and anaemia, is essential for the early detection of cachexia and may facilitate the attenuation of complications associated with cachexia.

BRCA2 variants and cardiovascular disease in a multi-ethnic study.

BACKGROUND: Germline mutations of BRCA1/2 are associated with hereditary breast and ovarian cancer. Recent data suggests excess mortality in mutation carriers beyond that conferred by neoplasia, and recent in vivo and in vitro studies suggest a modulatory role for BRCA proteins in endothelial and cardiomyocyte function. We therefore tested the association of BRCA2 variants with clinical cardiovascular disease (CVD). METHODS: Using data from 1,170 individuals included in two multi-ethnic population-based studies (SHARE and SHARE-AP), the association between BRCA2 variants and CVD was evaluated. 15 SNPs in BRCA2 with minor allele frequencies (MAF) > 0.01 had been previously genotyped using the cardiovascular gene-centric 50 k SNP array. 115 individuals (9.8%) reported a CVD event, defined as myocardial infarction (MI), angina, silent MI, stroke, and angioplasty or coronary artery bypass surgery. Analyses were adjusted for age and sex. The SNPs rs11571836 and rs1799943 were subsequently genotyped using the MassARRAY platform in 1,045 cases of incident MI and 1,135 controls from the South Asian subset of an international case-control study of acute MI (INTERHEART), and rs11571836 was imputed in 4,686 cases and 4500 controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS). RESULTS: Two BRCA2 SNPs, rs11571836 and rs1799943, both located in untranslated regions, were associated with lower risk of CVD (OR 0.47 p = 0.01 and OR 0.56 p = 0.03 respectively) in the SHARE studies. Analysis by specific ethnicities demonstrated an association with CVD for both SNPs in Aboriginal People, and for rs11571836 only in South Asians. No association was observed in the European and Chinese subgroups. A non-significant trend towards an association between rs11571836 and lower risk of MI was observed in South Asians from INTERHEART [OR = 0.87 (95% CI: 0.75-1.01) p = 0.068], but was not evident in PROMIS [OR = 0.96 (95% CI: 0.90-1.03) p = 0.230]. Meta-analysis of both case-control studies resulted in a combined OR of 0.94 (95% CI: 0.89-1.004, p = 0.06). CONCLUSIONS: Although there was an association between two SNPs in BRCA2 and CVD in a multi-ethnic population, these results were not replicated in two South Asian case-control studies of incident MI. Future studies exploring the association between BRCA variants and cardiovascular disorders are needed to clarify the role, if any, for BRCA variants in CVD pathogenesis.

Desmoplastic small round cell tumor involving the uterine cervix: The first reported case in the literature, and brief review of gynecologic presentations.

Background: Desmoplastic small round cell tumors are exceedingly rare, usually involve abdominal organs and predominantly affect male patients. We describe the first reported case arising from the uterine cervix and provide a summary of 20 previously reported cases involving gynecologic organs. Case: A 54 year-old was diagnosed with a rapidly growing 13 cm desmoplastic small round cell tumor of the cervix. She was treated through a multimodal approach involving neoadjuvant chemotherapy and surgery. She subsequently recurred, and this was successfully treated with radiation therapy. She is well and without evidence of disease 22 months after initial diagnosis. Conclusion: We report successful treatment through multidisciplinary and multimodal management. This can guide management of future patients as no gold-standard treatment has yet been described.

Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.

Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p < 0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p < 0.001), thyroid (5/10 versus 15/106, p < 0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.

Genomic and Clinical Correlates of Adrenocortical Carcinoma in an Adult Patient with Li-Fraumeni Syndrome: A Case Report.

Li-Fraumeni Syndrome (LFS) is defined by germline mutations of the p53 tumour suppressor gene. Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that is commonly associated with LFS. Most LFS-linked ACC cases occur in children, and limited research has been dedicated to the clinical outcomes and genomics of adult cases with LFS-linked ACC. We report on a 34-year-old female who was diagnosed with three separate malignancies: stage III invasive ductal carcinoma of the right breast, metastatic ACC from the right adrenal gland, and grade 2 pleomorphic sarcoma of the left hand. Her invasive breast ductal carcinoma was treated with neoadjuvant chemotherapy, and she received a bilateral mastectomy after her LFS was confirmed with genetic blood testing. Adrenal ACC was initially treated with a right nephrectomy and adrenalectomy, followed by adjuvant mitotane and two lines of chemotherapy after disease recurrence. Her hand sarcoma was treated by second ray amputation. Further, we conducted deep next-generation sequencing of each of her unique tumour tissue samples using FoundationONE CDx. A whole-genome shot capture followed by in vitro sequencing performed by the Illumina® HiSeq platform revealed a germline P191fs*18 TP53 mutation across all three tissue samples. This case provides insight into the genomics and clinical characteristics of LFS-linked adult-onset ACC and demonstrated that p53 mutations were preserved throughout each malignancy, without apparent treatment pressures on genomic profiling. This case reinforces the critical importance of adopting best practices for LFS, which include the implementation of highly vigilant screening and management of care in a multidisciplinary setting.

ATM whole gene deletion in an Italian family with hereditary pancreatic cancer: Challenges to cancer risk prediction associated with an 11q22.3 microdeletion.

Hereditary pancreatic cancer has been attributed to variants of several cancer predisposition genes including ATM. While heterozygous pathogenic variants in the ATM gene are implicated as a cause of familial breast and pancreatic cancers to our knowledge ATM whole gene deletions have not been previously reported. We describe a contiguous gene deletion of the ATM locus in a multi-generation family of Italian descent with a strong family history of pancreatic cancer. A deletion of one copy of the entire ATM gene was identified by routine panel testing and further characterized by chromosomal microarray analysis. An 11q22.3 microdeletion of approximately 960 kb was identified that is predicted to result in loss of 10 genes including ATM. The deletion was identified in two additional family members including a presymptomatic daughter and an affected sibling. A normal disomic complement of the 11q22.3 region was detected in a third family member with a history of prostate and pancreatic cancer. Additional family members were not available for testing. Given available evidence that ATM haploinsufficiency can increase cancer risk, we predict that the observed copy number loss has likely contributed to hereditary cancer in this family. However, absence of the familial microdeletion in at least one affected family member suggests that ATM deletions are unlikely the sole contributing factor influencing tumor development in affected individuals. This case highlights 11q22.3 microdeletions of the ATM gene region as a possible risk factor for hereditary cancer, including pancreatic cancer. The same case provides a further cautionary tale for over interpretation of cancer risk associated tumor suppressor microdeletions and suggests that the variant may not be sufficient for tumor development or may modify the cancer risks associated with other, yet unidentified hereditary cancer genes.

Colorectal cancer in young adults.

Colorectal cancer (CRC) is rare in young adults. It presents more frequently with stage 3 or 4 disease, underscoring its relevance in this population. Prognosis, matched for stage of disease at presentation, is likely similar to that in older adults, although survival is clearly lower for the youngest subgroups within this population. This article reviews the literature on the etiology, presentation, treatment, and outcome of CRC in young adults. New chemotherapeutic regimens have demonstrated survival benefits and the introduction of new biological agents has offered ways to control metastatic disease that may eventually show promise in the treatment of earlier-stage CRC. The benefit of these newer agents in young adults is assumed but currently unproven. Molecular genetic studies are increasing the understanding of the pathobiology of CRC and may ultimately allow at-risk patients to be identified at an earlier stage.

Germline mutations in PTEN and SDHC in a woman with epithelial thyroid cancer and carotid paraganglioma.

BACKGROUND: A 43-year-old woman presented to a cancer genetics clinic for a genetic risk assessment because of her personal history of multiple neoplasias. At 37 years of age, she was diagnosed with multifocal papillary thyroid cancer, and within a year was further diagnosed with a paraganglioma of the left common carotid artery. Two years later, she was diagnosed with a paraganglioma of the right carotid body. All three tumors were treated with surgical resection. There was no family history of malignancy. Past medical history includes uterine leiomyoma and fibrocystic breast disease. Physical examination revealed macrocephaly and papillomatous papules. INVESTIGATIONS: CT scan of the neck and thorax, 24-hour urine collection for measurement of metanephrines and catecholamines, MRI of the neck, thorax, and abdomen, metaiodobenzylguanidine scan, germline mutation analysis of PTEN, SDHB, SDHC and SDHD. DIAGNOSIS: Cowden syndrome due to a germline mutation of PTEN, and pheochromocytoma-paraganglioma syndrome due to a germline mutation of SDHC. MANAGEMENT: Clinical surveillance for breast, endometrial, thyroid, and renal cell carcinoma risks associated with Cowden syndrome according to the National Comprehensive Cancer Network guidelines, annual MRI of the neck, thorax, abdomen and pelvis, annual metabolic screening, and where available, annual 18-fluorodopamine PET scanning, predictive genetic testing of both PTEN and SDHC for the patient's daughter and parents.

Severe TMD/AMKL with GATA1 mutation in a stillborn fetus with Down syndrome.

BACKGROUND: A 34-year-old woman was referred for evaluation of a recent stillborn male fetus, gestational age 27 6/7 weeks, found to have congenital myeloid leukemia at autopsy. Autopsy findings included high weight for gestational age, hepatomegaly, and extensive intravascular leukemic infiltrates in the placenta, heart, liver, thymus, lung, kidneys, and brain. Genetic consultation and examination of photographs of the fetus revealed dysmorphic features. INVESTIGATIONS: Immunoperoxidase staining of placental tissue, fluorescence in situ hybridization of paraffin-embedded sections of the placenta using probes for t(12;21)(p13;q22), t(8;21)(q22;q22) and t/del(11q23), cytogenetic analysis of fetal tissue (tendon), sequence analysis of GATA1 in placental leukemic cells, and parental chromosome studies. DIAGNOSIS: Down syndrome with in utero onset of GATA1 mutation-positive severe transient myeloproliferative disorder/acute megakaryoblastic leukemia. MANAGEMENT: Genetic counseling for the recurrence risk of Down syndrome on the basis of maternal age.