Genetics of Lymphocytes Influences the Emergence of Second Cancer in Chronic Lymphocytic Leukemia

Discussion

We selected a series of 106 patients with CLL that did not receive any treatment during disease and we assessed the presence of second cancer in those cases. Eight patients (7.5%) developed second tumors.

The most frequent alteration in this series was del(13)(q14.3), as a sole genetic event or concomitant with other alterations (64/106 cases, 60.4%). Mono-allelic and bi-allelic deletions were observed in 34 and 30 cases, respectively. Interestingly, del(13)(q14.3) was the common genetic trait in seven out of the eight cases that developed second tumors. Only one out of the 42 cases that did not have del(13)(q14.3) presented a second cancer (Figure 1A). This patient (case 6), with a quiescent CLL (19 years of disease), had a normal karyotype and also a normal FISH pattern.

There are only three reported cases of CLL where both the presence of second tumors and the genetic data of CLL were considered: a basal cell carcinoma (BCC) of the skin (13), a breast cancer (9) and a lung cancer (14). The latter presented del(13)(q34) and monosomy 12, while the other two cases presented solely del(13q). Our results and those from the literature suggest that del(13q) could be involved in CLL with second cancer.

Out of the patients presented here, however, seven out of the eight with second cancer presented del(13)(q14.3) together with other alterations (Figure 1B, Table II). None of the 16 patients with sole del(13)(q14.3), some of them with more than three years of follow-up, developed a second cancer. As a consequence, it is reasonable to believe that del(13)(q14.3) could be a risky genetic alteration but not enough to trigger a second tumor. The acquisition of further genetic alterations must be necessary as a second step in tumorigenesis. Although the number of patients is scarce, our results support the concept that as the number of genetic alterations increases, including del(13)(q14.3), the risk of developing second cancer in patients with CLL also increases.

All cases of second cancer but one (case 107) were epithelial tumors, especially squamous cell carcinomas (SCC) and BCC of the skin. Our findings are in agreement with previous reports where skin tumors are described as the most frequent second tumors in patients with CLL (1, 2). Among the eight patients with second cancer, only two (cases 70 and 111) presented a concomitant second cancer at the time of diagnosis of CLL. In these cases, CLL might have been masked before the emergence of epithelial tumors. The other six patients were followed-up for a range of 2-19 years. This supports the nation that the risk of emergence of second tumors in patients with CLL might be related not only to the genetic background of lymphocytes in CLL but also to the duration of CLL.

It is also interesting to note that none of the patients we present here received any chemotherapy, consequently second tumors cannot be related to treatment. Literature concerning the association of CLL and carcinomas has varying interpretations. Immunological disorders and an underlying predisposing etiology are mostly postulated to explain this phenomenon (4-5, 9).

It is well-known that solid tumors emerge as a consequence of several genetic abnormalities that are progressively accumulated in cells. Therefore, a pre-neoplastic lesion is required before a tumor emerges. Interestingly, CLL lymphocyte infiltrates are not exclusively found at tumor sites but also in other diseases (actinic keratoses, benign prostate hypertrophy) (4, 16). This implies that in patients with CLL, a pre-neoplastic lesion (induced by chemicals, infections, ultraviolet radiation etc.), in an immunologically-impaired environment, could be the first step towards solid tumorigenesis. In agreement with Smoller and Warnke (4), the second step would be a paracrine action of leukemic cell infiltrates at the altered site. This would result in a somewhat altered cell environment at the infiltrate site, depending on the molecular trafficking, and this could be important for initiating an epithelial tumor. Based on our analyses, we suggest that del(13)(q14.3) in addition to other genetic alterations of lymphocytes in CLL is a risk factor for developing second cancer. In cases with only one alteration, or none, molecular trafficking was less altered and this would explain why these patients rarely developed second cancers.

All chromosomes altered in CLL carry several genes that are involved in epithelial tumors: absent in melanoma-1 (AIM1) (6q21), tumor suppressor TSG1 (TSG1) (6q16), squamous cell carcinoma antigen recognized by T-cells-3 (SART3) (12q24.1), fibroblast growth factors (12p13, 13q11-q12, 13q34, 17p13), epidermal growth factor receptor pathway substrate 8 (EPS8) (12p12), several keratins (12q13), P53 (17p13), regulator of cell cycle (RGCC) (13q14), epithelial stromal interaction 1 (EPSTI1) (13q13) and retinoblastoma 1 (RB1) (13q14), among others. In addition, deletions of chromosomes 6q, 13q and 17p; losses of X (in females) and Y (in males) chromosomes; and re-arrangements of chromosome 12 have been observed not only in CLL but also in skin, prostate and lung carcinomas (15).

In conclusion, the presence of second cancer in untreated patients with CLL cannot be attributed to chance. There is a genetic association between both diseases. The genetic background of CLL, particularly the presence of del(13)(q14.3) together with other genetic alterations in lymphocytes, increases the risk of developing second cancer in these patients.