Familial Clustering Of Cancer Research Articles

Abstract 802: Multi-cancer profiles in high-risk CLL families

Abstract Discovery of novel etiological factors for B-cell malignancies is hindered by the heterogeneity of these diseases. The identification of important multi-cancer profiles provides a new avenue for discovery, but requires novel approaches and specific resources. The Utah Population Database (UPDB) includes extensive genealogy for 5 million Utahns (from three to 18 generations). The UPDB also includes over 360,000 cancer diagnoses from the NCI SEER Utah Cancer Registry, making it a unique and ideal resource for analyzing cancer patterns in families. Here we performed a multi-cancer clustering approach to identify patterns of familial clustering of cancers in high-risk CLL families. Other cancers considered in the cancer profiles were: Hodgkins lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma and 25 solid tumors. High risk CLL pedigrees were extracted from the UPDB. Based on cancer rates in UPDB, standardized incidence ratios were calculated for each pedigree for each of the 29 cancers. These vectors of cancer risks per pedigree were used as the basis for k-mediods clustering of the high-risk CLL families. Resulting clusters of families share similar co-aggregations of other B-cell malignancies and solid tumors. High-risk CLL families with similar multi-cancer profiles may be more etiologically homogeneous and provide improved power for the identification of underlying risk factors. Citation Format: Nathan Scott Harris. Multi-cancer profiles in high-risk CLL families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 802.

Identification of novel sarcoma risk genes using a two-stage genome wide DNA sequencing strategy in cancer cluster families and population case and control cohorts

BackgroundAlthough familial clustering of cancers is relatively common, only a small proportion of familial cancer risk can be explained by known cancer predisposition genes.MethodsIn this study we employed a two-stage approach to identify candidate sarcoma risk genes. First, we conducted whole exome sequencing in three multigenerational cancer families ascertained through a sarcoma proband (n = 19) in order to prioritize candidate genes for validation in an independent case-control cohort of sarcoma patients using family-based association and segregation analysis. The second stage employed a burden analysis of rare variants within prioritized candidate genes identified from stage one in 560 sarcoma cases and 1144 healthy ageing controls, for which whole genome sequence was available.ResultsVariants from eight genes were identified in stage one. Following gene-based burden testing and after correction for multiple testing, two of these genes, ABCB5 and C16orf96, were determined to show statistically significant association with cancer. The ABCB5 gene was found to have a higher burden of putative regulatory variants (OR = 4.9, p-value = 0.007, q-value = 0.04) based on allele counts in sarcoma cases compared to controls. C16orf96, was found to have a significantly lower burden (OR = 0.58, p-value = 0.0004, q-value = 0.003) of regulatory variants in controls compared to sarcoma cases.ConclusionsBased on these genetic association data we propose that ABCB5 and C16orf96 are novel candidate risk genes for sarcoma. Although neither of these two genes have been previously associated with sarcoma, ABCB5 has been shown to share clinical drug resistance associations with melanoma and leukaemia and C16orf96 shares regulatory elements with genes that are involved with TNF-alpha mediated apoptosis in a p53/TP53-dependent manner. Future genetic studies in other family and population cohorts will be required for further validation of these novel findings.

Familial Cancer Clustering in Patients with Prolactinoma.

People are at higher risk for malignancy as they get older or have a strong family history of cancer. This study aims to collect family history of cancer in a large cohort of patients with pituitary adenomas (PA) in outpatient clinic from years 2005-2017. Overall, 46.6% of 1062 patients with PA had a family member affected with cancer. Breast cancer in family members was reported in 15.3% of patients with prolactinomas which was significantly higher than in families of patients with non-functioning pituitary adenomas (NFPA) (10.0%) or acromegaly (6.8%) (p = 0.004). Lung cancer in family members was reported in 12.1% of patients with prolactinomas, significantly higher than in families of NFPA patients (7.0%, p = 0.049). Colorectal cancer in relatives of patients with PA was reported with any type of PA. Furthermore, patients with a positive family history of malignancy were diagnosed with PA at an earlier age than patients with a negative family history (43.6 ± 15.9 vs 46.0 ± 16.4years, p = 0.015). Female patients with prolactinoma are more commonly diagnosed before the age of 25years. Forty-two percent of patients with PA diagnosed before the age of 25years had a second- and third-degree relative with cancer, significantly higher than patients with PA diagnosed later in life (25.8%, p < 0.001). Breast, lung, and colon cancers in second- and third-degree relatives were reported in significantly higher proportion of patients with PA diagnosed before the age of 25years, compared with patients with PA diagnosed later in life (breast cancer: 10.9 vs 6.1%, p = 0.033; lung cancer: 10.9 vs 5.8%, p = 0.02; colon cancer: 9.5 vs 4.0%, p = 0.004). These results suggest familial cancer clustering in patients with prolactinoma and young patients with PA (younger than 25years at diagnosis of PA). In particular, there is a strong association between prolactinoma and family history of breast and lung cancers. Further research of possible shared genetic susceptibility of prolactinoma and breast and lung cancers is needed.

Familial cancer clustering in patients with pituitary adenoma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Breast cancer family history and allele-specific DNA methylation in the legacy girls study

ABSTRACTFamily history, a well-established risk factor for breast cancer, can have both genetic and environmental contributions. Shared environment in families as well as epigenetic changes that also may be influenced by shared genetics and environment may also explain familial clustering of cancers. Epigenetic regulation, such as DNA methylation, can change the activity of a DNA segment without a change in the sequence; environmental exposures experienced across the life course can induce such changes. However, genetic-epigenetic interactions, detected as methylation quantitative trait loci (mQTLs; a.k.a. meQTLs) and haplotype-dependent allele-specific methylation (hap-ASM), can also contribute to inter-individual differences in DNA methylation patterns. To identify differentially methylated regions (DMRs) associated with breast cancer susceptibility, we examined differences in white blood cell DNA methylation in 29 candidate genes in 426 girls (ages 6–13 years) from the LEGACY Girls Study, 239 with and 187 without a breast cancer family history (BCFH). We measured methylation by targeted massively parallel bisulfite sequencing (bis-seq) and observed BCFH DMRs in two genes: ESR1 (Δ4.9%, P = 0.003) and SEC16B (Δ3.6%, P = 0.026), each of which has been previously implicated in breast cancer susceptibility and pubertal development. These DMRs showed high inter-individual variability in methylation, suggesting the presence of mQTLs/hap-ASM. Using single nucleotide polymorphisms data in the bis-seq amplicon, we found strong hap-ASM in SEC16B (with allele specific-differences ranging from 42% to 74%). These findings suggest that differential methylation in genes relevant to breast cancer susceptibility may be present early in life, and that inherited genetic factors underlie some of these epigenetic differences.

Familial Cancer Clustering in Urothelial Cancer: A Population-Based Case-Control Study.

Family history of bladder cancer confers an increased risk for concordant and discordant cancers in relatives. However, previous studies investigating this relationship lack any correction for smoking status of family members. We conducted a population-based study of cancer risks in relatives of bladder cancer patients and matched controls with exclusion of variant subtypes to improve the understanding of familial cancer clustering. Case subjects with urothelial carcinoma were identified using the Utah Cancer Registry and matched 1:5 to cancer-free controls from the Utah Population Database. Cox regression was used to determine the risk of cancer in first-degree relatives, second-degree relatives, first cousins, and spouses. A total of 229 251 relatives of case subjects and 1 197 552 relatives of matched control subjects were analyzed. To correct for smoking status, we performed a secondary analysis excluding families with elevated rates of smoking-related cancers. All statistical tests were two-sided. First- and second-degree relatives of case subjects had an increased risk for any cancer diagnosis (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 1.03 to 1.09, P < .001; HR = 1.04, 95% CI = 1.02 to 1.07, P = .001) and urothelial cancer (HR = 1.73, 95% CI = 1.50 to 1.99, P < .001; HR = 1.35, 95% CI = 1.21 to 1.51, P < .001). Site-specific analysis found increased risk for bladder (HR = 1.69, 95% CI = 1.47 to 1.95, P < .001), kidney (HR = 1.30, 95% CI = 1.08 to 1.57, P = .006), cervical (HR = 1.25, 95% CI = 1.06 to 1.49, P = .01), and lung cancer (HR = 1.34, 95% CI = 1.19 to 1.51, P < .001) in first-degree relatives. Second-degree relatives had increased risk for bladder (HR = 1.35, 95% CI = 1.2 to 1.5, P < .001) and thyroid cancer (HR = 1.18, 95% CI = 1.03 to 1.35, P = .02). Spouses showed an increased risk for laryngeal (HR = 2.68, 95% CI = 1.02 to 7.05, P = .04) and cervical cancer (HR = 1.57, 95% CI = 1.13 to 2.17, P = .007). These results did not substantively change after correction for suspected smoking behaviors. Our results suggest familial urothelial cancer clustering independent of smoking, with increased risk in relatives for both concordant and discordant cancers, suggesting shared genetic or environmental roots. Identifying families with statistically significant risks for non-smoking-related urothelial cancer would be extremely informative for genetic linkage studies.

Abstract 2765: Evaluation of family history of cancer in first-degree relatives and increased cancer risk: A multinational study

Abstract Family history of cancer is a known risk factor for several of the more prevalent cancer types. However, familial aggregation of cancer may not follow the genetic linkage pattern seen with most inherited cancer syndromes. In these instances, clustering may be due to unknown hereditary genetic mutations or to an aggregation of environmental risk factors and such clustering may still confer a significant risk. We assessed the association between family history of cancer in first-degree relatives and cancer risk among 9,122 cancer cases and 76,537 controls in a multinational study. Analyses also included evaluation of breast, colon and prostate cancer risk associated with family history of these respective cancer types. Cases were verified by physician diagnosis and all study participants were administered an in-depth survey to ascertain various demographic and lifestyle factors as well as a complete family history of cancer among first-degree relatives. Multivariable logistic regression was used to assess the association between family history of cancer and cancer risk. Among all subjects, the odds ratio (OR) for individuals with a family history of cancer was 1.79 [95% confidence interval = 1.7-1.9] after adjusting for age, gender, BMI, smoking pack years and ethnicity. Additionally, a greater cancer risk was associated with increasing number of first-degree relatives with a history of cancer. Ethnic groups studied included Caucasian-Americans, African-Americans, Hispanic/Latinas and Caucasian-Polish. All ethnic groups showed a significant association between family history of cancer and cancer risk with the highest adjusted OR of 2.65 [95% confidence interval = 2.0-3.6] among the Hispanic/Latina group. Further analyses indicated that family history of colon, breast and prostate cancer was significantly associated with an increased risk of these respective cancer types across studied ethnic groups. In particular, the adjusted ORs for breast, colon and prostate cancer risk in the Caucasian-Polish group were at least double the overall adjusted ORs for each cancer type. Our study shows that family history of cancer is a significant predictor of cancer risk especially among certain ethnic groups. In addition, family history of cancer can represent both a genetic predisposition and/or environmental exposure and risk associated with familial clustering of cancer. Citation Format: Laxmi Modali, Teresa A. Lehman, Ramakrishna Modali, Luke D. Ratnasinghe. Evaluation of family history of cancer in first-degree relatives and increased cancer risk: A multinational study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2765. doi:10.1158/1538-7445.AM2015-2765

Milestones of Lynch syndrome: 1895-2015.

Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.

Patterns of familial cancer clustering in Asian cancer patients.

e12528 Background: About 10-15% of patients develop cancer due to a genetic predisposition, but only a fraction is due to defined syndromes with known causative genes. Routine detailed collection of family history (FH) may yield useful information on the frequency and patterns of familial cancer clustering. Methods: A 3-generation FH was collected from cancer patients in a tertiary centre in Asia from 2001 to 2013 using a self-completed questionnaire. A genogram was constructed by a trained cancer genetics counselor and reviewed for hereditary cancer syndromes (HCS). Results: Of 7,104 patients included, majority were female (66.3%) and Chinese (80.5%). 13.8% were diagnosed at age 1 primary cancer, 39.5% had FH of cancer, of which 74.5% (2,095/2,805) had ≥1 affected first degree relative (FDR). The most common cancers of index patients were breast, colon, lung, nasopharyngeal (NPC) and gastric (39.2%, 16.7%, 10.4%, 5.4%, 4.4%). 73% of genograms were not suspicious of HCS, 16.9% were suspicio...

Abstract 74: Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation.

Abstract Current approaches to identification of cancer-predisposing alleles are primarily based on the comparison of DNA sequences between affected and non-affected individuals. Many contemporary gene-seeking studies, be it genome-wide association scans or mutation analysis of candidate genes, utilize genetically enriched cancer cases. Genetic enrichment is usually achieved by selection of patients with clinical signs of hereditary cancer predisposition, e.g. family history of the disease or presence of multiple primary tumors. We suggest that the preference towards familial vs. multiple primary cancer cases may in fact be indeed disadvantageous under certain circumstances. Let's consider for example the transmission of a recessive cancer predisposing allele (a), which has a frequency of 0.1 and a penetrance of 100%. In accordance with the Hardy-Weinberg distribution (p^2 + 2pq + q^2), only 1% of this population will be homozygous for this allele and therefore bear the at-risk genotype (aa). Notably, only 19% of cancer patients with the aa genotype will have one or both parents with the same genotype and hence report a history of cancer disease in their mother or father. Therefore, while the focus on familial cancer clustering is a powerful tool for identifying dominant predisposing mutations, the disease cases caused by the homozygous recessive at-risk alleles may be easily missed. On the other hand, non-selected patients with multiple primary tumors, being strongly enriched for cancer associated genotypes, are unlikely to have a bias towards accumulation of dominant vs. recessive alleles; in addition, a deliberate exclusion of the family history-positive patients from this group may further increase the proportion of recessively inherited cases. We considered the c.2515_2519delAAGTT mutation in a Holliday junction resolvase, GEN1, as an interesting candidate to test this hypothesis on breast cancer (BC) cases. We observed noticeably high frequency of the c.2515_2519delAAGTT frame-shift in Russian subjects, that permitted us to consider BC-predisposing impact of the homozygosity for this allele. Strikingly, we observed an overrepresentation of the c.2515_2519delAAGTT homozygotes in patients with bilateral breast cancer (biBC) versus healthy controls (11/360 (3.1%) vs. 18/1305 (1.4%); OR = 2.3 (1.02-4.75); p = 0.031). In accordance with the calculations outlined above, all patients with the biallelic c.2515_2519delAAGTT mutation belonged to the group with no evidence for the vertical transmission of the disease predisposition. The analysis of unilateral BC cases did not reveal an excess of c.2515_2519delAAGTT homozygotes (23/1851 (1.2%) vs. 18/1305 (1.4%); OR = 0.9 (0.49-1.69); p = 0.738), however this comparison lacked the power to detect the effect for a low-penetrance rare genotype. Interestingly, as in case of biBC, biallelic c.2515_2519delAAGTT genotype occurred only in patients whose mothers were not affected by this disease (21/1558 (1.3%) vs. 0/215 (0%); p = 0.087). When the data on bilateral and unilateral BC were combined, the association between the c.2515_2519delAAGTT homozygosity and the absence of BC in mother reached the formal level of statistical significance (Mantel-Haenszel p = 0.041). We acknowledge that the obtained data are insufficient to claim the BC predisposing role for the c.2515_2519delAAGTT homozygous genotype. However, this study indicates, that the consideration of patients with multiple cancers may be particularly fruitful for the identification of recessive determinants of cancer predisposition. Citation Format: Ekaterina S. Kuligina, Anna P. Sokolenko, Nathalia V. Mitiushkina, Svetlana N. Abysheva, Elena V. Preobrazhenskaya, Tatiana V. Gorodnova, Grigoriy A. Yanus, Alexandr V. Togo, Nadezhda V. Cherdyntseva, Alexey A. Larionov, Sergey G. Kuznetsov, Evgeny N. Imyanitov. Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 74.

A comprehensive survey of cancer risks in extended families

PurposeCancer is familial; yet known cancer predisposition genes, as well as recognized environmental factors, explain only a small percentage of familial cancer clusters. This population-based description of cancer clustering describes patterns of cancer coaggregation suggestive of a genetic predisposition. MethodsUsing a computerized genealogy of Utah families linked to a statewide cancer registry, we estimated the relative risks for 36 different cancer sites in first-, second-, and third-degree relatives of cancer cases, for each cancer site individually, and between cancer sites. We estimated the sex- and birth-year-specific rates for cancer using 1 million individuals in the resource. We applied these rates to groups of cases or relatives and compared the observed and expected numbers of cancers to estimate relative risks. ResultsMany cancer sites show significantly elevated relative risks among distant relatives for cancer of the same site, strongly supporting a heritable contribution. Multiple combinations of cancer sites were observed among first-, second-, and third-degree relatives, suggesting the existence of heritable syndromes involving more than one cancer site. ConclusionThis complete description of coaggregation of cancer by site in a well-defined population provides a set of observations supporting heritable cancer predispositions and may support the existence of genetic factors for many different cancers.Genet Med 2012:14(1):107–114

Familial clustering of cancer in two tertiary care hospitals in Nairobi, Kenya

To describe the occurrence of cancers in families of individuals diagnosed cancer. Cross-sectional descriptive study. Outpatient cancer clinics at Kenyatta National Hospital (KNH) and Radiotherapy Clinic at Nairobi Hospital. Patients with a tissue histological or cytological diagnosis of cancer. A reported family history of cancer. A total number of 485 cancer patients were recruited, 382, from KNH and 103 from Nairobi Hospital. These index cases had 45 different types of cancer, with the most common being breast and uterine-cervical malignancies. Prevalence of family history of cancer was found to be 18.8% and was highest among 1st degree relatives. Documentary evidence was seen in 48.4% and history of cancer corroborated by medical personnel in an additional 11%. In 18.7% of cases more than one relative was interviewed to confirm the family history of cancer. Educational levels of the index cases correlated with knowledge of family history of cancer, with those of higher educational level having been more informed about their families' medical history. There was a prevalence of familial cancers of 30% at Nairobi Hospital patients and 15.7% at KNH patients. We found the prevalence of family history of cancer in our population to be 18.8% and was highest among 1st degree relatives. This has implications for targeted screening and therefore early diagnosis which is beneficial.

Prevalence of familial malignancy in a prospectively screened cohort of patients with leukemia.

6590 Background: Newer studies are giving increased understanding of the genetic origins of cancer. We conducted a pilot study to determine the prevalence of familial malignancy among adult leukemia patients admitted to a leukemia service from April 2009 to Dec 2009. Methods: An IRB approved screening questionnaire was used to ascertain information from 104 leukemia patients. Pts who were adopted or uncertain of their family history were excluded. Fisher's exact test for analyzing categorical variables and a two-sample t-test for continuous variables were used. Results: Of the 92 pts analyzed, 41 (44.6%) reported a first degree relative and 61 (66.3%) reported a first or second degree relative with cancer. At least one first degree relative with cancer was reported from 66.7% of CLL pts, 54.9% of AML pts, 37.5% of ALL pts, and 27.3% of CML pts. The median age was 55 yrs for those pts with either a first or second degree relative with cancer and 62 for those without a family history (p = ns). The most common cancers reported were breast (20% of pts reported an effected relative), colon (13%), lung (12%), leukemia (9%), unknown cancer (8%), prostate (6%) and stomach (5%). In many cases, the percentage of family members with a specific cancer type was similar to that reported for the general US population (Jemal et al, Cancer J Clin 2009; 59:225- 249). However, significant differences were noted when comparing our pts' family history with that of the US population for the following cancer subtypes: leukemia (9% our pts vs. 3% US), stomach (5% vs. 1%), colon (13% vs. 7%) and NHL (0% vs. 4%). Numerical differences that were not significant were noted for breast (20% vs. 13%), prostate (6% vs. 3%), bladder (1% vs. 5%) and esophagus (3% vs. 1%). Nine pts had 12 family members with leukemia. The median and mean age of these pts was 50 and 47 resp compared with the remaining pts who had a median age of 59 and mean of 57 (p = 0.04). Of these pts, 5 had AML, 3 had CML and 1 had ALL. Eight pts had a Li-Fraumeni pattern of familial clustering of cancer. Conclusions: The pattern of familial cancers may be different for pts with leukemia compared to the general population. We continue to accrue pts to determine if these differences effect treatment outcome. No significant financial relationships to disclose.

Elevated Cancer Mortality in the Relatives of Patients with Pancreatic Cancer

Most inherited cancer syndromes are characterized by the familial clustering of cancers at several organ sites. To determine if cancers, other than pancreatic cancer, cluster in pancreatic cancer kindreds, we examined mortality patterns among the relatives of National Familial Pancreatic Tumor Registry probands. Over 200,000 person-years of follow-up from 8,564 first-degree relatives of probands and 1,007 spouse controls were included in these analyses. We compared mortality rates of National Familial Pancreatic Tumor Registry participants to US population rates using weighed standardized mortality ratios (wSMR). Analyses were stratified by family history of pancreatic cancer (sporadic versus familial), family history of young onset pancreatic cancer (<50 years), and family history score. Cancer mortality was increased in both the relatives of sporadic probands [wSMR 1.55, 95% confidence interval (95% CI) 1.39-1.73] and familial probands (wSMR 1.41, 95% CI 1.26-1.58). Relatives of familial probands had a significantly increased risk of dying from breast (wSMR 1.66, 95% CI 1.15-2.34), ovarian (wSMR 2.05, 95% CI 1.10-3.49), and bile duct cancers (wSMR 2.89, 95% CI 1.04-6.39). Relatives of sporadic probands were at increased risk of dying from bile duct cancer (wSMR 3.01, 95% CI 1.09-6.67). Relatives of young onset probands were at higher risk of dying from cancers of the breast (wSMR 1.98, 95% CI 1.01-3.52), colon (wSMR 2.31, 95% CI 1.30-3.81) and prostate (wSMR 2.31, 95% CI 1.14-4.20). Increased cancer mortality was not observed in the spouse controls. Our results show that relatives of pancreatic cancer patients are at higher risk of developing cancers at other sites and highlight the importance of complete family history in clinical risk assessment.

Anaplastic oligoastrocytoma in Turcot syndrome

Turcot syndrome (TS), a rare variant of hereditary non-polyposis colorectal cancer (HNPCC), is characterized by familial clustering of cancer of the large bowel, extracolonic body sites and brain. It is caused by germline mutations in genes encoding for components of the DNA mismatch repair system. We report a 72 year old woman with anaplastic oligoastrocytoma in the setting of TS. Careful analysis of tumor DNA is required to exclude the chance occurrence of a brain tumor in HNPCC kindreds and increase our understanding of the pathogenesis of the disease. Our case adds to the handful of cases published with detailed molecular data previously.

Molecular profiling to identify molecular mechanism in esophageal cancer with familial clustering

To identify the genes and molecular functional pathways involved in esophageal cancer, we analyzed the gene expression profile of esophageal tumor tissue from patients having family history of esophageal cancer by cDNA microarray. Three hundred and fifty differentially expressed genes (26 up-regulated and 324 down-regulated) were identified. Genes involved in humoral immune response (PF4), extracellular matrix organization (COL4A4), metabolism of xenobiotics (EPHX1), TGF-beta signaling (SMAD1) and calcium signaling pathways (VDAC1) were down-regulated and genes involved in regulation of actin cytoskeleton (WASL), neuroactive ligand receptor interaction (GRM3), Toll-like receptor (CD14), B-cell receptor (IFITM1) and insulin signaling pathways (FOXO1A) were up-regulated. Validation of differential expression of subset of genes by QRT-PCR and tissue microarray in familial and non-familial cases showed no significant difference in expression of these genes in two groups suggesting familial clustering occurs as result of sharing of common environmental factors. Gene expression profiling of clinical specimens from well characterized populations that have familial clustering of cancer identified molecular mechanism associated with progression of esophageal cancer.

Familial Pancreatic Cancer

AbstractContext.—Approximately 5% to 10% of individuals with pancreatic cancer report a history of pancreatic cancer in a close family member. In addition, several known genetic syndromes, such as familial breast cancer (BRCA2), the Peutz-Jeghers syndrome, and the familial atypical multiple mole melanoma syndrome, have been shown to be associated with an increased risk of pancreatic cancer. The known genes associated with these conditions can explain only a portion of the clustering of pancreatic cancer in families, and research to identify additional susceptibility genes is ongoing.Objective.—To provide an understanding of familial pancreatic cancer and the pathology of familial exocrine pancreatic cancers.Data Sources.—Published literature on familial aggregation of pancreatic cancer and familial exocrine pancreatic tumors.Conclusions.—Even in the absence of predictive genetic testing, the collection of a careful, detailed family history is an important step in the management of all patients with pancreatic cancer. While most pancreatic cancers that arise in patients with a family history are ductal adenocarcinomas, certain subtypes of pancreatic cancer have been associated with familial syndromes. Therefore, the histologic appearance of the pancreatic cancer itself, and/or the presence and appearance of precancerous changes in the pancreas, may increase the clinical index of suspicion for a genetic syndrome.

A compendium of familial relative risks of cancer among first degree relatives: A population‐based study

Familial clustering of cancer is expected to occur at practically all anatomical sites. However, few studies have had sufficient size to investigate different sites simultaneously and with adjustment for confounders. We evaluated familial clustering in the Netherlands Cohort Study in which 120,852 men and women, aged 55-69 years in 1986 were followed up for 13.3 years. 14,025 Probands, 6,629 parents and 4,271 siblings were diagnosed with cancer. Relative Risks (RR) of cancer in first degree family members were calculated by using multivariable Cox regression analyses. We also calculated false-positive reporting probabilities. Significant concordant familial clustering was observed for stomach (RR(father) = 1.89, RR(parent) = 1.66, RR(sister) = 3.33, RR(sibling) = 2.38, RR(1st degree) = 1.69), colon/rectum (RR(father) = 1.82, RR(mother) = 1.83, RR(parent) = 1.88, RR(1st degree) = 1.56), lung (RR(brother) = 1.50) and breast cancer (RR(mother) = 1.65, RR(sister) = 1.72, RR(1st degree) = 1.72) with low false-positive reporting probabilities. Significant discordant familial clustering has been observed for combinations of pancreas-colon/rectum (RR(mother) = 2.42, RR(parent) = 1.89, RR(1st degree) = 1.73), larynx-lung (RR(father) = 3.35, RR(parent) = 2.84, RR(1st degree) = 2.30), lung-oesophagus (RR(sibling) = 3.49), breast-bladder (RR(father) = 2.79, RR(parent) = 2.61), endometrium-stomach (RR(mother) = 2.32), ovarium-oesophagus (RR(1stdegree) = 4.19), prostate-colon/rectum (RR(parent) = 1.46) and bladder-larynx/pharynx (RR(father) = 2.49) cancer, although false-positive reporting probabilities were higher for these associations. Familial clustering of cancer occurs at most sites but is generally modest. Some observed discordant familial clustering is surprising but should be interpreted with caution as their prior probability is low.

Familial clustering of cancer at human papillomavirus‐associated sites according to the Swedish Family‐Cancer Database

Familial aggregation of cervical cancer has been demonstrated previously, however aggregation of other human papillomavirus-associated anogenital, upper aerodigestive tract and skin cancers has not been fully characterized. The Swedish Family-Cancer Database, which contains reliable data on cancer incidence and nuclear family linkages for all residents of Sweden between 1958 and 2004, was used to calculate standardized incidence ratios (SIR) and 95% confidence intervals for offspring site-specific cancer risks according to site-specific cancer in sibling and parental probands. Offspring cancer risk was significantly increased when either a sibling or parent was affected at the same site for penile squamous cell carcinoma (SCC, SIR = 7.54), cervical adenocarcinoma (AC, SIR = 2.31), vulvar SCC (SIR = 2.27), skin SCC (SIR = 2.14), rectal AC (SIR = 1.86), in situ cervical SCC (SIR = 1.80), invasive cervical SCC (SIR = 1.77) and upper aerodigestive tract SCC (SIR = 1.57). Significant aggregation on the order of 2-fold between anogenital cancers at different sites or histologies was also observed. In situ cervical SCC risk in offspring was strongly influenced by siblings affected with oropharyngeal SCC (SIR = 3.17) and tonsillar SCC (SIR = 1.84). Familial skin SCC was largely unassociated with anogenital or upper aerodigestive tract cancer risk in offspring. These data suggest that common host factors exist among individuals affected with anogenital and upper aerodigestive tract cancers.

Family history of colorectal cancer in Iran

BackgroundPrevious reports show a high proportion of young CRC patients in Iran. In this study we aim to look for the clustering of colorectal cancer in families of a series of CRC patients from Iran.MethodsThe family history of cancer is traced in 449 CRC patients of which 112 were 45 yrs or younger and 337 were older than 45 yrs at time of diagnosis. The patients were admitted in two hospitals in Tehran, during a 4-year period.ResultsClinical diagnosis of HNPCC was established in 21 (4.7%) probands. Family history of CRC was more frequently reported by early-onset than by late-onset patients (29.5% vs. 12.8%, p < 0.001).Distribution of tumor site differed significantly between those with and without family history of CRC. Right colon cancer was the most frequent site (23/45, 35.4%) observed in patients with positive family history of colorectal cancer.ConclusionThe relatively high frequency of CRC clustering along with HNPCC in our patients should be further confirmed with larger sample size population-based and genetic studies to establish a cost effective molecular screening for the future.