Hongyao Yu

Concordant and discordant familial cancer: Familial risks, proportions and population impact

Relatives of cancer patients are at an increased risk of the same (concordant) cancer but whether they are at a risk for different (discordant) cancers is largely unknown – beyond well characterized hereditary cancer syndromes ‐ but would be of major scientific and clinical interest. We therefore decided to resolve the issue by analyzing familial risks when family members were diagnosed with any discordant cancers. We compared the population impact of concordant to discordant familial cancer. The Swedish Family‐Cancer Database (FCD) was used to calculate familial relative risks (RRs) for family members of cancer patients, for the 27 most common cancers. Population attributable fractions (PAFs) were estimated for concordant and discordant family histories. Discordant cancers in the family were detected as significant risk factors for the majority of cancers, although the corresponding RRs were modest compared to RRs for concordant cancers. Risks increased with the number of affected family members with the highest RRs for pancreatic (2.31), lung (1.69), kidney (1.98), nervous system (1.79) and thyroid cancers (3.28), when 5 or more family members were diagnosed with discordant cancers. For most cancers, the PAF for discordant family history exceeded that for concordant family history. Our findings suggest that there is an unspecific genetic predisposition to cancer with clinical consequences. We consider it unlikely that shared environmental risk factors could essentially contribute to the risks for diverse discordant cancers, which are likely driven by genetic predisposition. The identification of genes that moderately increase the risk for many cancers will be a challenge.

Common cancers share familial susceptibility: implications for cancer genetics and counselling

Background It has been proposed that cancer is more common in some families than in others, but the hypothesis lacks population level support. We use a novel approach by studying any cancers in large three-generation families and thus are able to find risks even though penetrance is low. Methods Individuals in the nation-wide Swedish Family-Cancer Database were organised in three generations and the relative risk (RR) of cancer was calculated to the persons in the third generation by the numbers of patients with cancer in generations 1, 2 and 3. Results The RRs for any cancer in generation 3 increased by the numbers of affected relatives, reaching 1.61 when at least seven relatives were diagnosed. The median patient had two affected relatives, and 7.0% had five or more affected relatives with an RR of 1.46, which translated to an absolute risk of 21.5% compared with 14.7% in population by age 65 years. For prostate cancer, the RR was 2.85 with four or more affected family members with any cancer, and it increased to 14.42 with four or more concordant cancers in family members. RRs for prostate cancer were approximately equal (2.70 vs 2.85) if a man had one relative with prostate cancer or four or more relatives diagnosed with any cancer. Conclusions A strong family history of cancer, regardless of tumour type, increases cancer risk of family members and calls for mechanistic explanations. Our data provide tools for counselling of patients with cancer with both low and high familiar risks.

Familial associations of colorectal cancer with other cancers

Colorectal cancer (CRC) has a strong familial component which extends to discordant cancers (ie non-CRC tumors). This is best seen in cancer syndromes such as hereditary non-polyposis colorectal cancer (HNPCC) which predisposes to several tumor types. Population-based family studies have also found discordant associations for CRC but they have included cancers which manifest in HNPCC, and there is no convincing evidence of discordant associations beyond the known syndromes. We address familial associations of non-CRC tumors with CRC using the resources of the Swedish Family-Cancer Database and applying a powerful approach of assessing familial relative risks in families of increasing numbers of patients with discordant cancers. Among 1.8 million cancer patients and over 200,000 CRC cases consistent familial associations of CRC was observed for several HNPCC related cancers. However, for small intestinal, pancreatic and nervous system cancers RRs remained essentially unchanged when potential HNPCC families were excluded, suggesting involvement of genes not related to HNPCC. Two independent associations of CRC were found for melanoma, thyroid and eye cancers and these appeared not to be related to known syndromes. A number of other cancers associated with CRC in single analyses and independent studies are required to assess the relevance of such findings.

Familial associations of female breast cancer with other cancers

Familial risks of breast cancer (BC) are well established but whether BC clusters with other, i.e. discordant, cancers is less certain but of interest for the identification of common genetic and possible environmental factors contributing to a general cancer susceptibility. We apply a novel approach to search for familial associations of BC with other (discordant) cancers based on the Swedish Family‐Cancer Database. Relative risks (RRs) were calculated for BC in families with increasing numbers of patients with discordant cancer X, and conversely, familial RRs for cancer X in families with increasing numbers of BC patients. Joint p‐values were calculated from independent analyses. The total number of familial BCs was 12,266, 14.9% with one first‐degree relative with BC and 1.2% with at least 2 affected relatives. Ovarian and prostate cancers showed the strongest associations with BC (p‐value <10−11). The p‐value for melanoma was <10−6, for stomach and male colorectal cancer <2.5 × 10−6, for cancer of unknown primary <2.5 × 10−5 and for lung cancer <5 × 10−5. Significance level <5 × 10−4 was reached with pancreatic cancer. The remaining associations (p < 0.0025) included thyroid, endometrial, testicular, eye cancers (uveal melanoma), nervous system and endocrine tumors and non‐Hodgkin lymphoma. The RR for BC increased by increasing numbers of patients with any cancer in family members and it reached 1.62 when three or more family members were affected. The results suggest that BC shares susceptibility with a number of other cancers. This might alert genetic counselors and challenge approaches for gene and gene–environment identification.

Other cancers in lung cancer families are overwhelmingly smoking-related cancers

Familial risks of lung cancer are well-established, but whether lung cancer clusters with other discordant cancers is less certain, particularly beyond smoking-related sites, which may provide evidence on genetic contributions to lung cancer aetiology. We used a novel approach to search for familial associations in the Swedish Family-Cancer Database. This involved assessment of familial relative risk for cancer X in families with increasing numbers of lung cancer patients and, conversely, relative risks for lung cancer in families with increasing numbers of patients with cancers X. However, we lacked information on smoking. The total number of lung cancers in the database was 125 563. We applied stringent statistical criteria and found that seven discordant cancers were associated with lung cancer among family members, and six of these were known to be connected with smoking: oesophageal, upper aerodigestive tract, liver, cervical, kidney and urinary bladder cancers. A further novel finding was that cancer of unknown primary also associated with lung cancer. We also factored in histological evidence and found that anal and connective tissue cancers could be associated with lung cancer for reasons other than smoking. For endometrial and prostate cancers, suggestive negative associations with lung cancer were found. Although we lacked information on smoking it is prudent to conclude that practically all observed discordant associations of lung cancer were with cancers for which smoking is a risk factor. Among family members of lung cancer patients, 7 other cancers were found, all of which were smoking related http://ow.ly/ZLnt30csVfZ

Familial risks of ovarian cancer by age at diagnosis, proband type and histology

Ovarian cancer is a heterogeneous disease. Data regarding familial risks for specific proband, age at diagnosis and histology are limited. Such data can assist genetic counseling and help elucidate etiologic differences among various histologic types of ovarian malignancies. By using the Swedish Family-Cancer Database, we calculated relative risks (RRs) for detailed family histories using a two-way comparison, which implied e.g. estimation of RRs for overall ovarian cancer when family history was histology-specific ovarian cancer, and conversely, RRs for histology-specific ovarian cancer when family history was overall ovarian cancer. In families of only mother, only sisters or both mother and sisters diagnosed with ovarian cancer, cancer risks for ovary were 2.40, 2.59 and 10.40, respectively; and were higher for cases diagnosed before the age of 50 years. All histological types showed a familial risk in two-way analyses, except mucinous and sex cord-stromal tumors. RRs for concordant histology were found for serous (2.47), endometrioid (3.59) and mucinous ovarian cancers (6.91). Concordant familial risks were highest for mucinous cancer; for others, some discordant associations, such as endometrioid-undifferentiated (9.27) and serous-undifferentiated (4.80), showed the highest RRs. Familial risks are high for early-onset patients and for those with multiple affected relatives. Sharing of different histological types of ovarian cancer is likely an indication of the complexity of the underlying mechanisms.

Risk of second primary cancer following myeloid neoplasia and risk of myeloid neoplasia as second primary cancer : a nationwide, observational follow up study in Sweden

BACKGROUND Although advances in the treatment of myeloid neoplasms have led to improved patient survival, this improvement has been accompanied by an increased risk of second primary cancer (ie, the risk of another cancer after myeloid neoplasia). We aimed to assess bi-directional associations between myeloid cancers and other cancers-ie, development of second primary cancer in patients who have previously had myeloid cancer, and risks of myeloid neoplasia in patients who have previously had another cancer-to provide insight into possible mechanisms beyond side-effects of treatment and shared risk factors. METHODS Using the Swedish Family-Cancer Database, we identified 35 928 individuals with primary myeloid cancer, including myeloproliferative neoplasms, acute myeloid leukaemia, chronic myeloid leukaemia, and myelodysplastic syndrome diagnosed between 1958 and 2015. The Swedish Family-Cancer Database includes every individual registered as a resident in Sweden starting in 1932, with full parental history. The primary endpoint was the assessment of relative risks (RRs) for second primary cancer, which we performed using means of incidence rate ratios, regressed over a generalised Poisson model. FINDINGS Between 1958 and 2015, overall relative risk of second primary cancers was significantly increased after acute myeloid leukaemia (RR 1·29, 95% CI 1·17-1·41), chronic myeloid leukaemia (1·52, 1·35-1·69), myelodysplastic syndrome (1·42, 1·26-1·59), and all myeloproliferative neoplasms (1·37, 1·30-1·43) relative to the incidence of these cancers as first primary cancer. With myeloid neoplasia as a second primary cancer, risks were significantly increased for acute myeloid leukaemia (1·57, 1·48-1·65), chronic myeloid leukaemia (1·26, 1·13-1·40), and myelodysplastic syndrome (1·54, 1·42-1·67) relative to the incidence of these myeloid neoplasms as first primary cancers. Relative risk of upper aerodigestive tract cancer, squamous cell skin cancer, and non-Hodgkin lymphoma as second primary cancers were increased after all four types of myeloid neoplasia relative to their incidence as first primary cancers. High risks of myelodysplastic syndrome and acute myeloid leukaemia as second primary cancers were found after haematological cancers (RRs between 5·08 and 10·04). INTERPRETATION The relative risks of second primary cancer are important for the long-term management of patients with myeloid cancers. The bi-directional associations of myeloid cancers with many other cancers suggest a number of candidate mechanisms that might contribute to the development and aetiology of a second primary cancer. These mechanisms might include immune dysfunction or the effects of treatment, and these should be assessed in future investigations. FUNDING Deutsche Krebshilfe, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Finnish Cancer Organizations, Swedish Research Council, ALF from Region Skåne, and Bloodwise.

Familial Associations in Testicular Cancer with Other Cancers

Familial risks for testicular cancer (TC) are among the highest of all cancers. However, data are limited for histological types of TC and for possible familial associations of TC with other cancers. We used the nationwide Swedish Family-Cancer Database for years 1958 to 2015 to analyse familial relative risks (RR) for 11,138 TC patients when first-degree relatives were diagnosed with TC or other cancer in reference to those without a family history. A total of 191 familial TCs were found, which accounted for 2.0% of all TC. The RR was 5.06 when one family member was diagnosed with TC with no significant difference between seminoma and nonseminoma. However, the risk for nonseminoma was 33.59 when two family members were affected. Internally consistent familial associations of TC, particularly of seminoma, were found with breast and nervous system cancers and melanoma. Individual significant associations were found for a number of sites, including ovarian, endometrial and prostate cancers. Our results suggest that nonseminoma may have a stronger genetic background than seminoma but seminoma shares more familial associations with discordant cancers. Clustering of TC with hormone-dependent cancers of the breast, ovary, endometrium and prostate may suggest mechanistic links and possibly gene-environment interactions.

Correction: Familial risks of ovarian cancer by age at diagnosis, proband type and histology

[This corrects the article DOI: 10.1371/journal.pone.0205000.].

RE: Familial Cancer Clustering of Urothelial Cancer: A Population-Based Case–Control Study

Martin and coworkers reported data on familial associations of urothelial cancers (n 1⁄4 7266) with urothelial cancers and with other (discordant) cancers based on the Utah Population Database, asserting novelty in being able to control for smoking and histology (1). Studies with multiple discordant cancers are subject to chance findings, but the authors guarded against these by assessing consistency of the findings between firstdegree relatives, second-degree relatives, and cousins. They referred to four previous studies on the same subject but stated that their study had the advantages of focusing on urothelial histology and being conducted on a population with a low frequency of smokers, thus reducing confounding by smoking. The concern about smoking is valid, but one of the previous studies was conducted on the same Utah population (2); the remaining three were done in Sweden, which has historically had the lowest frequency of smokers in Europe, particularly for men (15% since 2000; http://www.pnlee.co.uk/downloads/iss/iss-sweden_ 111024.pdf) (3–5). Moreover, Supplementary Table 2 from Martin et al. (available online) showed a weak association of urothelial cancers with smoking-related cancer (hazard ratio [HR] 1⁄4 1.13, 95% confidence interval [CI] 1⁄4 1.07 to 1.20, among first-degree relatives) compared with familial urothelial cancers (HR 1⁄4 1.73, 95% CI 1⁄4 1.50 to 1.99). The advantage of specifically selecting urothelial cancers is not supported by their own data, which show almost identical hazard ratios for urothelial vs bladder cancer without histologic specification: 1.73 (95% CI 1⁄4 1.50 to 1.99) vs 1.69 (95% CI 1⁄4 1.47 to 1.95) in first-degree relatives; 1.35 (95% CI 1⁄4 1.21 to 1.51) vs 1.35 (95% CI 1⁄4 1.20 to 1.50) in second-degree relatives; and 1.07 (95% CI 1⁄4 0.99 to 1.14) vs 1.08 (95% CI 1⁄4 1.00 to 1.16) in cousins (Supplementary Table 2, available online). This is in fact understandable because more than 90% of bladder cancers are of urothelial type (6). Strangely, Figure 1 confuses the issue about histology. On top 13 724 patients are listed for “all bladder and upper tract cancer patients.” These are then divided into 7266 “urothelial bladder and upper tract patients” and 6462 “nonurothelial upper and lower tract histology” patients. It is not possible that 47% of bladder and upper tract cancer patients have nonurothelial histology, but whether this group includes kidney cancer and patients lacking histology is not stated. Our previous analyses were based on the Swedish FamilyCancer Database, which we have recently updated to include cancers from 1958 to 2015 (7). It includes 86 058 cancers of the bladder and urinary tract (International Classification of Diseases, version 7, code 181). Of these, 96.7% were bladder cancers, 2.0% were ureter cancers, and the remainder were tumors in other parts of the urinary tract. Among bladder cancer, 98.0% of histology was transitional cell carcinoma. Squamous cell carcinoma, specifically pointed out by Martin and coworkers as a deviant histology, accounted for 1.2% of all bladder cancer. In Table 1, we show the influence of anatomic location and histology on bladder cancer risk based on the above Swedish data. Familial relative risk for urinary tract cancer (International Classification of Diseases, version 7, code 181) was 1.81 (95% CI 1⁄4 1.68 to 1.94) when first-degree relatives were diagnosed with urinary tract cancer. The relative risk increased to 1.87 (95% CI1⁄4 1.73